Table of contents :

• Organogenesis

The originally simple aggregate of cells involved in food absorption has thus evolved into a very large and complex structure that is highly patterned in its longitudinal, dorsoventral (DV), left-right (LR), and radial axes. Over the past decade or so, studies in a number of invertebrate and vertebrate model systems, including Caenorhabditis elegans, Drosophila, sea urchins, ascidians, Xenopus, zebrafish, the chick, and the mouse, have provided insights into the genes and cellular mechanisms regulating endoderm formation^{ref1, ref2}. There is a high degree of conservation in some of the transcriptional regulators of endoderm formation; for example, members of the Gata and Forkhead transcription factor families have been implicated in this process across the phyla, although the intercellular events regulating endoderm formation appear to be more divergent. The Wnt signaling pathway has been implicated in the formation of the endoderm in C. elegans, sea urchins, and ascidians, whereas Nodal signaling has been implicated in the formation of the endoderm in vertebrate embryos. However, this apparent lack of conservation of the signaling pathways regulating endoderm formation probably reflects our incomplete understanding of the process. Indeed, we have not yet gained sufficient knowledge to control the efficient differentiation of mammalian stem cells into endoderm, meaning that the investigation of endoderm formation must proceed using multiple approaches in multiple model systems. As mentioned above, the mesoderm can be thought of, at some level, as a derivative of the endoderm and indeed, the endoderm and mesoderm often originate from the same or adjacent regions of the embryo. Although the mechanisms leading to the segregation of these 2 lineages are fairly well understood in C. elegans and sea urchins, for example, much remains to be learned about this process in vertebrates. Again, this knowledge will be necessary to enhance our ability to coax stem cells into various endodermal or mesodermal lineages. After segregating from the mesoderm during late blastula stages, the endoderm undergoes complex morphogenetic processes, first during gastrulation and then as it converges toward the midline and extends to cover the entire anteroposterior (AP) extent of the embryo. These movements lead to the formation of a hollow tube either from the cavitation of a solid rod, as in zebrafish and Xenopus, or the folding of a sheet, as in birds and mammals. Thus, what started out in the most primitive multicellular organisms as a small aggregate of cells involved in food absorption has evolved into a tube several times the length of the organism, so long in fact that it has to fold extensively to fit into the body cavity. At pregnancy week 3-4 :
• buccopharyngeal or oropharyngeal membrane : a transient embryonic septum at the cranial limit of the foregut, in the depths of the stomodeum
• stomodeum : an invagination of the surface ectoderm of the embryo during the fourth week, at the point where later the mouth is formed.
• foregut : the endodermal canal of the embryo cephalic to the junction of the yolk stalk; it gives rise to the pharynx, trachea, thyroid, bronchi and lung (respiratory diverticulum), esophagus, stomach, liver and its ducts (liver bud), and first part of the duodenum
• midgut / mesenteron : the region of the embryonic digestive tube into which the yolk sac opens; it gives rise to most of the intestines (second part of duodenum, jejunum, ileum, right colon, 2/3 of transverse colon)
• hindgut : the embryonic structure from which the distal 1/3 of the transverse colon, left colon, sigma, rectum, and upper part of anal canal are formed
• cloaca : in mammalian embryology, the terminal end of the hindgut before division into rectum, bladder, and genital primordia
• ectodermal cloaca : that portion of the embryonic cloaca originally external to the cloacal membrane.
• entodermal cloaca : that portion of the embryonic cloaca originally internal to the cloacal membrane.
• congenital or persistent cloaca : the congenital persistence of a common cavity into which the intestinal, urinary, and reproductive ducts open
• cloacal membrane : the thin, temporary barrier between the hindgut and the exterior, formed by the endoderm of the hindgut and the ectoderm of the cloaca of the embryo; its dorsal part forms the anal membrane.
• anal plate : the anal part of the cloacal membrane
• cloacal or urorectal septum : the caudally and outwardly growing wedge of endoderm-covered mesoderm that divides the cloaca into the urogenital sinus and rectum
• anal membrane : the dorsal part of the cloacal membrane after its division by the urorectal septum.
• proctodeum / anal pit : an invagination of the surface ectoderm of the embryo at the point where later the anus is formed
• distal tongue bud / lateral lingual swelling : either of the 2 oval swellings, one on each side of the median tongue bud in the embryo; they grow over the median tongue bud and converge to form the anterior part of the tongue
• median tongue bud / tuberculum impar : a small tubercle in the midline on the floor of the pharynx of the embryo, between the ends of the first and second pharyngeal arches (mandibular and hyoid arches), which is a primordium of the tongue. It forms no recognizable part of the adult tongue
• tooth bud : a knoblike tooth primordium developing into an enamel organ surrounded by a dental sac and encasing the dental papilla
• tooth germ :
• meconium : a dark green, gelly mucilaginous material (60-200 ml) in the intestine of the full-term fetus, being a mixture of the secretions of the liver (bile), pancreas, and intestinal glands, gastrointestinal epithelium, and some amniotic fluid. It is expelled within 12-24 hours since delivery.
• 27% in delivery room
• 69% within 12 hours
• 100% within 24 hours
Complications include meconium ileus and meconium aspiration syndrome (MAS).

The precise location of these accessory organs as well as the demarcation of the various territories along the gut tube has been attributed to a set of complex yet mostly uncharacterized interactions between the gut and the surrounding mesoderm, both of which appear to be patterned along the AP axis. For example, in Drosophila, specific Hox genes are expressed in localized regions of the midgut endoderm and the visceral mesoderm surrounding it.
• One of the best-studied examples is the regulation of labial expression in the endoderm by Ubx, which itself is expressed in the adjacent mesoderm^ref. By regulating Bmp and Wnt signals, Ubx controls the segmental expression of labial, which in turn regulates the differentiation of a specialized set of endodermal cells.
• Hox genes have also been implicated in endoderm patterning in chordates. They are expressed in specific AP domains in both the endodermal and mesodermal germ layers, and loss- and gain-of-function experiments have illustrated a few of their roles in patterning the gut along the AP axis^{ref1, ref2, ref3}. For example, Hoxd-13 is expressed in the hindgut region of mouse and chick embryos^{ref1, ref2, ref3}, and mice that are homozygous mutant for this gene have a hindgut defect^ref. In addition, misexpression of Hoxd-13 in the embryonic chick midgut mesoderm results in the induction of aspects of hindgut morphology in the midgut epithelium^ref. Therefore, mesodermal expression of Hox genes can function in the mesoderm-endoderm interactions to pattern the endodermal epithelium, although the downstream targets of the Hox genes that induce this patterning remain unknown. Similarly, how the pattern of Hox gene expression is determined is unclear, although it lies downstream of the events that pattern the early embryo. There is also strong evidence that retinoic acid signaling is involved in patterning the endoderm along the AP axis^ref, probably acting directly on Hox gene expression^{ref1, ref2}. In addition to Hox genes, at least 2 ParaHox transcription factor genes, Cdx2 and Pdx1, are critical for gut tube development.
• Cdx2 is specifically important for hindgut development in humans, mice, and Drosophila
• Pdx1 is critical for pancreas formation in humans and mice^ref. Cdx2 likely patterns the vertebrate gut by regulating Hox gene expression in the endoderm, as it appears to do so in Drosophila, C. elegans, and the mouse spinal cord^ref.
In summary, the early patterning of the embryo determines the expression pattern of ParaHox, Hox, and other transcription factor genes in the endoderm and adjacent mesoderm. Thereafter, a complex dialogue between these 2 tissues leads to the final pattern of the gut tube along the AP axis. In addition to its elaborate patterning along the AP axis, the gut also undergoes some fascinating morphogenetic processes, including extensive and, at least initially, highly stereotyped looping movements. Again, as is the case with AP patterning, the adjacent mesoderm appears to play a critical role in this process. For example, the initial looping of the zebrafish foregut appears to result from the asymmetric displacement of the neighboring lateral plate mesoderm^ref. Whether the subsequent and extensive looping movements of midgut derivatives seen in higher vertebrates are also driven by the surrounding tissues remains to be investigated. Although the mammalian gut tube forms through a folding process, rearrangement of the endodermal epithelium leads to the complete occlusion of the lumen^ref. Defects in the subsequent recanalization, or reluminization, of the gut tube can lead to partial stenosis or duplication of the digestive tract. As the lumen expands and epithelial cells proliferate, the gut epithelium, possibly because it is constrained in its outer diameter by the surrounding muscle layer, starts undergoing folding morphogenesis. This process leads to the formation of characteristic fingerlike intestinal villi, which greatly increase the absorptive surface of the digestive tract^{ref1, ref2, ref3, ref4, ref5}. Pitlike intestinal crypts also form at the base of the villi, and they contain the stem cells that serve as the source of epithelial cells for the entire intestinal surface. The life-span of differentiated intestinal epithelial cells in humans is estimated to be approximately 4 days, with as many as 1400 cells per villus shed into the lumen on a daily basis. There are four cell types currently recognized in the intestinal epithelium. Enterocytes secrete enzymes that help digest sugars and proteins and absorb nutrients. Goblet cells, most abundant in the posterior gut, secrete mucus, which protects against shear stress and chemical damage (among other functions). The rare enteroendocrine cells secrete hormones such as serotonin, substance P, cholecystokinin, gastrin, and secretin. Paneth cells secrete antimicrobial peptides such as defensins (cryptdins), as well as enzymes such as lysozyme and phospholipase A2 (and they live for about 20 days). The signaling pathways and transcriptional effectors regulating the differentiation of these cells are only starting to be investigated and, not surprisingly, a role for Notch signaling in this process has been reported^{ref1, ref2}. Another interesting question concerns the migration of these different cell types in the radial axis, because Paneth cells remain at the bottom of the crypts while the other cell types migrate upward toward the tip of the villi. Ephrin signaling has been implicated in this fascinating process, which begs for further investigation^ref. Intestinal stem cells have been studied for many years because of their well-defined position, extreme sensitivity to chemo- and radiotherapy, and likely association with the development of cancer^{ref1, ref2, ref3, ref4, ref5}. Each crypt is estimated to contain 1-6 stem cells and, in the mouse intestine, each of these cells appears to divide about once a day. Interestingly, despite the roughly equivalent number of stem cells in the large and small intestine in humans, the incidence of cancer in the former is about 70 times greater than in the latter, for reasons that remain largely unknown. Recent work has started to shed light on the genes that regulate the behavior of the intestinal stem cells in vivo. For example, Wnt signaling has been implicated in many aspects of intestinal stem cell biology, including stem cell maintenance and the proliferation/differentiation switch in intestinal crypts and subsequent positioning of the differentiated cells^{ref1, ref2, ref3}. However, many interesting issues remain unresolved, including how Wnt signaling regulates so many different aspects of stem cell biology, as well as the identity and location of the putative Wnt source close to the crypt bottom^{ref1, ref2}. As the gut tube forms, cells from the lateral plate mesoderm begin to encircle it. These cells proliferate and differentiate into connective tissue as well as the characteristic circular and longitudinal muscle layers. At the same time, cranial neural crest cells migrate ventrally, and once in contact with the developing gut, they migrate posteriorly to colonize its entire AP extent. Defects in this process lead to the common intestinal motility disorder Hirschsprung disease^ref. Again, the tissue interactions leading to the differentiation of both mesodermal and ectodermal cells in the vicinity of the gut endoderm are only starting to be investigated at the molecular level.  The most visible manifestation of DV and LR patterning of the gut is in the stereotyped emergence of gut-associated organs such as the thyroid, lungs, liver, and pancreas. For example, the thyroid and lungs bud from a ventral region of the foregut, and the homeobox gene Nkx2.1 / TITF1, whose expression is restricted ventrally, is required for this process^ref. Concomitant with the looping movement mentioned above, the gut is also thought to rotate slightly, thereby blurring the lines between DV and LR patterning. However, as with the other patterning events (AP and radial), the surrounding mesodermal tissues are thought to play critical roles in patterning the gut along the DV and LR axes and in the resulting emergence of the various organ buds. Hedgehog, Bmp, Fgf, and Wnt signaling have all been implicated in various aspects of gut development^{ref1, ref2, ref3, ref4}. Such studies have revealed that these signaling pathways are used at multiple steps of the process, as the endoderm and mesoderm become involved in an increasingly complex set of interactions. As a consequence, understanding the role of these signaling pathways in gut development will require sophisticated genetic studies in which one modulates them with precise spatiotemporal control. For example, expressing the pan-Hedgehog (Hh) inhibitor Hedgehog-interacting protein (Hhip) in the intestinal epithelium (using the mouse Villin1 promoter) has shed some light on the complex role of Hh signaling in patterning the intestinal crypt-villus axis^ref. Further insights into the signaling pathways regulating gut development are likely to come from such intricate loss- and gain-of-function approaches. In addition to the hardwired program of gut development discussed above, it is clear that environmental influences, such as diet^ref and the microbial community of the gut^ref, play important roles in the differentiation and function of the gut. For example, in mammals, the changing dietary input in the pre- and postnatal periods imposes different demands on the intestine and influences its morphology, enzymatic diversity, and transport. In addition, the diet contains substances such as polyamines and epidermal growth factor that do not play a nutritional role but appear to directly stimulate the growth of the intestinal epithelium^ref. Similarly, C. elegans worms adjust the size of their pharynx, intestine, and intestinal microvilli depending on their nutritional state^ref, and such plasticity is also seen in the willow ptarmigan, in which the winter consumption of fibrous food is associated with relatively long caecae. Investigations into the cellular and molecular underpinnings of such phenomena are just beginning. In addition to the few disorders mentioned earlier in this article, naturally occurring human gut malformations are not rare; in fact, they are a major cause of perinatal morbidity and mortality. Also, because the endoderm extends along most of the AP axis of the embryo, it plays critical roles in many developmental events. For example, the anterior or pharyngeal endoderm contributes substantially to craniofacial structures and lies in close proximity to the developing heart, and thus defects in this tissue are likely to play a major role in the formation of these organs. It is clear, however, that although we can make educated guesses about which signaling pathway is likely to be defective in a select subset of gut malformations^ref, much work remains to be done to establish molecular causality. In this regard, human genetic studies of gut malformations have certainly lagged behind those of the cardiovascular system, for instance. And as has already been illustrated regarding other organ systems such as the cardiovascular system, more subtle mutations in key developmental genes are likely to predispose one to gut disease and/or functional defects. Closer interactions between clinical and basic scientists interested in the gastrointestinal tract will greatly accelerate the pace of discovery in these areas. Compared to readily accessible organs such as the limb, or to organs such as the heart and pancreas that are the focus of resourceful charities, the gut has been left behind. However, it is clear from the few vignettes presented here that the many fascinating developmental, evolutionary, and medical aspects of the gut will continue to attract much attention and generate pertinent information.
• Organs
• beaker, caliciform, chalice or goblet cells : a unicellular mucous gland found in the epithelium of intestines. Droplets of mucigen collect in the upper part of the cell and distend it, while the basal end remains slender, and the cell assumes the shape of a goblet.
• trefoil factors (TFFs) are protease-resistant peptides that promote epithelial cell migration and mucosal restitution during inflammatory conditions and wound healing in the gastrointestinal tract. Members of the trefoil family are characterized by having at least one copy of the trefoil motif, a 40-amino acid domain that contains 3 conserved disulfides. To date, the molecular mechanism of TFFs action and their possible role in tumor progression are unclear
• TFF1 / pS2 (gastric mucosa, conjuctival goblet cells)
• TFF2 / spasmolytic polypeptide (gastric mucosa)
• TFF3 / intestinal trefoil factor (goblet cells of the intestines and colon)
TFF1, TFF2, and TFF3 are paralogous genes located within a 55 kb region on chromosome 21q22.3
• mouth / os : the anterior or proximal opening of the alimentary canal, which is bounded anteriorly by the lips and which contains the tongue and teeth
• sublingual crescent : the crescent-shaped area on the floor of the mouth, formed by the lingual wall of the mandible and the adjacent part of the floor of the mouth.
• stomatognathic system : the structures of the mouth and jaws, considered collectively, as they subserve the functions of mastication, deglutition, respiration, and speech
• masticatory system or apparatus / organs of mastication : the organs and structures involved in mastication, including the teeth and jaws and their supporting structures, temporomandibular joints, mandibular muscles, accessory facial muscles, tongue, lips, cheeks, and oral mucosa together with their innervation
• jaw or mandibular movement : any movement of which the mandible is capable
• free mandibular movement : any unhampered movement of the mandible.
• functional mandibular movements : those movements of the mandible which occur in the performance of some function, as mastication, swallowing, articulation of vocal sounds, and yawning.
• border movement : any extreme compass of mandibular movement limited by bone, ligaments, or soft tissues; usually applied to horizontal mandibular movements.
• masticatory movements : those movements of the mandible occurring in the mastication of food.
• Bennett movement : the lateral shift of the mandibular condyles and articular disks in the direction of the working bite as the lower jaw swings in preparation for mastication
• opening movement : a mandibular movement during jaw separation.
• intermediary or intermediate movements : mandibular movements between the extremes of mandibular excursions.
• posterior opening movement : the opening movement of the mandible about the terminal hinge axis.
• lip : either the upper or lower fleshy margin of the mouth, together called labia oris
• labial groove : an embryonic groove produced by degeneration of the central cells of the labial lamina, which later becomes the vestibule of the oral cavity.
• lip line : a line at the level to which the margin of either lip extends on the teeth
• high lip line : the greatest height to which the maxillary lip is raised
• low lip line : the lowest position of the lower lip during the act of smiling or voluntary retraction.
• tuberculum labii superioris / tubercle of upper lip / procheilon / labial tubercle : the central prominence of the superior border between the skin and the mucous membrane of the upper lip, marking the distal termination of the philtrum
• oral cavity (see also diseases of oral cavity)

Ontogenesis :
• primordial, premaxillary or primary palate : that portion of the palate in embryonic development that forms first, being contributed by the median nasal process
• secondary palate : in embryonic development, the part of the palate that forms later than the primordial palate, by fusion of the lateral nasal process
• ductus incisivus / incisive duct /incisor canaliculus / incisor duct : a passage sometimes found in the incisive canal that interconnects the nasal and oral cavities during embryonic development; it occasionally fails to close
Anatomy :
• Fleischmann's follicle : an occasional follicle in the mucosa of the floor of the mouth, near the anterior border of the genioglossus muscle.
• palate : the tissues forming the roof of the mouth that separates the oral and nasal cavities
• hard palate / palatum durum : the anterior part of the palate, characterized by an osseous framework, covered superiorly by mucous membrane of the nasal cavity and, on its oral surface, by mucoperiosteum
• palatum osseum / bony (hard) palate : the bony part of the anterior 2/3 of the roof of the mouth, formed by the palatine processes of the maxillae and the horizontal plates of the palatine bones
• vibrating line : an imaginary line across the palate that separates its immovable portion, the hard palate, from its movable portion, the soft palate
• soft palate / palatum molle / velum palatinum : the fleshy part of the roof of the mouth, extending from the posterior edge of the hard palate; from its free inferior border is a projection of variable length, the pendulous palate / uvula
Cell types :
• surface cell in squamous epithelia of the oral cavity
• basal stem cell of squamous epithelia of the oral cavity
• salivary glands (see also diseases of salivary glands)

Cell types :
• mucous cell (secreting  polysaccharides)
• serous cell (secreting glycoproteic enzymes)
• von Ebner gland cell / gustatory gland (secretion wash out gustatory papillae) : serous secreting glands in the posterior part of the tongue near the vallate papillae
Anatomy : glandulae oris
• glandulae salivariae majores / major salivary glands : the larger exocrine glands of the oral cavity
• internal salivary gland
• submaxillary gland / submandibular gland / glandula submandibularis => ductus submandibularis / submandibular duct / ductus submaxillaris / submaxillary duct of Wharton / Wharton's duct opens at the sublingual caruncle. Sympathetic or ganglionic saliva is submaxillary saliva produced in response to stimulation of its sympathetic nerve supply : it is more viscid and turbid than that of the unstimulated gland.
• sublingual gland / Rivinus gland / glandula sublingualis =>
• ductus sublingualis major / major sublingual duct / Bartholin's duct opens alongside the submandibular duct on the sublingual caruncle
• ductus sublinguales minores / minor sublingual ducts / canals or ducts of Rivinus / Walther's ducts open along the crest of the sublingual fold
Sublingual saliva is that produced by the sublingual gland, the most viscid of all.
• external salivary gland / parotid gland / glandula parotidea => ductus parotideus / parotid duct / Blasius' duct / Stensen's canal or duct / duct or canal of Steno empties into the oral cavity opposite the second superior molar. Parotid saliva is that produced by the parotid gland; thinner and less viscid than the other varieties
• admaxillary gland / accessory parotid gland / glandula parotidea accessoria
• glandulae salivariae minores / minor salivary glands (MSG) / lesser salivary glands (LSG) : the smaller exocrine glands of the oral cavity
• buccal glands / cheek glands / glandulae buccales / malar gland : the serous and mucous glands on the inner surface of the cheeks
• glandula incisiva : a small intraoral gland in the median line of the upper jaw near the incisors.
• lingual glands / glandulae linguales / glands of tongue : the mucous and serous glands on the surface of the tongue
• Bauhin's glands / Blandin and Nuhn's glands / apical glands of tongue / glandulae linguales anteriores / intramuscular glands of tongue : deeply placed mucoserous glands near the apex of the tongue.
• palatine glands / glandulae palatinae : the mucous glands on the soft palate and the posteromedial part of the hard palate.
• glandulae labiales oris / labial glands of the mouth : the serous and mucous glands on the inner part of the lips.
• retromolar glands / glandulae molares / molar glands : the glands on the external aspect of the buccinator muscle, their ducts piercing it to open on the internal aspect of the cheek
• Suzanne's gland : a mucous gland of the mouth, beneath the alveololingual groove
Saliva : the clear, alkaline, somewhat viscid secretion that serves to moisten and soften the food, keeps the mouth moist, and contains
• a-amylase, a digestive enzyme which converts starch into maltose
• mucin
• serum albumin
• salivary corpuscle : a white blood cell that has migrated through the oral epithelium and is mixed in the saliva
• epithelial debris
• potassium thiocyanate
• toxins
• lactoperoxidase
• SIgA
• lactoferrin
• lysozyme
• acidic Pro-rich proteins (PRPs)
• histatins
• teeth (see also diseases of teeth)

Phylogenesis : dimer theory : the theory that the tooth organ of primates is composed of 2 halves, each of which is a representative of an independent tooth in the lower orders of animals.
Odontogenesis : at week 6 of pregnancy cells from neural crest migrate into maxillary region inducing ectoderm to proliferate into the dental lamina / lamina dentalis / dentogingival lamina (a horizontal band projecting perpendicularly from the vestibular lamina and extending into the substance of the embryonic gum, assuming a horseshoe-like shape to conform with the dental arches)
• lateral dental lamina / lateral enamel strand : a lateral band of cells believed to be functionally and structurally similar to the parent dental lamina, which connects the developing tooth germ to the dental lamina
• primitive dental groove : a groove in the border of the jaws of the embryo
• developmental grooves or lines / segmental lines : fine grooves or lines marking the fusion area between adjacent cusps, named according to the portion of the crown which they connect
• mesiobuccal developmental groove : the mesial of the two buccal grooves ordinarily found on the mandibular first molar
• mesiolingual developmental groove : a groove marking the junction of the fifth cusp with the palatal surface on an upper molar tooth.
• lingual developmental groove : a developmental groove on the lingual surface of a posterior tooth.
• occlusal groove : one of the developmental grooves on the occlusal surface of a posterior tooth
• supplemental grooves : grooves on the surface of a tooth that do not mark (as do the developmental grooves) the junction of the primary lobes of the tooth.
Staging :
• lamina-bud stage (weeks 6-7) : initial formation of the tooth bud and development of dental lamina
• cup stage (weeks 8-9) : formation of the enamel cap and dental papilla in the tooth germ and organization of the dental cells into 3 layers (dentin and pulp)
• bell stage (week 10 - eruption) : morphodifferentiation and histodifferentiation in which the enamel organ changes in shape from a cap to a bell that has 4 distinct layers.
Cell types : preeruptive stage : the period of tooth development, before tooth eruption, characterized by growth of the coronal portion of the tooth, prior to the beginning of the growth of the root.
• ameloblast / adamantoblast / enamel cell => enamel matrix
• amelogenins (degraded by MMP20 / enamelysin)
• X chromosome
• Y chromosome
• enamelanin
• ameloblastin
• tuftelin 1
• dentin sialophosphoprotein (DSPP) (transient expression)
=hydroxyapatite crystals calcification (85% of final enamel volume)=> enamel : hard, calcified, white tissue covering dentin of the crown of tooth. During foetal amelogenesis the pulp of enamel organ and the intermediate layer of adamantoblasts (lost at birth) produce enamel : Tomes' processes are finger-like projection of the ameloblast, occurring during the secretory phase of the cell, which extends from the point of separation of the adjacent cell membrane to the distal free surface. Stellate reticulum is the soft, middle part of the enamel organ of a developing tooth, the cells being separated by an increase in the gelatinous intercellular substance that forces the cells apart without breaking the intercellular connections, giving them a stellate appearance and providing protection later for the enamel-forming cells
• Hannover's intermediate enamel membrane : the inner layer of cells within the enamel organ of the dental germ in the fetus
• enamel knot : a small dense group of epithelial cells in the stellate reticulum of a developing tooth, which disappears before enamel formation begins.
• dentinoenamel membrane : a continuous thin membrane laid down by ameloblasts adjoining the basement membrane separating them from the dentin in an early developing tooth
• Nasmyth's membrane : primary (enamel) cuticle
• odontoblast / dentin cell (undergoes activation to repair fractures) => odontocyte => predentin
• dentin sialophosphoprotein (DSPP)
• dentin matrix acidic phosphoprotein
• matrix, extracellular phosphoglycoprotein with ASARM motif (MEPE)
=calcification=> dentin : that part of the tooth that is beneath enamel and cementum, between the pulp and the enamel, comprised of a series of dentinal tubules (microscopic canals that run from the outside of the dentin to the nerve inside the tooth) stacked on top of each other.
• incremental, accretion, calcification or Retzius' l's lines / Retzius' parallel striae : lines showing the successive layers deposited in a tissue. In the enamel, they are brown striations visible under transmitted light and colorless in reflected light. They may be observed under the microscope in longitudinal sections as oblique lines running inward from the surface and toward the root and in cross sections as rings similar to those in a tree trunk. Dry dentin often shows a series of somewhat parallel lines caused by imperfectly calcified dentin arranged in layers
• incremental lines of Ebner : delicate lines indicating periods of rest between daily increments of dentin, which are visible on ground sections of a tooth
• imbrication lines of Pickerill : lines formed by ends of rod bundles that overlie one another and are arranged in scalariform fashion on the surface of the crown of a tooth; seen on longitudinal sections of a tooth together with the incremental lines, but forming areas not completely contained in the enamel
• lines of Schreger / Hunter-Schreger bands, Schreger's bands or striae, and zones of Schreger : the dark and light lines visible under reflected light in a ground section of a tooth, which terminate at the dentinoenamel junctions, coinciding with the enamel prism curvatures. The dark bands are known as diazones, and the light ones as parazones
• neonatal line : a line seen on longitudinal sections of a tooth, showing a demarcation between the structures present at birth and those deposited postnatally; in cross sections, the lines are seen as rings (neonatal rings), and their variations indicate adaptational changes in tooth formation
• lines of Owen / contour lines / Salter's lines : the sweeping bands seen on longitudinal section that outline the growth of the coronal or radicular dentin, representing a lag of several days between calcification phases, each lasting about 4 days
• cementoblast => cementocyte => cementum : hard connective tissue covering the tooth root, serves as the anchor point for the ligaments that join the tooth to the boney tooth socket. It is the softest part of the tooth structures
• imbrication or incremental lines of cementum : very fine dark lines present in longitudinal sections of a tooth, which follow the contour of the root and border with wider light bands, revealing the cyclic activity of cementogenesis
Anatomy :


• gingival sulcus : space between gum and tooth
• gingival crevicular fluid (GCF) is the clear fluid which continually flushes out the sulcus. In a state of health, there is little gingival crevicular fluid; however as inflammation increases, the amount of GCF increases also.
• gingiva / gum : soft tissues overlying the crowns of unerupted teeth and encircling the necks of those that have erupted, covering the alveolar bone and serving as the supporting structure for sub-adjacent tissues
• free gingiva : the marginal part of the gingival (gums) that can be deflected from the tooth surface. The free gingiva forms a collar around the tooth.
• gingival crevice / gingival margin / gumline : area of gingiva closest to the tooth surface
• free gingival groove : a shallow groove on the facial surface of the gingiva, running parallel to the margin of the gingiva at a distance of 0.5 to 1.5 mm., and usually at the level of, or somewhat apical to, the bottom of the gingival sulcus
• keratinized gingiva : the oral surface of the gingiva extending from the mucogingival junction to the gingival margin. In gingival health, the coronal portion of the sulcular epithelium may also be keratinized
• interdental papilla : refers to the "v" shaped gum tissue between individual teeth
• interdental groove : a linear, vertical depression on the surface of the interdental papillae; it functions as a sluiceway for the egress of food from the interproximal areas.
• frenum : muscle fibers covered by a mucous membrane that attaches the cheek, lips and or tongue to associated dental mucosa
• frenulum linguae / frenulum of tongue / frenum of tongue : the vertical fold of mucous membrane inferior to the tongue, attaching it to the floor of the mouth
• buccal frenum : a fold of mucous membrane connecting the alveolar ridge to the cheek and separating the labial vestibule from the buccal vestibule
• frenulum labii inferioris / frenulum of lower lip : the fold of mucous membrane on the inside of the middle of the lower lip, connecting the lip with the gums
• frenulum labii superioris / frenulum of upper lip : the fold of mucous membrane on the inside of the middle of the upper lip, connecting the lip with the gums
• alveolar bone : the bone which surrounds the root of the tooth, holding it in place. Loss of this bone is typically associated with severe periodontal disease
• alveolus / socket : the hole in the jawbone into which the tooth fits
• periodontal ligament / alveolodental ligament or membrane / desmodontium / peridental or periodontal membrane : the fibrous connective tissue that surrounds the cementum, separating it from and attaching it to the alveolar bone. It extends from the base of the gingival mucosa to the fundus of the bony socket, and its main function is to hold the tooth in its socket.
• syndesmosis dentoalveolaris / dentoalveolar syndesmosis / gomphosis : one of the fibrous joints by which a tooth is held in its socket
• Hertwig's sheath / root sheath : an epithelial extension of the cervical loop of the enamel organ, consisting of the inner and outer enamel epithelium, and directing the number and morphological growth of the roots. It is bordered externally by the dental sac and internally by developing cementum and root dentin, and ultimately becomes the epithelial diaphragm : an epithelial structure that narrows the opening into the pulp chamber, diminishing its caliber. It is in close contact with the bone forming the fundus of the developing alveolus, from which it is separated by the dental sac
• Malassez rest : the remaining cells of the root sheath in the periodontal ligament, which persist and sometimes form an epithelial network and occasionally develop into a dental cyst.
• pulp cavity : the space within a tooth which contains the soft pulp / pulpa dentis, the living part of the tooth, located inside the dentin, containing nerve tissue and the blood vessels which supply nutrients to the tooth.
• root canal : the portion of the pulp cavity inside the root of a tooth; the chamber within the root of the tooth that contains the pulp
• root / radix denti : the anatomic portion of the tooth that is covered by cementum and is located in the alveolus where it is attached by the periodontal apparatus; radicular portion of tooth.
• apex : the tip or end of the root end of the tooth.
• furcation : the anatomic area of a multirooted tooth where the roots diverge.
• cementoenamel junction (CEJ) / cervix dentis / neck is the point at which the crown and root come together
• cervical line : an anatomical landmark determined by the junction of the enamel- and the cementum-covered portions of a tooth (the cementoenamel junction); the dividing line between the crown and root portions of a tooth.
• crown / corona dentis
• anatomical crown : that portion of tooth normally covered by, and including, enamel.
• corona clinica / clinical crown / extra-alveolar crown : that portion of the tooth above the clinical root, i.e., the portion exposed beyond the gingiva, and thus visible in the oral cavity
• buccolingual diameter : the distance from the buccal to the lingual surface of a tooth crown at its widest point or greatest curvature.
• cusp : pointed or rounded eminence on or near the masticating surface of a tooth.
• pit : a recessed area found on the surface of a tooth, usually where the grooves of the tooth meet
Dental arch : the curved composite structure of the natural dentition and the residual ridge, or the remains thereof after the loss of some or all of the natural teeth
• quadrant : one of the 4 equal sections into which the dental arches can be divided; begins at the midline of the arch and extends distally to the last tooth.
• sextant : one of the 6 relatively equal sections into which a dental arch can be divided, for example: tooth numbers 1-5; 6-11; 12-16; 17-21; 22-27; 28-32. Sometimes used for recording periodontal charting


Dental regions :
• vertical axis
• crown
• occlusal region
• intermediate region
• cervical region
• root
• cervical region
• intermediate region
• apical region
• anteroposterior axis
• mesial region
• intermediate region
• distal region
• laterolateral axis
• facial or vestibular region
• labial region
• buccal region
• intermediate region
• lingual region
Dentition : the teeth in the dental arch.
• teething : the effects of baby teeth pushing through gums.
• operculum : the flap of tissue over an unerupted or partially erupted tooth
• eruption : when teeth first peek through gums
• diastema : a space, such as one between 2 adjacent teeth in the same dental arch
• anterior diastema : a space between the incisor teeth, generally one between the maxillary central incisors
• ugly duckling stage : a development stage in the mixed dentition when the upper central and lateral incisors may be flared, with the crowns distally and with diastema present before the maxillary canine teeth erupt.
• anterior, labial or morsal teeth : these are the 6 teeth located in the front of the mouth, and are used as cutting (biting) surfaces rather than chewing surfaces
• incisor (teeth) /dentes incisivi : 8 front teeth
• central incisors
• lateral incisors
Used to cut, gnaw and tear food.
• incisal edges : refers to the biting edges of the anterior teeth.
• mamelon : one of three tubercles sometimes present on the cutting edge of an incisor tooth.
• canines / cuspid (teeth) / dentes canini : 4 pointed conical teeth located between the incisors and the first molars
• eye tooth : colloquial term for a canine tooth of the maxilla
• stomach tooth : a canine tooth of the mandible.
• incisal angle : one of the angles formed by the junction of the incisal and the mesial or distal surfaces of an anterior tooth; called the mesial and distal incisal angle respectfully.
• anterior arch length : the length of a line segment within the median plane perpendicular to and extending from the line connecting the first premolars to the most labial point on the anterior arch, usually to the point between the maxillary central incisors
• buccal, cheek or posterior teeth are those used for grinding food, having large crowns and broad chewing surfaces
• premolars / bicuspid (teeth) / dentes premolares (P) : the permanent teeth between the canines and the molars; there are 2 on either side in each jaw
• upper premolars are bicuspid
• lower have from 1 to 3 cusps
Premolars are succedaneous to the deciduous molar teeth
• molars / dentes molares : the most posterior teeth on either side in each jaw, totaling 8 in the deciduous dentition (2 on each side, upper and lower), and usually 12 in the permanent dentition (3 on each side, upper and lower). They are the grinding teeth, having large crowns with broad chewing surfaces. Symbol M.
• upper molars characteristically have 4 major cusps and 3 roots
• Carabelli cusp or tubercle : an accessory cusp on the lingual aspect of the mesiolingual cusp of an upper molar, which may be unilateral or bilateral and may vary considerably in size; it is common in Caucasians but quite rare in East Asians and certain other groups
• lower first molars characteristically have 5 cusps, and the remaining lower molars 4 cusps. Normally all lower molars have 2 roots
• wisdom teeth / third molars / dens molaris tertius / dens serotinus : the tooth most distal to the medial line on either side in each jaw, so called because it is the last of the permanent dentition to erupt, usually at the age of 17 to 21 years. Some people are born without third molars.
• paramolar / supernumerary molar : a supernumerary tooth, usually small and rudimentary, sometimes found in the maxilla buccally or lingually to a molar or interproximally between 2 of the first 2 molars
• occlusal : the biting surface of the posterior teeth
• diodontous animals
• deciduous or primary dentition : the 20 baby, deciduous, milk or primary teeth. They are shed and replaced by the permanent teeth. They begin to calcify at about month 4 of fetal life, and near the end of the month 6 they all have begun to develop. See also deciduous tooth stem cells. Timing of eruption :
• maxillary deciduous teeth : paracone : the mesiobuccal cusp of a maxillary tooth of mammals, which normally occludes between the paraconid and hypoconid of the corresponding lower molar
• central incisors : 7 1/2 months
• lateral incisors : 8 months
• canines : 16-20 months
• first molars : 12-16 months
• second molars : 20-30 months / 2 1/2 years
• mandibular deciduous teeth :
• first incisors : 6 1/2 months
• second incisors : 7 month
• canines : 16-20 months
• first molars : 12-16 months
• paraconid : the mesiobuccal cusp of a mandibular molar tooth.
• second molars : 20-30 months
Mandibular teeth erupt before maxillary teeth. First molar erupt before canines. The deciduous dentition formula (one side) is as follows : I 1/2 C 1/1 M 2/2 = 10. Symbol D.
• permanent dentition : the 32 permanent teeth. Timing of eruption :
• maxillary permanent teeth
• first incisors : 7-8 years
• second incisors : 8-9 years
• canines : 11-12 years
• first premolars : 10-11 years
• second premolars : 10-12 years
• sixth-year molar : the permanent first molar tooth, so called because it usually erupts at the age of 6 years just posterior to the last molar of the deciduous dentition : 6-7 years
• twelfth-year molar : the permanent second molar tooth, so called because it usually erupts at the age of 12-13 years
• third molars : 17-21 years
• mandibular permanent teeth
• first incisors : 6-7 years
• second incisors : 7-8 years
• canines : 9-10 years
• first premolars : 10-12 years
• second premolars : 11-12 years
• first molars : 6-7 years
• second molars : 11-13 years
• third molars : 17-21 years
They take their position posterior to the deciduous teeth and erupt in succession, whenever the jaws grow sufficiently to accommodate them. Upper incisors cover lower incisors by 0-2 mm (physiological overbite); growth of maxillary bone carries upper teeth more anteriorly than lower teeth (Mediterranean closure : upper central incisor greater than lower one => every cuspid in upper teeth goes behind correspondent cuspid in lower teeth), while mandibular displacement.
• succedaneous teeth / successional teeth : the permanent teeth that have deciduous predecessors in the dental arch. Exfoliation of the deciduous teeth is brought about by resorption of their roots, and the succedaneous permanent teeth take their place
• accessional teeth : the molar teeth of the permanent dentition, so called because they do not supplant any deciduous predecessors in the dental arch
The permanent dentition formula (one side) is as follows: I 2/2 C 1/1 P 2/2 M 3/3 = 16
• occlusion : any contact between biting or chewing surfaces of maxillary (upper) and mandibular (lower) teeth in all mandibular positions and movements
• occlusal harmony : proper occlusion of the teeth occurring in various positions of the mandible.
• functional occlusal harmony : such occlusion of the teeth in all positions of the mandible during mastication as will provide the greatest masticatory efficiency without imposing undue strain or trauma on the supporting tissues.
• glide : a smooth continuous movement
• mandibular glide : the side-to-side, protrusive, and intermediate movement of the mandible occurring when the teeth or other occluding surfaces are in contact.
• occlusal glide : the movement induced by deflective tooth contact that diverts the mandible from a normal path of closure to a centric jaw relation
• curve of occlusion / dental curve / occlusal curvature / curva occlusalis : a curved surface that makes simultaneous contact with major portions of the incisal and occlusal prominences of the existing teeth
• on a sagittal plane : Spee curve (anatomic curvature of the occlusal alignment of teeth, beginning at the tip of the lower canine, following the buccal cusps of the natural premolars and molars, and continuing to the anterior border of the ramus)
• on a frontal plane : Wilson curve (the curvature of the cusps of the teeth as projected on the frontal plane; that of the inferior dental arch is concave and that of the superior dental arch is convex)
• interarch or interridge distance : the vertical distance between the maxillary and mandibular arches (alveolar or residual) under certain conditions of vertical dimension that must be specified.  The vertical distance between the maxillary and mandibular ridges
• interocclusal distance / freeway space / interocclusal clearance, gap, or space : the distance between the occluding surfaces of the maxillary and mandibular teeth when the mandible is in physiologic rest position
• dental guides
• incisor guide : cuspid of lower incisors flow on back surfaces of upper incisors
• canine guide is used during lateral movements
• mastication : the act of chewing
• mandibular movements : Posselt envelope of motion (the area within which all movements are possible : G=>A movement is not spontaneous)
• hinge position : the position of the condyle in the temporomandibular joint from which an opening by hinge movement is possible beyond the amplitude of rest position.
• condylar hinge position : the position of the condyles in the glenoid fossa at which hinge axis movement is possible.
• mandibular hinge position : a position of the mandible that allows the condyles to move on the hinge axis during the opening or closing of the jaws.
• terminal hinge position / centric relation / centric jaw relation / median retruded jaw relation / terminal hinge position /  true centric : the position of the mandible, obtained principally by operator guidance, in which the condyles are in the rearmost uppermost position in the fossae of the temporomandibular joint
• centric position : the rest position of the mandible, as it is influenced by the muscle tone, while the patient remains standing or is sitting with jaw open, from which the teeth will come into centric occlusion when the jaw is closed.
• occlusal position / occlusal relation : a functional position of the jaws in which contact between some or all of the upper and lower teeth occurs when the mandible is closed, which may or may not coincide with centric occlusion
• posterior border position / posterior border jaw relation : the most posterior position of the mandible at any specific vertical relation to the maxillae
• rest position / physiologic rest position / rest jaw relation : the position of the mandible when its muscles are at rest, the body is in the upright standing or sitting position, and the eyes are focused toward the horizon; the lips are slightly touching and the distance between the upper and lower teeth has a free-way space of about 2 to 5 mm
Periodontium / alveolar periosteum / odontoperiosteum / paradentium / peridontium : the tissues that invest or help to invest and support the teeth, including :
• periodontal ligament
• gingivae
• cementum
• alveolar and supporting bone
• tongue / lingua / glossa : the movable, muscular organ on the floor of the mouth, subserving the special sense of taste and aiding in mastication, deglutition, and the articulation of sound
• ductus thyroglossalis / thyroglossal duct / duct of His or Vater / Bochdalek's duct / His canal / thyrolingual duct : a duct in the embryo extending between the thyroid primordium and the posterior part of the tongue, which opens as the foramen caecum; the distal part usually differentiates to form the pyramidal lobe the thyroid and the remainder becomes obliterated, but occasionally persists into adult life, giving rise to cysts, fistulas, or sinuses
• copula linguae : a median ventral elevation on the embryonic tongue formed by union of the second pharyngeal arches; it represents the future root of the tongue.
• frenulum linguae / frenulum of tongue / frenum of tongue : the vertical fold of mucous membrane inferior to the tongue, attaching it to the floor of the mouth

Cell types :
• surface cell in squamous epithelia
• basal stem cell of squamous epithelia
• see also taste
• orthognathic : functional relationship of maxilla and mandible.
• oropharynx / pars oralis pharyngis : the division of the pharynx lying between the soft palate and the upper edge of the epiglottis.
• palatopharyngeal sphincter : a transverse band of muscle fibers in the posterior wall of the pharynx, derived from the superior constrictor or palatopharyngeal muscle, which contracts during swallowing to form Passavant's bar; it also contracts during speech in persons with cleft palate.
Coats : tunica mucosa pharyngis : the mucous coat of the pharynx
• neck
• 
• hypopharynx / pars laryngea pharyngis / laryngopharynx : the portion of the pharynx that lies below the upper edge of the epiglottis and opens into the larynx and esophagus
• retrocricoid area / pharyngo-esophageal junction
• pharyngolaryngeal splint / recessus piriformis / piriform recess or sinus : a pear-shaped fossa in the wall of the laryngeal pharynx lateral to the arytenoid cartilage and medial to the lamina of the thyroid cartilage
• posterior area / posterior pharyngeal wall
• pharyngoesophageal junction : the area where the esophagus and pharynx meet
• pharyngoesophageal sphincter : a region of higher muscular tone at the pharyngoesophageal junction, involved in movements of swallowing.
• esophagus / oesophagus / gullet (see also diseases of esophagus) : the musculomembranous passage extending from the pharynx to the stomach
• upper esophageal sphincter (UES) : the upper 3–5 cm of the esophagus, including the cricopharyngeal muscle, which prevents the aspiration of air from the pharynx into the esophagus
• cervical esophagus / pars cervicalis oesophagi or esophagi / cervical part of esophagus : the part of the esophagus located in the cervical region, posterior to the trachea and the recurrent laryngeal nerves, anterior to the longus colli muscle and vertebral column, and medial to the lobes of the thyroid gland and the common carotid arteries (C5-T1)
• thoracic esophagus / pars thoracica oesophagi or esophagi / thoracic part of esophagus : the part of the esophagus located in the thoracic region, posterior to the trachea and pericardium and anterior to the vertebral column (T1-T12)
• upper third
• middle third
• lower third
• diaphragmatic esophagus
• lower esophageal sphincter (LES) / gastroesophageal sphincter : the terminal few centimeters of the esophagus, which prevents reflux of gastric contents into the esophagus
• abdominal esophagus / pars abdominalis oesophagi or esophagi / abdominal part of esophagus : the part of the esophagus below the diaphragm, joining the stomach (from hiatus to cardias)
Anatomical variations in caliper
• strictures :
• cricoid stricture
• aortic stricture
• bronchial stricture
• diaphragmatic stricture
• phrenic ampulla : the dilatation at the lower end of the esophagus.
Coats :
• tunica adventitia oesophagi : the adventitious coat of the esophagus.
• tunica muscularis oesophagi : the muscular coat of the esophagus.
• tunica mucosa oesophagi : the mucous coat of the esophagus
Cell types :
• surface cell in squamous epithelia of the esophagus
• basal stem cell of squamous epithelia of the esophagus
• glandulae oesophageae / esophageal glands / glandulae esophageae : the mucous glands in the submucosa of the esophagus
• interstitial cells of Cajal (CD117 / c-kit⁺) : pleomorphic cells of the myenteric plexus having an oval nucleus and long, branching cytoplasmic processes that interlace with processes of adjacent cells, interspersed between the circular and longitudinal muscle layers of the gastrointestinal tract and in the smooth muscle of the esophagus; they are thought to act as pacemakers and give rise to gastrointestinal stromal tumours (GIST)
• enteric plexus
Vascularization :
• upper esophageal artery (receiving lower thyroid artery, which also drains into azygos vein) enters upper cava vein
• lower esophageal artery (receiving left gastric artery) enters left gastric vein
• cardioesophageal esophagogastric or gastroesophageal junction : the site of transition from the stratified squamous epithelium of the esophagus to the simple columnar epithelium of the cardia of the stomach
• cardiac sphincter / cardioesophageal sphincter : muscle fibers about the opening of the esophagus into the stomach.
• gastroesophageal refluxes (GER) :
• prevalence : physiological if short-lasting, asymptomatic and involving only the distal esophagus ("happy splitter")
• 50% in 3-month infants
• 67% in 4-months infants
• 5% in 12-months infants
• episodes lasting > 5' : 9.7/day at 0-11 months, 6.8/day at 1-9 yrs, 3.2/day in adults
• reflux index (time in which esophageal pH < 4) : 11.7% in 0-11 months, 5.4% at 1-9 yrs, 2% in adults
• threshold with gastroesophageal reflux disease (GERD) : 73 a days
• abdomen / belly / venter : that portion of the body which lies between the thorax and the pelvis; it contains a cavity (abdominal cavity) separated by the diaphragm from the thoracic cavity above, and by the plane of the pelvic inlet from the pelvic cavity below, and lined with a serous membrane, the peritoneum. This cavity contains the abdominal viscera and is enclosed by a wall (abdominal wall) formed by the abdominal muscles, vertebral column, and the ilia. It is divided into 9 regions by 4 imaginary lines projected onto the anterior wall (see illustration); 2 of the lines pass horizontally around the body (the upper at the level of the cartilages of the 9th ribs, the lower at the tops of the crests of the ilia), and 2 extend vertically on each side of the body from the cartilage of the 8th rib to the center of the inguinal ligament. The regions are:
• 3 upper—right hypochondriac, epigastric, left hypochondriac
• 3 middle—right lateral, umbilical, left lateral
• 3 lower—right inguinal, pubic, left inguinal..

Regions of abdomen bounded according to (A) the standard and (B) a variant system:
• 1, epigastric
• 2, right hypochondriac
• 3, left hypochondriac
• 4, right lateral (or lumbar)
• 5, umbilical
• 6, left lateral (or lumbar)
• 7, right inguinal (or iliac)
• 8, pubic (hypogastric)
• 9, left inguinal (or iliac)
• peritoneum : the serous membrane lining the abdominopelvic walls and investing the viscera. A strong, colorless membrane with a smooth surface, it forms a double-layered sac that is closed in the male and is continuous with the mucous membrane of the uterine tubes in the female
• peritoneum parietale / parietal peritoneum : the peritoneum that lines the abdominal and pelvic walls and the inferior surface of the thoracic diaphragm.
• peritoneum viscerale / visceral peritoneum : a continuation of the parietal peritoneum reflected at various places over the viscera, forming a complete covering for the stomach, spleen, liver, ascending portion of the duodenum, jejunum, ileum, transverse colon, sigmoid flexure, upper end of rectum, uterus, and ovaries; it also partially covers the descending and transverse portions of the duodenum, the cecum, ascending and descending colon, the middle part of the rectum, the posterior wall of the bladder, and the upper portion of the vagina. It holds the viscera in position by its folds, some of which form the mesenteries, connecting portions of the intestine with the posterior abdominal wall; other folds, the omenta, are attached to the stomach; and still others form the ligaments of the liver, spleen, stomach, kidneys, bladder, and uterus. The potential space between the visceral and the parietal peritoneum is the peritoneal cavity, which consists of the pelvic peritoneal cavity below and the general peritoneal cavity above. The general cavity communicates by the epiploic foramen / omental foramen / foramen omentale / foramen of Winslow (situated below and behind the porta hepatis) with the cavity of the greater omentum / lesser peritoneal cavity.
• Morison's pouch : a pouch of peritoneum inferior to the liver and to the right of the right kidney and extending inferiorly to the transverse mesocolon
• excavatio rectouterina / rectouterine excavation / Douglas' cul-de-sac / pouch of Douglas / Douglas' space / rectouterine, rectovaginal, uterovesical, or vesicouterine pouch : a sac or recess formed by a fold of the peritoneum dipping down between the rectum and the uterus
• pararectal pouch : the lateral part of the excavatio recto-uterina
• abdominovesical pouch : the pouch formed by reflection of the peritoneum from the anterior abdominal wall to the distended bladder.
• excavatio rectovesicalis / rectovesical excavation or pouch : the space between the rectum and the bladder in the peritoneal cavity of the male
• excavatio vesicouterina / uterovesical or vesicouterine excavation or pouch : the space between the bladder and the uterus in the peritoneal cavity
• paracystic pouch : the lateral part of the excavatio vesico-uterina
• uteroabdominal pouch : the compartment of the pelvic cavity anterior to the uterus and broad ligaments.
• obturator or paravesical pouch : the lateral part of the uteroabdominal pouch, beside the bladder and in which the obturator canal opens
• peritoneum urogenitale / urogenital peritoneum : the peritoneum lining the urogenital structures in the lower pelvis.
• ligamentum serosum / serous ligament : a fold of peritoneum or other serous membrane that helps to hold an organ or part in position and transmits blood vessels and nerves.
• ligamentum duodenorenale / duodenorenal ligament : a fold of peritoneum that passes from the duodenum to the right kidney.
• ligamentum phrenicocolicum / phrenicocolic ligament : a peritoneal fold that passes from the left colic flexure to the adjacent costal portion of the diaphragm.
• ligamenta hepatis / hepatic ligaments : the ligaments of the liver
• ligamentum coronarium hepatis / coronary ligament of liver : the line of reflection of the peritoneum from the diaphragmatic surface of the liver to the under surface of the diaphragm.
• ligamentum triangulare dextrum hepatis / right triangular ligament of liver : the pointed right extremity of the coronary ligament of the liver where the superior and the inferior layer join in their attachment to the diaphragm.
• ligamentum triangulare sinistrum hepatis / left triangular ligament of liver : a triangular extension of the left extremity of the coronary ligament, which helps to attach the left lobe of the liver to the diaphragm.
• ligamentum hepatocolicum / hepatocolic ligament : an occasional fold of peritoneum, an extension of the lesser omentum to the right, passing from the lower surface of the liver near the gallbladder to the right colic flexure.
• ligamentum hepatoduodenale / hepatoduodenal ligament : a peritoneal fold that passes from the porta hepatis to the superior portion of the duodenum. It is continuous on the left with the gastrohepatic ligament, and on the right it forms one of the borders of the epiploic foramen. It contains the hepatic artery, portal vein, bile duct, nerves, and lymphatics.
• ligamentum hepatorenale / hepatorenal ligament : a fold of peritoneum that passes from the back part of the lower surface of the liver to the front of the right kidney and forms the right margin of the epiploic foramen.
• ligamentum falciforme hepatis / falciform ligament of liver / broad ligament of liver : a sickle-shaped sagittal fold of peritoneum that helps to attach the liver to the diaphragm, separates the right and left lobes of the liver, and extends from the coronary ligament of the liver behind to the umbilicus in front
• ligamentum latum uteri / broad ligament of uterus : a broad fold of peritoneum extending from the side of the uterus to the wall of the pelvis; it is divided into the ...
• mesosalpinx : the part of the broad ligament of the uterus above the mesovarium, composed of layers that enclose the uterine tube.
• mesovarium : the portion of the broad ligament of the uterus between the mesometrium and mesosalpinx, which is drawn out to enclose and hold the ovary in place.
• ligamentum ovarii proprium / ovarian ligament / utero-ovarian ligament : a musculofibrous cord in the broad ligament, joining the ovary to the upper part of the lateral margin of the uterus just below the attachment of the uterine tube
• mesometrium : the portion of the broad ligament below the mesovarium, composed of the layers of peritoneum that separate to enclose the uterus
• ligamentum lienorenale, phrenicolienale, phrenicosplenicum, splenorenale / splenorenal, lienophrenic, phrenicosplenic, or splenophrenic ligament : a peritoneal fold that passes from the diaphragm to the concave surface of the spleen
• ileocecal pouch : a peritoneal pouch at the ileocecal junction
• Waldeyer's fossa : the recessus duodenalis inferior and recessus duodenalis superior considered as one space.
• recessus duodenalis inferior / inferior duodenal recess : a pocket in the peritoneum on the left side of the ascending portion of the duodenum, bounded by the inferior duodenal fold
• recessus duodenalis superior / recessus duodenojejunalis / superior duodenal recess : a peritoneal pocket behind the superior duodenal fold
• Gruber-Landzert fossa : a recess in the peritoneum in the same situation as the superior duodenal recess, but extending downward behind the duodenojejunal angle.
• fossa intermesocolica transversa : a recess of the peritoneum in the same situation as the recessus duodenalis superior, but extending transversely
• infraduodenal fossa : a recess in the peritoneum below the third portion of the duodenum
• parajejunal fossa : a pouch of peritoneum below the lower end of the first part of the jejunum
• recessus hepatorenalis / hepatorenal recess : a peritoneal pouch between the liver and the kidney
• recessus ileocecalis or ileocaecalis inferior / inferior ileocecal recess : a peritoneal pocket situated behind the ileocecal fold, above the vermiform appendix below the ileum, and medial to the cecum;
• recessus ileocecalis or ileocaecalis superior / superior ileocecal recess : a peritoneal pocket situated behind and below the vascular cecal fold, above the ileum and medial to the lower end of the ascending colon
• recessus inferior bursae omentalis / inferior omental recess : the lower portion of the omental bursa, including its extension down into the great omentum. It is bounded in front by the posterior wall of the stomach, and behind by the pancreas, the transverse colon and its mesocolon, the left suprarenal gland, and part of the left kidney.
• recessus infundibuli or infundibularis / infundibular recess : a funnel-shaped depression in the anterior part of the floor of the third ventricle of the brain, within the infundibulum of the hypophysis
• recessus intersigmoideus / intersigmoidal recess : a shallow peritoneal pocket running downward and to the left at the base of the sigmoid mesocolon
• splenic fossa of omental sac / recessus lienalis or splenicus / splenic recess : an extension of the omental bursa to the left behind the gastrosplenic ligament almost to the spleen
• fossa of Jonnesco : the duodenojejunal fossa between the superior and inferior duodenal folds
• Landzert's fossa / recessus paraduodenalis / paraduodenal recess : a pocket occasionally found in the peritoneum behind a fold containing a branch of the left colic artery
• subsigmoid fossa : a fossa between the mesentery of the sigmoid flexure and that of the descending colon
• processus vaginalis peritonei (a.k.a. canal of Nuck / Nuck's diverticulum in the female) : a diverticulum of the anterior parietal peritoneal membrane extending into the inguinal canal, developing at the third month of intrauterine life, accompanying the round ligament down to the homolateral labium majus in the female, or the testis in its descent into the scrotum in the male (tunica vaginalis testis); usually completely obliterated in the female (otherwise forming Nuck's duct cyst); patency varies with age :
• 80-94% in newborns
• 50% at age 1
• 40% at age 2
• 15% in adults (the distal region is normally patent in the male)
• mesenterium / mesentery : the peritoneal fold attaching the small intestine to the posterior abdominal wall
• caval mesentery : a ridge, at the right of the embryonic mesogastrium, in which develops a hepatic segment of the inferior vena cava
• ventral mesentery : the embryonic mesentery attaching the stomach and the proximal duodenal region of the primordial intestine to the ventral body wall.
• Riolan's arch : the arch formed by the mesentery of the transverse colon
• mesoappendix / mesenteriolum processus vermiformis : the peritoneal fold attaching the appendix to the mesentery of the ileum
• mesocolon : the process of the peritoneum by which the colon is attached to the posterior abdominal wall. It is divided into ascending, transverse, descending, and sigmoid or pelvic portions, according to the segment of the colon to which it gives attachment.
• mesocolon ascendens / ascending or right mesocolon : the peritoneum attaching the ascending colon to the posterior abdominal wall, usually obliterated when the ascending colon becomes retroperitoneal.
• mesocolon descendens / descending or left mesocolon : the peritoneum attaching the descending colon to the posterior abdominal wall; it is usually absent because the descending colon is ordinarily retroperitoneal.
• mesocolon sigmoideum / sigmoid, pelvic or iliac mesocolon : the peritoneum attaching the sigmoid colon to the posterior abdominal wall
• mesocolon transversum / transverse mesocolon : the peritoneum attaching the transverse colon to the posterior abdominal wall.
• mesorectum : the fold of peritoneum connecting the upper portion of the rectum with the sacrum
• omentum / epiploon : a fold of peritoneum extending from the stomach to adjacent organs in the abdominal cavity
• omentum majus / greater omentum / great epiploon / colic omentum / gastrocolic omentum : a prominent peritoneal fold suspended from the greater curvature of the stomach and passing inferiorly a variable distance in front of the intestines; it is attached to the anterior surface of the transverse colon.
• mesogastrium : the portion of the primordial mesentery that encloses the stomach, and from which the greater omentum is developed.
• ligamentum gastrocolicum / gastrocolic ligament : a peritoneal fold, part of the greater omentum, that extends from the greater curvature of the stomach to the transverse colon.
• ligamentum gastrophrenicum / gastrophrenic ligament : a fold of peritoneum continuous with the gastrosplenic ligament, extending from the right undersurface of the diaphragm to the cardiac part of the stomach.
• ligamentum gastrolienale or gastrosplenicum / gastrosplenic ligament or omentum / splenogastric omentum / gastrolienal or splenogastric ligament : a peritoneal fold extending from the greater curvature of the stomach to the hilum of the spleen
• omentum minus / lesser omentum or epiploon / gastrohepatic omentum / Willis' pouch : a peritoneal fold joining the lesser curvature of the stomach and the first part of the duodenum to the porta hepatis.
• lesser omentum / ligamentum hepatogastricum / hepatogastric ligament : a peritoneal fold, part of the lesser omentum, that passes from the under surface of the liver to the lesser curvature of the stomach.
• epiploic or omental foramen / foramen omentale or epiploicum : the opening connecting the greater and the lesser peritoneal sacs, situated below and behind the porta hepatis
• pancreaticosplenic omentum : a fold of peritoneum connecting the tail of the pancreas and the visceral surface of the spleen.
• pericolic membrane : occasional bands of peritoneum extending between the abdominal wall and the serosa of the colon
• plica paraduodenalis / paraduodenal fold : an occasionally found peritoneal fold containing a branch of the left colic artery
• Treitz's arch : an arch sometimes found in the paraduodenal fold, composed of the left superior colic artery and the inferior mesenteric vein
Cell types : serous cell
• ligamentum teres hepatis : a fibrous cord, the remains of the left umbilical vein, extending from the porta hepatis, where it is attached to the left branch of the portal vein, out through the fissure of the ligamentum teres and the falciform ligament to the umbilicus.
• fascia of Camper : the superficial layer of the superficial fascia of the abdomen.
• Cloquet's fascia : the condensation of extraperitoneal tissue closing the femoral ring (septum femorale).
• Treitz's fascia : fascia posterior to the head of the pancreas
• subperitoneal or extraperitoneal fascia or tissue / fascia extraperitonealis or subperitonealis : the thin layer of areolar connective tissue separating the parietal peritoneum from the abdominal walls
• Richet's fascia : a fold of extraperitoneal fascia enveloping the obliterated umbilical vein
• exocrine stomach / gaster / ventriculus (see also diseases of stomach and physiology of endocrine stomach) :  the musculomembranous expansion of the alimentary tract between the esophagus and the duodenum. Food mixed with gastric secretion forms a semifluid substance (chyme) suitable for further digestion by the intestine.

Macroscopic anatomy :
• hypertonic
• orthotonic
• hypotonic
• atonic
Areas :
• cardiac stomach : the portion of the stomach close to the esophagus
• curvatura major gastris / curvatura gastrica major / greater curvature of stomach / greater gastric curvature : the left or lateral and inferior border of the stomach, marking the inferior junction of the anterior and posterior surfaces
• curvatura minor gastris / curvatura gastrica minor / lesser curvature of stomach / lesser gastric curvature : the right or medial border of the stomach, marking the superior junction of the anterior and posterior surfaces
• cardia / pars cardiaca gastris / cardiac or cardial part of stomach : the part of the stomach immediately adjacent to and surrounding the cardiac opening of the esophagus, distinguished only by the presence of the cardiac glands, and lacking acid (parietal) and pepsin (chief) cells
• incisura cardialis / cardial or cardiac notch of stomach / incisura cardiaca gastris : a notch at the junction of the esophagus and the greater curvature of the stomach
• fundus gastricus / gastric fundus / fundus of stomach / fundus ventricularis / fundus ventriculi : that part of the stomach to the left and above the level of the entrance of the esophagus
• fornix gastricus / gastric fornix / fornix of stomach / fornix ventricularis / fornix ventriculi : a term used in radiographic anatomy to refer to the arch of the fundus of the stomach
• body of stomach / corpus ventriculare, ventriculi or gastricum / gastric body : that part of the stomach between the fundus and the pyloric part
• antrum pylori or pyloricum / pyloric, Willis or gastric antrum : the dilated portion of the pyloric part of the stomach, between the body of the stomach and the pyloric canal
• ligamenta pylori / ligaments of Helvetius : thickened bands of the longitudinal muscular layer of the stomach situated on the anterior and the posterior surfaces of the antrum pyloricum
• pyloric canal / canalis pyloricus : the short, narrow part of the stomach extending from the gastroduodenal junction to the pyloric antrum
• pylorus : the distal aperture of the stomach surrounded by a strong band of circular muscle, and through which the stomach contents are emptied into the duodenum. It is variously used to mean pyloric part of the stomach, pyloric antrum, pyloric canal, pyloric opening, and pyloric sphincter.
• prepyloric sphincter : a band of muscle fibers in the wall of the stomach proximal to the pyloric sphincter.
• valvula pylori / pyloric valve : a prominent circular fold of mucous membrane at the pyloric orifice of the stomach
• pyloric sphincter / musculus sphincter pyloricus : a thickening of the circular muscle of the stomach around its opening into the duodenum
• incisura angularis gastris or ventriculi / angular incisure or notch of stomach / gastric notch : the lowest point on the lesser curvature of the stomach, marking the junction of the cranial two-thirds and caudal one-third of the stomach
Coats :
• tunica mucosa gastris

Inner look :
• pliques
• longitudinal pliques in small curve
• cerebroid pliques in large curve
• areoles result from tone of muscularis mucosae
• areae gastricae / gastric areas : small patches of gastric mucosa, 1 to 5 mm in diameter, separated by the plicae villosae and containing the foveolae (gastric pits); they present a reticular pattern on endoscopy and double-contrast radiography
Cell types :
• stomach lining mucous cells : EP₃ and M₃ on basolateral membrane
• glands :
• cardiac glands : mucin-secreting glands at the cardiac end of the stomach surrounding the entrance of the esophagus into the stomach; they are similar to pyloric glands
• fundic glands / fundus glands / gastric glands : numerous branched simple tubular glands located in the mucosa of the fundus and body of the stomach; they consist of mucous neck cells, principal cells, parietal cells, and enteroendocrine cells
• intermediate glands : in a narrow region between the fundic and pyloric glands
• pyloric glands / glandulae pyloricae : the mucin-secreting glands of the pyloric part of the stomach; they consist of rare parietal cells and enteroendocrine cells, but have no principal cells
Cell types :
• mucous neck cells : cells found in the necks of gastric glands; they fill the spaces between the parietal cells and are filled with pale transparent granules.
• gastric gland chief or peptic or principal or zymogenic cells secrete
• pepsinogen : 5 types of zymogens of pepsins are known :
• group I pepsinogen / pepsinogen A (PgA)
• pepsinogen 3
• pepsinogen 4
• pepsinogen 5 / pepsinogen F
• group II pepsinogen / pepsinogen C (PgC) / progastricsin is an aspartic protease
• prochymosin / rennin : an aspartatic protease that catalyzes the cleavage of a single bond in casein to form soluble paracasein, which then reacts with calcium to form a curd, insoluble paracasein and is responsible for milk coagulation. It is found in the fourth stomach of the calf and other ruminants in a number of mammalian offspring, but the human genome contains only a pseudogene. A commercial preparation, rennet, is used for making cheese and rennet custards
Pepsin activity is higher at pH = 4. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin, and that pepsinogens A and F are most closely related. 2 aspartates in the center of the cleft, Asp³² and Asp²¹⁵, function as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds autocatalytically at acidic pH by 2 different pathways, a 1-step pathway to release the intact activation segment directly, and a stepwise pathway through a pseudo-pepsin(s). The active-site cleft is large enough to accommodate at least seven residues of a substrate, thus forming S4 through S'3 subsites. Hydrophobic and aromatic amino acids are preferred at the P1 and P'1 positions. Interactions at additional subsites are important in some cases, for example with cleavage of kappa-casein by chymosin. 2 potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors, including steroid hormones.
• pepsin unit : a unit for measuring the proportion of pepsin in the gastric juice.
• gastric gland acid or oxyntic or parietal cells / border cells / Heidenhain's cells : large spheroidal or pyramidal cells that secrete
• hydrochloric acid (H⁺Cl^-)
• intrinsic factor production
They are found scattered along the walls of the gastric glands, with their tapered ends pushed between the chief cells. They express EP₃, H₂, CCK₂, and M₃ on basolateral membrane
Gastric juice :
• [H⁺] = 160 mEq/L => pH = 0.8-1.8
• [K⁺] = 5-10 mmol/L
• acid secretion

	males	females
basal	3.0±2.0 mEq/hr = 0.8±0.6 mEq/hr	2.0±1.8 mEq/hr = 0.6±0.5 mmol/s
maximal	23±5 mEq/hr = 6.4±1.4 mEq/hr	16±5 mEq/hr = 4.4±1.4 mmol/s

Gastric fluid at Weizmann Institute
• tunica submucosa gastris / submucous coat
• tunica muscularis gastris : the muscular coat of the stomach, composed of ...
• circular fibers
• longitudinal fibers
• oblique fibers
Gastric emptying is delayed (=> satiety) by :
• CCK1 receptors on the pyloric sphincter :
• fat-rich meal
• protein-rich meal
• gastrin
• secretin
but not sugar-rich meals
• tunica serosa gastris : the serous coat of the stomach
• gastric pacemaker : a saddle-shaped area of the greater curvature of the stomach at the junction of its proximal and middle thirds, where originate electric potentials which regulate the frequency of gastric contractions.
• exocrine liver / hepar (see also diseases of exocrine liver and physiology of endocrine liver) : a large gland of a dark-red color situated in the upper part of the abdomen on the right side. Its domed upper surface fits closely against and is adherent to the inferior surface of the right diaphragmatic dome, and it has a double blood supply from the hepatic artery and the portal vein. It comprises thousands of minute lobules, the functional units of the liver. Its manifold functions include the storage and filtration of blood, the secretion of bile, the excretion of bilirubin and other substances formed elsewhere in the body, and numerous metabolic functions, including the conversion of sugars into glycogen, which it stores.

While the sexual dimorphism of the liver has been recognized for several decades, scientists are only recently beginning to uncover the genes involved : regulator of sex limitation 1 (Rsl1) and Rsl2 are 2 KRAB-ZFP gene family members that repress male-specific liver gene expression in female mice^ref
Hepatogenesis : the specification of the vertebrate liver is thought to occur in a 2-step process, beginning with the establishment of competence within the foregut endoderm for responding to organ-specific signals, followed by the induction of liver-specific genes. On the basis of expression and in vitro studies, it has been proposed that the Foxa transcription factors establish competence by opening compacted chromatin structures within liver-specific target genes. Foxa1 and Foxa2 (forkhead box proteins A1 and A2) are required in concert for hepatic specification in mouse. In embryos deficient for both genes in the foregut endoderm, no liver bud is evident and expression of the hepatoblast marker AFP is lost. Furthermore, Foxa1/Foxa2-deficient endoderm cultured in the presence of exogenous FGF2 fails to initiate expression of the liver markers albumin and transthyretin. Thus, Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis^ref.
Coats :
• tunica fibrosa hepatis / fibrous tunic of liver : the fibroelastic layer that surrounds the liver beneath the peritoneum; it is continuous at the hepatic portal with the perivascular fibrous capsule.
• tunica serosa hepatis : serous coat of the liver.
• area nuda hepatis / bare area of liver : the superior surface of the liver, adjacent to the diaphragm, that lacks a peritoneal covering; its boundaries are formed by the hepatic coronary ligament proper and the triangular ligaments
• fossa ductus venosi : fossa of ductus venosus: an impression on the posterior part of the diaphragmatic surface of the liver in the fetus, lodging the ductus venosus
• fossa sagittalis sinistra hepatis : a longitudinal fissure in the left lobe of the liver, composed of the fossa venae umbilicalis in front and the fossa ductus venosi dorsally
• fossa vesicae biliaris / fossa of gallbladder / fossa vesicae felleae : the fossa on the posteroinferior surface of the liver that lodges the gallbladder and helps to separate the right and left lobes
• fossae sagittales hepatis :
• fossae sagittales dextrae hepatis : a longitudinal fissure in the right lobe of the liver.
• fossa sagittalis sinistra hepatis : a longitudinal fissure in the left lobe of the liver, composed of the fossa venae umbilicalis in front and the fossa ductus venosi dorsally.
Cell types :
• hepatocytes / liver, hepatic or parenchymal cells (70%) are arranged in cords between the capillaries and remain after liver transplantation
• synthetize many proteins :
• albumin
• clotting factors
• haptoglobin
• produce bile and secrete it into smal channels (bile canaliculi) between adjacent hepatocytes. The bile collects in bile ducts formed by biliary epithelial cells and drains from the liver into the gallbladder (or, if the gallbladder has been removed, bile drains directly into the duodenum).
• regulate carbohydrate, fat, and protein metabolism
• detoxify the ammonia product of nitrogen metabolism
• break down drugs
• cholangiocytes are modified hepatocytes gGT⁺ secreting bile
• non parenchymal cells (NPC) are eventually exchanged with host cells after liver transplantation
• sinusoidal cells
• endothelial cells :
• sinusoidal endothelial fenestrae (SEF)
• Kupffer cells / stellate cells of the liver (2%; placed between endothelial cells or into lumen of sinusoids. Their nucleus is more vesicular than that of endothelial cells. After a liver transplant, these cells come from the RES of the recipient)
... line the sinusoids, thus separating hepatocytes from blood
• perisinusoidal space of Disse contains :
• plasma allowing exchange of plasma proteins, nutrients, and metabolites
• Ito cells / stellate lipocytes / interstitial cells / fat- or vitamin A-storing cells of liver : they also synthesize collagen and may be involved in hepatic tissue repair and be responsible for the excess collagen produced in liver cirrhosis.
• pit cells
• liver stem cells
Microscopic anatomy :
• hepatic or portal triads : the grouping of the tributaries of the hepatic artery, vein, and bile duct at the angles of the lobules of the liver (portal area / portal space). It is a complex composed of :
• terminal hepatic vein (THV) (branches of the portal vein)
• terminal branches of hepatic artery
• bile duct : bile flows in direction opposite to blood
• nerve
• liver lobules / lobuli hepatitis
• "classic" or traditional liver lobule : the unit drained by a central vein
• portal lobule : the unit supplied and drained by a portal triad
• liver acinus : the unit supplied and drained by terminal branches of portal triad vessels

Macroscopic topographic anatomy : segments are defined according to vascular marks detected during imaging (e.g. falciform ligament, plane of middle hepatic vein, ..). Each segment has a proper segmental root consisting of vascular afferences (portal vein branch and hepatic artery branch) and biliary efferences. At hilus both porta vein and hepatic artery divide into right and left branches. 45% has anatomical variants (e.g. hepatic artery from mesenteric artery, portal trifurcation, ...). Oxygenated blood enters the liver from the heart via the hepatic artery (25%) and from the gut via the hepatic portal vein (75%), mixes in the sinusoids, and drains via the hepatic central vein back to the heart. Hepatic sphincter is a thickened portion of the muscular coat of the hepatic veins near their entrance into the inferior vena cava. In 80% of cases the middle and left suprahepatic veins join and then the right ones joins to the common trunk.
Old anatomical terminology :
• lobus hepatis sinister / left lobe of liver : the smaller of the 2 main lobes of the liver. Anteriorly, it is separated from the right lobe by the falciform ligament. Posteroinferiorly, it is separated from the caudate and quadrate lobes by the attachment of the gastrohepatic ligament and the ligamentum teres
• lobus hepatis dexter / right lobe of liver : the largest of the 4 lobes of the liver. Anteriorly, it is separated from the left lobe by the falciform ligament. Posteroinferiorly, it is separated from the caudate lobe by the inferior vena cava and from the quadrate lobe by the gallbladder. Used in the broad sense, the term includes the caudate and quadrate lobes
• appendicular or linguiform Riedel's lobe : an anomalous tongue-shaped mass of tissue projecting from the right lobe of the liver
Macroscopic functional and surgical anatomy (Coinaud's segments (CS), 1957) : 3 vertical planes that divide the liver into 4 segments and of a transverse scissura that further subdivides the segments into 2 subsegments each. The 2 hemilivers are divided by Cantile's cholecystocleaving line / middle portal scissure (an ideal line joining the middle suprahepatic vein (approximated radiologically as the left border of the inferior vena cava (IVC)) and the gallbladder)
• segment I = caudate lobe
• processus caudatus hepatis / caudate process : the right of the 2 processes seen on the caudate lobe of the liver.
• processus papillaris hepatis / papillary process of liver / Spiegel's lobe : the left of the 2 processes seen on the caudate lobe of the liver.
Surgeons have divided the caudate lobe into 3 parts: papillay process, caudate process, and the paracaval portion corresponding to the dorsally located parenchyma in front of the inferior vena cava. All 3 parts are supplied by primary branches originating from the left and right portal veins, including the hilar bifurcation area : this double vascularization explains why the caudate lobe hypertrophies during cirrhosis. The hilar bifurcation branch often (50%) supplies the paracaval portion and it sometimes (29%) extends its territory to Spiegel's lobe. It was postulated by Couinaud that the paracaval portion or the S9 is not defined by its supplying portal vein branch but by its 'dorsal location' in the liver. Couinaud's caudate lobe or dorsal-liver concept cause, and still now causes, great logical confusion for surgeons^ref.
• right liver : divided by the right suprahepatic vein / right portal scissure (an ideal line joining the right border of the inferior vena cava with the midpoint of the line joining right liver border and gallbladder fundus) into ...
• right paramedian sector: divided by the right branch of the portal vein into ...
• segment VIII / right anterosuperior segment = vascularized by the upper branch of the anterior branch of the right branch of the portal vein
• segment V / right anteroinferior segment  = vascularized by the lower branch of the anterior branch of the right branch of the portal vein
• right posterolateral (posterior in vivo and lateral in vitro) sector
• segment VII / right posterosuperior segment  = vascularized by the upper branch of the posterior branch of the portal vein
• segment VI / right posteroinferior segment = vascularized by the lower branch of the posterior branch of the portal vein
• left liver : divided by the left suprahepatic vein / left portal scissure (an ideal line joining the left border of the inferior vena cava to the midpoint of left hepatic border) into ...
• left posterolateral sector (posterior in vivo and lateral in vitro) = segment II
• left medial sector = separated by the falciform ligament into ...
• segment III / left anterolateral segment
• segment IV = lobus quadratus hepatis / quadrate lobe of liver : a small lobe of the liver bounded on the right by the gallbladder, which separates it from the right lobe, and on the left by the ligamentum teres, which separates it from the left lobe. It is sometimes divided by the portal vein into :
• IVA / left superomedial segment
• IVB / left inferomedial segment


• Goldsmith-Woodburne classification (1957) names Coinaud's sectors as segments, and Coinaud's segments as subsegments.
• Liebermeister's grooves : developmental grooves on the surface of the liver.
• portal vein segments (PVS)
A major obstacle to coherent terminology for liver anatomy and resections has been that American and French anatomists have divided the left side of the liver through different planes. Couinaud divided the left hemiliver into "sectors" by a plane through the left hepatic vein. Healey and Schroy divided it into "segments" through the umbilical fissure. One anatomic justification for Couinaud's system of sectors is that the transverse portion of the left portal vein was said to terminate by dividing into the umbilical portion of the left portal vein and the vein to segment II. However, corrosion cast studies fail to consider the position of the ligamentum venosum, the structure defining the end of the transverse portion of the left portal vein. Therefore, it is uncertain whether the branch to segment II is a terminal branch of the transverse portion of the left portal vein or a branch of the first part of the umbilical portion. Ten cadaver livers were dissected to determine the position of the branch to segment II in relation to the ligamentum venosum. In all, the branch to segment II came off downstream to the ligamentum venosum, showing that it is a branch of the umbilical portion of the left portal vein. This study does not support the "sectoral" system of Couinaud on the left side of the liver. Division of the left side of the liver through the umbilical fissure as proposed by Healey is anatomically logical and fits well with common surgical resections^ref.

• biliary apparatus : the parts concerned in the formation, conduction, and storage of bile, including :
• the secreting cells of the liver
• biliary ways
• intrahepatic bile ducts
• cholangiole / bile or biliary ductule / bile capillary : one of the fine terminal elements of the bile duct system, leaving the portal canal, and pursuing a course at the periphery of a lobule of the liver
• ductuli interlobulares / interlobular ductules / ductus interlobulares / interlobular biliary canals / bile ducts : small channels between the hepatic lobules, draining into the bile ductules
• ductuli biliferi / bile ductules or vessels / ductus biliferi / biliary ductules : the small channels that connect the interlobular ductules with the right and left hepatic ducts
The phenotypic similarity between cytokine-stimulated human intrahepatic biliary epithelial cells (HIBEC) and a known APC is consistent with a potential role for biliary epithelial cells in antigen presentation^ref.
• extrahepatic bile ducts
• ductus hepaticus dexter / right hepatic duct : the duct that drains the right lobe and part of the caudate lobe of the liver.
• ductus lobi caudati dexter : the right duct of the caudate lobe of the liver.
• ductus hepaticus sinister / left hepatic duct : the duct that drains the left and quadrate lobes and part of the caudate lobe of the liver.
• ductus lobi caudati sinister : the left duct of the caudate lobe of the liver.
• ductus hepaticus communis / common hepatic duct : the duct which is formed by union of the right and left hepatic ducts, and in turn joins the cystic duct to form the common bile duct.
• Mirizzi's sphinter in common hepatic duct
• ductus cysticus / cystic duct / duct of gallbladder : the passage connecting the neck of the gallbladder and the common bile duct
• ductus choledochus / choledochous duct / biliary duct / common bile duct (CBD) / ductus biliaris / hepatic funiculus / hepatocystic duct : the duct formed by union of the common hepatic and the cystic ducts which empties into the duodenum at the major duodenal papilla, along with the pancreatic duct
• retropancreatic portion
• suprapancreatic portion
• glandulae ductus choledochi / glands of bile duct / biliary glands / glandulae biliaris / glandulae ductus biliaris / glandulae hepaticae / glandulae mucosae biliosae / hepatic glands : tubuloacinar glands in the mucosa of the bile ducts and the neck of the gallbladder
• sphincter of Boyden : a superior choledochal sphincter encircling the common bile duct just proximal to the duodenum.
• sphincter of Oddi / Oddi's muscle / sphincter muscle of hepatopancreatic ampulla / Glisson's sphincter : muscle fibers investing the hepatopancreatic ampulla in the wall of the duodenum; the combination of
• musculus sphincter ampullae hepatopancreaticae :
• musculus sphincter ductus choledochi / musculus sphincter ductus biliaris : an annular sheath of muscle that invests the bile duct within the wall of the duodenum.
• gall-bladder / vesica biliaris / cholecyst / cystis fellea / vesica fellea : the pear-shaped reservoir for the bile on the posteroinferior surface of the liver between the right and quadrate lobes; from its neck, the cystic duct projects to join the common bile duct (see also diseases of gall-bladder)
• fundus vesicae biliaris / fundus of gallbladder / fundus vesicae felleae : the inferior dilated portion of the gallbladder
• infundibulum vesicae biliaris
• Lütkens' sphincter : a thickening of the muscle fibers in the neck of the gallbladder.
• Rokitansky-Aschoff sinuses : small outpouchings of the mucosa of the gallbladder extending through the lamina propria and the muscular layer
• Calot's cystohepatic triangle : the triangle formed by the cystic artery superiorly, the cystic duct inferiorly, and the hepatic duct medially
Cell types :
• gall-bladder epithelial cell

Bile / fel / gall : a fluid secreted by the liver and poured into the small intestine via the bile ducts. Important constituents are
• conjugated bile salts, synthetized in the liver from cholesterol and conjugated to glycine and taurine before secretion via SLC10A1 and SLC10A2
• gall-bladder pool 4÷6 g
• 2÷3 recirculations after every meal
• secretion : 15÷30 g / die
• hepatic neosynthesis - loss = 0.6 g / die
While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs ... :
• activate MAPK pathways, are ligands for
• the G protein-coupled bile acid receptor 1 (GPBAR1) / TGR5
• activate nuclear hormone receptors such as
• pregnane X receptor (PXR) => repression of cholesterol 7a-hydroxylase and the transcriptional induction of cytochrome P450 3a, the bile acid-metabolizing enzyme^{ref1, ref2}
• farnesoid X receptor a (FXR-a; NR1H4). FXR-a regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. Through the activation of farnesoid X receptor bile acids repress the expression of cholesterol 7a-hydroxylase, the rate-limiting enzyme in bile acid synthesis^{ref1, ref2}. The FXR-a-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and VLDL production mediated by SREBP1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. The administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cAMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2^-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-a, and instead are mediated by increased cAMP production that stems from the binding of BAs with the GPCR TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA–TGR5–cAMP–D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control^ref.
In hepatobiliary diseases including obstructive jaundice, viral hepatitis, and primary biliary cirrhosis, the mean serum concentration of bile acids exceeds 100 µM (range, 70-400 µM), whereas normally this remains below 10 µM^ref. At such high concentrations, bile acids are known to exhibit immunosuppressive effects on cell-mediated immunity and macrophage functions^{ref1, ref2, ref3}. The phagocytic capacity of the reticuloendothelial system including Kupffer cells is depressed in cholestasis or obstructive jaundice^ref. Cholestatic jaundice frequently causes infectious complications and endotoxemia, which are closely related to elevated serum bile acid levels^{ref1, ref2}. Furthermore, bile acids including deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) have been demonstrated to have inhibitory activities on the lipopolysaccharide (LPS)-induced production of cytokines in macrophages, including IL-1, IL-6, and TNF-a^{ref1, ref2}. Bile acids suppress macrophage functions via TGR5^ref
• phospholipid
• bilirubin : 6.3 g/day of hemoglobin are catabolyzed and converted to bilirubin, which is then
• monoglucuronated (50%)
• bilirubin diglucuronide (50%)
• electrolytes
• cholesterol
• hepatic pool : 5 g
• esogenous introduction : 250÷1000 mg / die
• endogenous production : 300÷500 mg / die
• 20% is expelled together with biliary salts
• 80% is used in the synthesis of biliary salts
Bile is alkaline due to its bicarbonate content, is golden brown to greenish yellow in color, and has a bitter taste. Bile secreted by the liver is concentrated in the gallbladder. Its formation depends on active secretion by liver cells into the bile canaliculi. Excretion of bile salts by liver cells and secretion of bicarbonate rich fluid by ductular cells in response to secretin are the major factors which normally determine the volume of secretion. Conjugated bile salts and phospholipid normally dissolve cholesterol in a mixed micellar solution. In the upper small intestine, bile is in part responsible for alkalinizing the intestinal content, and conjugated bile salts play an essential role in fat absorption by dissolving the products of fat digestion (fatty acids and monoglycerides) in water soluble micelles
• secretion : 500÷1500 cc / die
• H₂O represents 97.5 % ==reabsorption==> 82 %
• biliary salts : 12 %
• cholesterol : 0.7 %
• phospholipids : 4 %
• others : 1.3 %
• A bile : bile from the common bile duct; samples are obtained by use of a duodenal tube before gallbladder stimulation. It usually contains 20–200 mg. of bilirubin per 100 mL
• B bile : bile from the gallbladder; samples are obtained by use of a duodenal tube after gallbladder contraction stimulation, usually with magnesium sulfate. It may occur despite absence of the gallbladder and contains up to 1 gram of bilirubin per 100 mL
• C bile : hepatic bile; it is obtained from a duodenal drainage tube after the gallbladder has been emptied.
• cystic or gallbladder bile : the bile that is held for some time in the gallbladder before moving into the intestine
• limy bile / milk of calcium bile : bile containing an increased amount of calcium, usually as the carbonate but sometimes as the phosphate or bilirubinate. It varies in consistency from a thick, milky fluid to a putty, gel, or solid. It is usually suspended in a thin, more watery bile
• syncholia : the secretion of substances of exogenous origin in the bile.
• exocrine pancreas (see also diseases of exocrine pancreas and physiology of endocrine pancreas) :  a large, elongated, racemose gland situated transversely behind the stomach, between the spleen and the duodenum. Its right extremity, the head, is larger and directed downward; the neck / isthmus joins the head to the intermediate part, termed body; the left extremity, or tail, is transverse and terminates close to the spleen. It is subdivided into lobules by septa that extend into the gland from the thin, areolar tissue that forms an indefinite capsule. The exocrine part (exocrine pancreas) consists of pancreatic acini, secretory units that produce and secrete into the duodenum pancreatic juice, which contains enzymes essential to protein digestion.
• dorsal pancreas : an embryonic outpocketing or bud from the endodermal lining of the gut on the dorsal wall cephalad to the level of the hepatic diverticulum, which forms most of the pancreas and its main duct
• ventral pancreas : an embryonic outpocketing or bud from the endodermal lining of the gut on the ventral wall, in the caudal angle between the gut and the hepatic diverticulum, which forms the head of the pancreas and the stem of its main duct
• processus uncinatus pancreatis / uncinate process of pancreas / lesser pancreas / Willis' or Winslow's pancreas : the left and caudal part of the head of the pancreas, which hooks around behind the pancreatic vessels
• pancreas accessorium / accessory pancreas : an inconstant separate part of the head of the pancreas, usually an unattached uncinate process.
• ductus pancreaticus / pancreatic duct / duct or canal of Wirsung / hepaticopancreatic duct : the main excretory duct of the pancreas, which usually unites with the common bile duct before entering the duodenum at the major duodenal papilla
• ductus pancreaticus accessorius / accessory pancreatic duct / minor pancreatic duct / duct of Santorini or Bernard : a small inconstant duct draining a part of the head of the pancreas into the minor duodenal papilla
Cell types :
• pancreatic acinar or acinic or acinous cell (HCO₃^- and enzyme-secreting)
• pancreatic lipase (PNLIP)
• pancreatic colipase (CLPS)
• elastase 1, pancreatic (ELA1)
• pancreatic elastase IIB (ELA2B)
• elastase 3A, pancreatic (protease E) (ELA3A)
• elastase 3B, pancreatic (ELA3B)
• regenerating islet-derived 1 alpha (pancreatic stone protein, pancreatic thread protein) (REG1A)
• regenerating islet-derived 1 beta (pancreatic stone protein, pancreatic thread protein) (REG1B)
• regenerating islet-derived-like, pancreatic stone protein-like, pancreatic thread protein-like (rat) (REGL)
• pancreatic ductal or centroacinal cell
• principal or Wirsung's duct
• accessory or Santorini's duct
• in 66% of cases it goes directly in duodenum
• in 33% of cases it goes into Wirsung's duct
• exocrine pancreas stem cells
Secretions : 1,500-2,000 mL / die. Stimulated by secretin
• exocrine bowel / intestinum / intestine / gut (see also diseases of exocrine bowel and physiology of endocrine bowel) : the portion of the alimentary canal extending from the pyloric opening of the stomach to the anus: it is a membranous tube, comprising the intestinum tenue and the intestinum crassum, whose function is to complete the processes of digestion, to provide the body (through absorption) with water, electrolytes, and nutrients, and to move along and store fecal wastes until they are expelled
• siqua [coined from L. sidentis altitudinis quadratio, the square of the sitting height] : Pirquet's unit for calculating the area of the absorptive surface of the intestine; it is the square of the sitting height (in centimeters)
Cell types :
• enterocyte / intestinal absorptive cell (GM₁ ganglioside⁺) : BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number. BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through PI-3K–Akt, mediates the convergence of the BMP and Wnt pathways on control of b-catenin^ref
• glandulae intestinales / intestinal glands / crypts or glands of Lieberkühn / Lieberkühn's or intestinal follicles : simple tubular glands in the mucous membrane of either the small intestine (glandulae intestinales intestini tenuis), opening between the bases of the villi and containing argentaffin cells; the large intestine (glandulae intestinales intestini crassi); or of the rectum (glandulae intestinales intestini recti)
• zona transformans / transformation zone / Turck's zone : the connective tissue layer of the intestinal wall where bacteria penetrating from the intestine are destroyed
• Heller's plexus : an arterial network in the submucosa of the intestine.
Anatomy :
• small bowel / intestinum tenue / small intestine / enteron (see also diseases of small bowel) : the proximal portion of the intestine, smaller in caliber than the large intestine, and about twenty feet long, extending from the pylorus to the cecum
• villi intestinales / intestinal villi : the multitudinous threadlike projections that cover the surface of the mucosa of the small intestine and serve as the sites of absorption (by active transport and diffusion) of fluids and nutrients.

Cell types :
• enterocyte / intestinal absorptive cell (GM₁ ganglioside⁺)
• goblet cells / beaker cells / caliciform cells / chalice cells : a unicellular mucous gland found in the epithelium of intestines. Droplets of mucigen collect in the upper part of the cell and distend it, while the basal end remains slender, and the cell assumes the shape of a goblet
• crypts of Lieberkühn / glandulae intestinales intestini tenuis

Cell types :
• undifferentiated cells
• goblet cells / beaker cells / caliciform cells / chalice cells : a unicellular mucous gland found in the epithelium of intestines. Droplets of mucigen collect in the upper part of the cell and distend it, while the basal end remains slender, and the cell assumes the shape of a goblet
• enteroendocrine cells
• Paneth cell / Davidoff's (Davidov's) cells : narrow, pyramidal, or columnar epithelial cells with a round or oval nucleus close to the base of the cell, occurring in the fundus of the crypts of Lieberkühn; they contain large secretory granules that may contain peptidase, lysozyme and defensins
• M cell (MHC II^-, costimulatory molecules^-, GM₁ ganglioside⁺) (10÷50 %). They are used for IgA-mediated transcytosis of lumenal particles into the underlying lymphoid tissue of the Peyer's patches and follicles in lamina propria, where APCs present Ags to T_h cells. Their apical and basolateral surfaces have distinct features that enable them to rapidly and efficiently deliver mucosal Ags from the lumen to underlying leukocytes. For example, M cells lack the well-developed brush border and thick glycocalix present on enterocytes^ref. Consequently, M cell apical membranes are more accessible to particles, viruses, and bacteria than adjacent enterocytes. Bacteria and other large particles induce modifications of the apical plasma membrane of the M cell and rearrangement of the acin cytoskeleton, which then mediates the formation of pseudopodia-like structures that reach deep into the lymphoid area underneath. Viruses and other adherent particles are endocytosed through clathrin-coated vesicles, and non-adherent material is internalized by fluid-phase endocytosis^ref. The mechanisms used for the active uptake of antigen by M cells have evolved from polarized transport mechanisms that are actie in the surrounding absorptive epithelial cells, demonstrating their enterocyte origin^ref. In addition, the number of M cells rapidly increases after microbial challenge, promoting enhanced uptake of specific pathogen antigens to ensure effective immune responses^ref. M cells do not process the antigens, but deliver them through basolateral long protrusions that make direct contact with the lymphoid cells underneath. The M cell basolateral membrane is deeply invaginated to form a large intraepithelial pocket containing both B and T lymphocytes and occasional dendritic cells. The pocket brings the M cell basolateral surface to within a few microns of the apical surface, shortening the distance that transcytotic vesicles must travel to cross the epithelium. There is evidence that neonatal and adult M cells express an IgA receptor (different from pIgR and requiring domains C_a1 and C_a2) on their apical surfaces that functions in the binding and transepithelial transport of Abs from secretions to the GALT
Anatomy :
• duodenum : the first or proximal portion of the small intestine, extending from the pylorus to the jejunum; so called because it is about 12 fingerbreadths in length.
• pars superior duodeni / superior part of duodenum : the part of the duodenum adjacent to the pylorus, forming the superior flexure.
• duodenal ampulla / ampulla duodeni / duodenal cap : the superior part of the duodenum, as seen radiographically after a barium meal. A true duodenal ampulla is seen in some domestic mammals.
• flexura duodeni superior / superior flexure of duodenum / superior angle of duodenum : the bend in the first or superior part of the duodenum
• pars descendens duodeni / descending part of duodenum : the part between the superior and inferior parts, into which the bile and pancreatic ducts open.
• hepatopancreatic ampulla / ampulla hepatopancreatica / biliaropancreatic ampulla / ampulla biliaropancreatica / ampulla of Vater : the dilatation formed by junction of the common bile and the pancreatic ducts proximal to their opening into the lumen of the duodenum
• flexura duodeni inferior / inferior flexure of duodenum / inferior angle of duodenum : the bend in the duodenum at which the descending duodenum becomes horizontal or transverse
• pars horizontalis duodeni / horizontal part of duodenum / pars inferior duodeni / inferior part of duodenum : the part of the duodenum between the descending and ascending parts, crossing from right to left ventral to L3
• pars ascendens duodeni / ascending part of duodenum : the terminal part of the duodenum, ending at the duodenojejunal flexure.
Cell types :
• Brunner's glands / Galeati's glands / glandulae duodenales Brunneri / duodenal glands : tubuloacinar glands in the submucous layer of the duodenum that open into the crypts of Lieberkühn; they secrete urogastrone, HCO₃^- and enzymes
• flexura duodenojejunalis / duodenojejunal flexure : the bend in the small intestine at the junction between the duodenum and jejunum; the suspensory muscle of the duodenum attaches to this point
• intestinum tenue mesenteriale : the portion of the small intestine which has a mesentery
• (intestinum) jejunum : that portion of the small intestine which extends from the duodenum to the ileum; so called because it is empty in the cadaver
• (intestinum) ileum : the distal portion of the small intestine, extending from the jejunum to the cecum. It absorbes :
• carbohydrates, proteids and lipids are absorbed in duodenum > jejunum > ileum
• Fe²⁺, Ca²⁺ and folates are absorbed in duodenum > jejunum
• vitamin B₁₂ is absorbed in ileum
• biliary salts are reabsorbed in duodenum < jejunum < ileum
Movements :
• pendular movement : one of the movements of the small intestine in digestion, consisting of a gentle swinging to and fro of the different loops; these movements are ascribed to rhythmical contractions of the longitudinal muscles
• segmentation movement : one of the movements of the small intestine in digestion, consisting of small, irregular or rhythmic, circular contractions that segment a portion of the intestine into evenly spaced parts somewhat resembling a string of sausages
• ileocecal junction : the junction of the ileum and cecum, located at the lower right side of the abdomen and fixed to the posterior abdominal wall.
• valva ileocaecalis / ileocecal valve / ileocolic valve / valva ilealis / valvula ileocolica : a so-called valve formed by the flaps or lips, one above and one below, of the ileocecal opening. In the cadaver the flaps project into the lumen of the large intestine as thickened folds, but in the living individual the ileum forms a conical or papillary projection, the papilla ilealis
• frenulum valvae ileocaecalis / frenulum of ileocecal valve / frenulum valvae ilealis / frenum of Morgagni : a fold formed by the joined extremities of the ileocecal valve, extending partly around the lumen of the colon
• large bowel / intestinum crassum / large intestine : the distal portion of the intestine, about 5 feet long, extending from its junction with the small intestine to the anus (see also diseases of large bowel). Each day about 600 ml (2 pints) of chyme leave the small intestine and enter the colon
• cecocolon : the cecum and colon considered as a unit
• intestinum caecum / caecum / cecum / blindgut / blind intestine : the first part of the large intestine, forming a dilated pouch into which open the ileum, colon, and appendix vermiformis
• appendix vermiformis / vermiform appendix : a wormlike diverticulum of the cecum, varying in length from 7 to 15 cm, and measuring about 1 cm in diameter.
• aggregated lymphoid nodules of vermiform appendix
• valvula processus vermiformis : an inconstant fold of mucous membrane at the opening into the cecum of the canal of the vermiform appendix.
• colon : that part of the large intestine which extends from the cecum to the rectum; sometimes used inaccurately as a synonym for the entire large intestine.
• colon ascendens / ascending colon : the portion of the colon between the cecum and the right colic flexure.
• flexura coli dextra / flexura coli hepatica / flexura hepatica coli / hepatic or right flexure of colon : the bend in the large intestine at which the ascending colon becomes the transverse colon
• colon transversum / transverse colon : the portion of the colon that runs transversely across the upper part of the abdomen, from the right to the left colic flexure.
• flexura coli sinistra / left or splenic flexure of colon / flexura lienalis coli : the bend in the large intestine at which the transverse colon becomes the descending colon
• colon descendens / descending colon : the portion of the colon between the left colic flexure and the sigmoid colon at the pelvic brim; the portion of the descending colon lying in the left iliac fossa is sometimes called the iliac colon
• iliac colon : that part of the descending colon lying in the left iliac fossa and continuous with the sigmoid colon.
• colon sigmoideum / sigmoid or pelvic colon / sigmoid flexure : the S -shaped part of the colon which lies in the pelvis, extending from the pelvic brim to the third segment of the sacrum, and continuous above with the descending (or iliac) colon and below with the rectum
• left colon : the distal portion of the colon; it develops embryonically from the hindgut and functions in the storage and elimination of waste.
• right colon : the proximal portion of the colon, extending from the ileocecal valve usually to a point proximal to the left colic flexure; it develops embryonically from the terminal portion of the midgut and functions in absorption.
• haustra coli / haustra of colon : sacculations in the wall of the colon produced by adaptation of its length to that of the tenia coli, or by the arrangement of the circular muscle fibers.
• haustral segmentation : the formation of pouches in the wall of the large intestine, by alternating contraction and relaxation of circular muscle fibers. It keeps the intestinal contents plastic and assists in propelling them toward the rectum.
• (intestinum) rectum : the distal portion of the large intestine, beginning anterior to the third sacral vertebra as a continuation of the sigmoid and ending at the anal canal
• plicae transversae or transversales recti / transverse folds of rectum / Houston's valves : permanent transverse folds in the rectum, usually three in number (2 on the left and 1 on the right), involving the tunica mucosa and tela submucosa, and the circular layer of the tunica muscularis
• flexura anorectalis recti / anorectal or perineal flexure of rectum / flexura perinealis recti : the dorsal and caudal bend at the caudal end of the rectum
• flexura sacralis recti / sacral flexure of rectum : the dorsal first bend in the rectum.
• rectal ampulla / ampulla recti : the dilated portion of the rectum just proximal to the anal canal.
• Hyrtl's rectal sphincter : an incomplete band or thickening of the muscle fibers in the rectum a few inches above the anus in the upper part of the rectal ampulla
• Nélaton's sphincter : an occasional and often incomplete band of muscle fibers about the rectum at the level of the prostate.
• musculus sphincter ani internus / internal sphincter muscle of anus / internal anal sphincter : a thickening of the circular lamina of the tunica muscularis at the caudal end of the rectum
• Hilton's white line / anal intersphincteric groove : a narrow wavy zone, usually not visible macroscopically but palpable on digital examination, that forms the lower border of the pecten, at the level of the interval between the subcutaneous part of the external anal sphincter and the lower border of the internal sphincter
Coats : tunica mucosa (intestini) recti : the mucous coat of the rectum
Functional division :
• intraperitoneal rectum (3 cm in length; protected by local diffusion of tumors), whose lymphatics drains to upper peduncle
• extraperitoneal or subperitoneal rectum (easier spreading into fatty tissue, blood vessels, sacrum => nerve roots (coccigodynia), whose lymphatics drain into 3 collector ducts (abdominal aortic, aortic, and lateral lymph nodes)
• upper rectum : 11-15 cm above the anus (8-12 cm in surgical classification), vascularized by the superior rectal artery
• middle rectum : 7-11 cm above the anus, up to the second Houston's valve, vascularized by the middle rectal artery
• lower rectum : 0-7 cm above the anus (including anal canal) (3-7 cm in surgical classification), up to the first Houston's valve, vascularized by the inferior rectal artery
• paraproctium : the tissues that surround the rectum and the anus.
• junctio or linea anorectalis / anorectal junction : the site at which the rectum becomes continuous with the anal canal
• anal canal / canalis analis / pars analis recti : the terminal portion of the alimentary canal, extending from the dentate (pectinate) line to the anus. The distance between the dentate line and the anal verge is 2.1 cm (1-3.8 cm). In the surgical classification it starts from the insertion of levator ani muscle = beginning of columns of Morgagni, long on average 4.2 cm (3-5.3 cm)). The lining epithelium transforms from muciparous columnar into cloacogenic (transitional) into modified squamous and finally into keratinized squamous. The lymphatic drainage is to superficial inguinal lymph nodes.
• columnae anales or rectales [Morgagnii] / columni ani / anal or rectal columns / columns of Morgagni / mucous folds of rectum : vertical ridges or folds of mucous membrane at the upper half of the anal canal
• valvulae anales / anal valves : archlike folds of mucous membrane connecting the caudal ends of the anal columns.
• zona hemorrhoidalis / hemorrhoidal zone : that part of the anal canal extending from the anal valves to the anus and containing the rectal venous plexus.
• linea anocutanea / anocutaneous, dentate or pectinate line or margin : the sinuous line following the level of the anal valves and crossing the bases between them, marking the junction of the zone of the anal canal lined with stratified squamous epithelium and that lined with columnar epithelium
• anal verge : the external or distal boundary of the anal canal; the line where the walls of the anus come in contact during the normal state of apposition.
• anus : the distal or terminal orifice of the alimentary canal.
• circumanal or anal glands / glandulae circumanales / Gay's glands : specialized sweat and sebaceous glands situated in an annular zone around the anus
• musculus sphincter ani externus / external sphincter muscle of anus / external anal sphincter : origin, tip of coccyx, anococcygeal ligament; insertion, tendinous center of perineum; innervation, inferior rectal and fourth sacral; action, closes anus
Cell types :
• surface cell in squamous epithelium of the anal passage
• basal stem cell of squamous epithelium of the anal passage
• saccus profundus perinei / spatium profundum perinei / deep perineal pouch or space : the region superior (deep) to the perineal membrane and extending into the pelvis
• saccus subcutaneus perinei / subcutaneous perineal pouch : a potential space between the membranous layer of the perineal subcutaneous tissue and the superficial layer of the fascia of the perineal muscles.
• defecation : the evacuation of fecal material from the rectum. Defecation usually arises when gastrocolic reflex or orthocolic reflex push at least 90÷120 mL of stools in rectal bulb : sampling of material is an autonomic response acquired since age 1.
• defecation or rectal reflex : the process by which the accumulation of feces in the rectum excites defecation
• rectoanal inhibitory reflex : relaxation of the internal anal sphincter in response to increased pressure in the rectum; it can be tested by inflating a balloon in the lumen. It is absent in cases of congenital megacolon.
Stools / faeces :
• bacteria : > 50% mass
• water : 100 mL/die
• potassium : 8 mEq/die
• iodine : 20 mg/die
• nitrogen : < 2 g/die or < 10% azoturia
• lipids < 5 g/die or < 4% lipids in a 3 days-diet
• skatole : a crystalline amine, with a strong characteristic odor, from human feces. It is produced by the decomposition of proteins in the intestine and directly from the amino acid tryptophan by decarboxylation.
• ethyl mercaptan : a thioalcohol which has a revolting odor and contributes to the odor of feces.
• Nothnagel's bodies : oval or round bodies, plain or striated, from 15 to 60 mm in diameter, sometimes found in the stools of persons who eat meat
Web resources : Stools at Weizmann Institute
Movements : vermicular movements : the wormlike movements of the intestines in peristalsis.
• physiological reflexes :
• vomiting reflex : vomiting due to reflexive stimulation of muscles of the gastrointestinal tract and throat, allowing their contents to be forcibly expelled; it is mediated by centers in the medulla oblongata and can be set in motion by many different stimuli such as touching the back of the pharynx.
• faucial reflex : reflex vomiting caused by irritation of the fauces,
• abdominocardiac reflex : any reflex in the heart produced by stimulating the abdominal sympathetic nerves
• enterogastric reflex : inhibition of gastric motility when irritants enter the duodenum.
• epigastric reflex : contraction of the abdominal muscles caused by stimulating the skin of the epigastrium or over the fifth and sixth intercostal spaces near the axilla
• gastrocolic reflex : an increase in intestinal and colonic peristaltic activity following entrance of food into the empty stomach
• gastroileal reflex : an increase in ileal motility and opening of the ileocecal valve when food enters the empty stomach
• gastropancreatic reflex : an increase in pancreatic secretion induced by distention of the corpus of the stomach; it is mediated by the vagus nerve
• ileogastric reflex : inhibition of gastric motility by distention of the ileum
• intestinointestinal reflex : when a part of the intestine becomes overdistended or its mucosa becomes excessively irritated, activity in other parts of the intestine is inhibited as long as the distention persists
• peristaltic reflex : when a portion of the intestine is irritated or distended, the area just proximal contracts and the area just distal relaxes
• peritoneointestinal reflex : inhibition of motility of the stomach and intestine resulting from retroperitoneal irritation or hemorrhage
• renointestinal reflex : inhibition of motility of the intestine resulting from renal irritation
• somatointestinal reflex : inhibition of intestinal motility when the skin over the abdomen is stimulated.
• swallowing : deglutition center
• salivation and buccal detersion
• oral stage => palatal, palatine swallowing reflex : stimulation of the palate causes swallowing
• pharyngeal stage
• esophageal stage
• gastric stage
• digestion :
• gastric residuum : the contents of the stomach during the interdigestive period, as in the morning before eating.
• intestinal epithelia : regeneration of the epithelial lining of the stomach and small intestine. Note differences in the location of stem cells.


The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt-villus axis. A rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells occurs after conditional removal of the common Notch pathway transcription factor CSL/RBP-J. A similar phenotype is obtained by blocking the Notch cascade with a g-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that -secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease^ref. The Notch signalling pathway plays a crucial role in specifying cellular fates in metazoan development by regulating communication between adjacent cells. Correlative studies suggested an involvement of Notch in intestinal development. Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium^ref.
The intestinal epithelium represents an exquisite model for the study of stem cell biology and lineage specification. It is likely the simplest mammalian study model for tissue self-renewal, yet it features multipotent stem cells, transit-amplifying compartments, several binary lineage decisions, as well as programmed cell death. The function of the mammalian intestinal epithelium poses formidable challenges that evolution has met, often very elegantly. Like the epidermis of the skin, the intestinal epithelium constitutes a barrier between the body and the outside world (of which the intestinal lumen may be considered a particularly threatening version). Whereas the epidermis consists of multiple layers of cells and cell remnants that are harnessed by robust internal meshes of keratins, the intestinal epithelium consists of a single layer of fragile epithelial cells. These cells digest food and absorb the resulting mix of biological building blocks while keeping indigestible bulk and associated microflora inside the lumen. For this, the intestinal epithelium has distributed divergent biological tasks over only four differentiated cell types. The basic tissue architecture of the mouse intestine is established during mid- to late gestation^ref. At first, a pseudostratified intestinal epithelium of endodermal origin proliferates vigorously. In mice, conversion of this pseudostratified epithelium into a single-layered epithelium occurs around embryonic day 14.5 (E14.5) in a wave that progresses from stomach to colon. The epithelium of the small intestine forms protrusions, the prospective villi, and cell cycling becomes restricted to shallow pockets positioned between these villi. Simultaneously, the surrounding splanchnic mesoderm differentiates into smooth muscle and connective tissue. These processes are completed at E18.5. Around the third week of life, the proliferative pockets invade into the submucosa to form mature crypts of Lieberkühn^ref. The epithelium of the adult small intestine forms a contiguous two-dimensional sheet (Fig. 1). New cells are added in the crypts and removed by apoptosis upon reaching the villus tips a few days later^ref. Stem cells and Paneth cells at the crypt bottom escape this flow^ref. Although intestinal stem cells cannot currently be studied ex vivo and no unique in vivo markers are available, they can be labeled with ³H-thymidine or bromodeoxyuridine during early postnatal life or after irradiation^ref. Long-term label retention and the study of mouse chimeras^{ref1, ref2} and postinjury regeneration have allowed an operational definition of stem cell characteristics. Stem cells of the small intestine occupy position +4, the fourth cell position counting from the crypt bottom [positions 1 to 3 being taken by the Paneth cells (Fig. 1)]. In the colon, Paneth cells are absent, and the stem cells reside directly at the crypt bottom^ref. The epithelial stem cells self-renew throughout life, cycling infrequently to produce vigorously proliferating transit-amplifying cells that fill the remainder of the crypts. Transit-amplifying cells have a very limited self-renewal capacity; after three to four cell divisions, their offspring inevitably differentiates into one of the mature cell lineages. Whereas the shallow neonatal inter-villus pockets are polyclonal, all cells in an adult crypt derive from one stem cell^ref. Committed progenitors differentiate upon reaching the crypt-villus junction and migrate in colinear bands toward the tips of the villi. Thus, each villus receives inputs from several crypts and is essentially polyclonal^{ref1, ref2}. The surface epithelium of the colon lacks villi: Proliferative cells occupy the bottom two-thirds of colonic crypts, whereas differentiated cells constitute the top third and the surface epithelium. The crypt architecture of the small intestine is compared to that of the colon in Fig. 2.

 Fig. 1. The anatomy of the small intestinal epithelium. The epithelium is shaped into crypts and villi (left). The lineage scheme (right) depicts the stem cell, the transit-amplifying cells, and the two differentiated branches. The right branch constitutes the enterocyte lineage; the left is the secretory lineage. Relative positions along the crypt-villus axis correspond to the schematic graph of the crypt in the center

 Fig. 2. Comparison of normal epithelium and adenomas in murine small intestine and colon. (A) Small intestinal crypt and villus. (B) Colonic crypt and surface epithelium. Proliferative cells are stained for the cell cycle marker Ki67 (brown nuclei) in (A) and (B). (C) An adenoma residing inside a villus of the small intestine of a min mouse. (D) A small aberrant crypt focus in the colon of a min mouse. (C) and (D) are stained for ß-catenin. Note the presence of ß-catenin (in brown) in the cell boundaries of all nondiseased epithelial cells and the accumulation of ß-catenin throughout the cells in the adenoma and aberrant crypt focus
A sheath of specialized fibroblasts is directly apposed to the epithelial crypt cells, separated only by the basal lamina^ref. These so-called myo-epithelial fibroblasts form a syncytium that extends along the intestinal tract. It is believed that these cells are critical to the establishment of the crypt niche, which as discussed above harbors a few stem cells as well as a much larger number of transit-amplifying cells and Paneth cells. The crypt epithelium shapes the underlying myo-epithelial meshwork through secreted Hedgehog signals^ref. Very little is known about putative reverse signals emanating from the myo-epithelial fibroblasts. Moreover, although a specialized stem cell niche is likely to exist within crypts, such a niche has not been identified yet by either morphological or molecular criteria. Two main lineages of differentiated cell types are discerned within the intestinal epithelium: the enterocyte or absorbtive lineage and the secretory lineage. The latter lineage encompasses goblet cells, the enteroendocrine lineage, and Paneth cells (Fig. 1). Enterocytes are abundant in the small intestine, secreting hydrolases and absorbing nutrients. Goblet cells, secreting protective mucins, increase in numbers from duodenum to the colon. Enteroendocrine lineage cells can be further subdivided on the basis of the hormones they secrete, e.g., serotonine, substance P, or secretin^{ref1, ref2}, and these represent a small proportion (< 1%) of all cells. Paneth cells occur only in the small intestine and reside at the crypt bottom. Paneth cells secrete antimicrobial agents such as cryptdins and defensins and lysozyme to control the microbial content of the intestine^{ref1, ref2}. About 50% of the Western population develops an adenomatous polyp by the age of 70. Some of these will progress to cancer, and the lifetime cancer risk is estimated to be 5%^ref. From a molecular-genetic perspective, CRC is likely the best-understood solid malignancy, which relates to the accessibility of the tumors and the fact that different stages of the same malignancy can coexist within one patient. Histopathological and molecular analyses have led to the definition of the seminal adenoma-carcinoma sequence of tumor progression^ref. The model integrates the notions that (i) colorectal tumors result from mutational activation of oncogenes combined with the inactivation of tumor-suppressor genes, (ii) multiple gene mutations are required to produce malignancies, and (iii) genetic alterations may occur in a preferred sequence, yet the accumulation of changes rather than their chronologic order determines histopathological and clinical characteristics of the colorectal tumor. In the adenoma-carcinoma sequence, the earliest identifiable lesion is an aberrant crypt focus, a small dysplastic lesion in the colonic epithelium. 2 different models propose the origin and growth of dysplastic aberrant crypt foci. Vogelstein and colleagues suggested a top-down morphogenesis model in which mutant cells at the surface epithelium of the colon spread laterally and downward to form new crypts^ref. This view was challenged with an alternative model proposing that adenomas grow initially in a bottom-up pattern^ref. Aberrant crypt foci expand over time to form macroscopically visible adenomatous polyps. The transition from benign (adenoma) to malignant growth (carcinoma) is believed to be progressive. Adenomas first advance to the carcinoma in situ stage. Overtly invasive carcinomas often represent the first clinical presentation of colorectal tumors. Little is known about the genetic alterations and precise mechanisms driving progression from early stage in situ carcinomas through the successive clinically defined stages of regional invasion and distant metastasis. Our current molecular insights into CRC rely heavily on studies on hereditary forms of this disease. Five to 10% of CRC cases are inherited in an autosomal-dominant fashion^ref. Hereditary cancer syndromes are often divided into two categories on the basis of absence or presence of polyposis, best exemplified by the two major forms of hereditary colorectal cancer: hereditary nonpolyposis CRC and familial adenomatous polyposis (FAP). The hallmark of tumors in hereditary nonpolyposis CRC is instability of microsatellites (repeats of short DNA sequences)^{ref1, ref2}. Indeed, hereditary nonpolyposis CRC can be caused by mutations in mismatch repair genes, such as MSH2 and MLH1^{ref1, ref2}, collectively termed the caretakers of genome integrity^ref. It is believed that these DNA repair defects lead to mutations in cancer-causing genes such as adenomatous polyposis coli (APC)^ref, which in turn transform cells. For further reading on the subject of microsatellite instability, we refer the reader to the above references; the polyposis syndrome FAP is more extensively discussed below. Wnt signaling maintains crypt progenitor compartments. A crypt and its associated villus can be viewed as the smallest self-renewing unit from which the epithelium is built. Position along the crypt-villus axis defines the various stages in the life of an epithelial cell (Fig. 1). Current evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt-villus axis. Wnt genes encode secreted signaling proteins and are found in the genomes of all animals. Signaling is initiated when Wnt ligands engage a complex consisting of a serpentine receptor of the frizzled family and a member of the low-density lipid receptor family, Lrp5 or Lrp6^ref (Fig. 3A). The key molecule in the cascade is a cytoplasmic protein termed ß-catenin, whose stability is regulated by the so-called destruction complex. When Wnt receptors are not engaged, two scaffolding proteins in the destruction complex, the tumor suppressors adenomatous polyposis coli (APC) and axin, bind newly synthesized ß-catenin. CKI and GSK3, two kinases residing in the destruction complex, then sequentially phosphorylate a set of conserved Ser and Thr residues in the N terminus of ß-catenin. The resulting phosphorylated footprint recruits a ß-TrCP–containing E3 ubiquitin ligase, which targets ß-catenin for proteasomal degradation. When Wnts bind the receptor complex, the activity of the destruction complex is inhibited. As a consequence, ß-catenin accumulates and binds to nuclear DNA binding proteins of the Tcf/Lef family^ref. In the absence of a Wnt signal, Tcf/Lef proteins repress target genes through association with corepressors such as groucho. The interaction with ß-catenin transiently converts Tcf/Lef factors into transcriptional activators, a process that also involves legless/Bcl9 and pygopus, 2 additional partner proteins of ß-catenin. In sum, the canonical pathway translates a Wnt signal into transient transcription of a Tcf/Lef target gene program^ref.

Fig. 3. Wnt, BMP, and Notch pathways control target gene transcription. (Left) Wnt-responsive cells carry a receptor complex consiting of a frizzled seven-transmembrane receptor (Fz) and Lrp5 or Lrp6. In the absence of secreted Wnt factor (left), the destruction complex (APC, axin, and the kinases CK1 and GSK3 ß) induces degradation of cytoplasmic ß-catenin. Tcf complexed to corepressors such as groucho represses specific Wnt target genes. Receptor engagement (right) blocks the destruction complex; ß-catenin accumulates and binds to Tcf in the nucleus to activate transcription of Wnt target genes. (Center) Type I and type II BMP receptors are not complexed in the absence of signal. Secreted BMP factors bring the two receptors together, ultimately leading to the phosphorylation of R-SMADs, their association with co-SMAD, translocation to the nucleus, and subsequent activation of BMP target genes in the nucleus. (Right) When Notch receptor meets its cell-bound ligand (jagged or delta), sequential proteolytic steps lead to the release of its intracellular domain (NICD), which travels to the nucleus, where it complexes with the transcription factor CSL to activate Notch target gene transcription.
Wnt signaling is intimately linked with the biology of the intestinal epithelium. This first became clear when APC, originally identified as an intestinal tumor suppressor gene, was recognized as a key negative regulator of the cascade (see below). Later evidence implied a role for the Wnt cascade in controlling epithelial physiology. Nuclear ß-catenin, the indicator of active Wnt signaling, was observed in crypts^ref. In Tcf4-/- neonatal mice, the proliferative compartment was entirely absent, indicating that Wnt is required for maintenance of progenitors^ref. Concordantly, inhibition of Wnt receptors by transgenic dickkopf-1 leads to loss of proliferative crypts in adult mice^ref. Expression analysis of all mouse Wnt genes has revealed that at least 4 are expressed by the crypt cells proper, whereas no Wnt expression was detected in the directly apposed mesenchyme, implying the existence of an autocrine mechanism. FAP patients carry in their colon numerous florid adenomatous polyps, which are defined as benign epithelial neoplasia (polyps) built from glandular elements (adenomatous)^ref. Because of the polyp burden, FAP patients invariably develop colorectal cancer around the age of 40. FAP patients carry one mutant copy of the tumor suppressor gene adenomatous polyposis coli (APC) in their genome^{ref1, ref2}. APC is not only mutated in the hereditary FAP syndrome, but somatic APC mutations also occur in the vast majority of sporadic adenomas and adenocarcinomas^{ref1, ref2, ref3}. The earliest identifiable lesion in the adenoma-carcinoma sequence^ref, the aberrant crypt focus, already bears detectable APC mutations^ref, implying that loss of APC function represents the initiating event in sporadic CRC. Taking these observations together, APC appears to be the key gene, the gatekeeper, in the molecular pathogenesis of most sporadic and hereditary forms of CRC. The APC mutations in intestinal polyps and adenocarcinomas typically truncate the protein, suggesting a critical tumor-suppressive role for the C-terminal domain. This domain binds to and causes the degradation of cytoplasmic ß-catenin^{ref1, ref2, ref3, ref4}. Indeed, stable ß-catenin accumulates to high concentrations in the cytoplasm and nucleus of epithelial cells transformed upon loss of APC function. The discovery of the partnership of ß-catenin and Tcf proteins as the ultimate effectors of Wnt signaling^{ref1, ref2} led to the realization that the increased amounts of ß-catenin in APC mutant cancer cells inappropriately activate transcriptional activity of the intestinal Tcf family member TCF4^ref. The recognition of nuclear ß-catenin/Tcf4 complexes as the key effectors in cancer initiation was confirmed by rare mutations in other WNT pathway components, i.e., in ß-catenin^{ref1, ref2} and in axin2/conductin^ref. Ultimately, malignant transformation of intestinal epithelial cells is thus caused by the inappropriate, constitutive transcription of Tcf target genes. On the basis of the determination of the Tcf4 target gene program in human CRC cell lines, we have proposed the following scenario^ref. In crypts, Wnt signaling drives the formation of ß-catenin/Tcf4 complexes, thus imposing a proliferative phenotype onto crypt epithelial cells. The strict compartmentalization along the crypt-villus axis itself is controlled at least in part by the Wnt source at the crypt bottom and translated through Wnt-controlled expression of the EphB sorting receptors^ref. The absence of Wnt signaling in the villus compartment results in rapid cell cycle arrest and differentiation. Thus, Tcf4 constitutes the dominant switch between the proliferative progenitor and the differentiated epithelial cell. At all stages of CRC this switch is permanently on, because Tcf4 is constitutively activated by mutations in the Wnt cascade. This overrides the physiological signals leading to cell cycle arrest and induces the slow formation of long-lived adenomatous polyps. Several Apc-mutant mouse models have been generated^ref. Min (multiple intestinal neoplasia) mice carry a nonsense mutation at codon 850 of Apc^ref. Heterozygous Apcmin mice develop as many as 100 intestinal tumors, which have typically inactivated the second Apc allele. Although most Min tumors develop in the small intestine rather than the colon, these mice are used extensively as animal models for FAP and CRC. Because homozygosity for Apc mutations invariably results in embryonic lethality^ref, conditional Apc mutant mice have also been generated. In these mice, focal deletion of both alleles of Apc rapidly induced colorectal adenomas, proving that loss of APC is the only requirement for adenoma formation^ref. When deletion of the Apc gene was induced throughout the adult intestine, all epithelial cells displayed a proliferative crypt progenitor phenotype within days^ref. DNA array analysis revealed upregulation of a Tcf4-driven crypt progenitor program, resembling that of human CRC cell lines^ref. The induced transgenic expression of an activated ß-catenin gene has independently confirmed that persistent Wnt signaling is sufficient to induce adenomas^ref. Taken together, mutational activation of the Wnt signaling pathway now appears strongly to represent the key initiating event of intestinal tumorigenesis in human and mouse. Not all polyposis syndromes are manifested as adenomatous lesions. Hamartomatous polyposis syndromes are characterized by an overgrowth of tissues native to the organ area, which are usually of mesenchymal origin^ref. The juvenile polyposis syndrome (JPS) is one such autosomal hamartoma syndrome, and in this condition patients bear between 50 and 200 polyps, usually in the rectosigmoid region of the gut. Polyps display gross chronic inflammation and contain cystic spaces lined by a columnar epithelium and surrounded by abundant stroma^ref. JPS patients have an increased risk of developing gastrointestinal polyps and colorectal cancer. Inactivating mutations in Smad4^ref and bone morphogenic protein (BMP) receptor type 1A^{ref1, ref2} account for up to 50% of JPS cases, implying that loss of intestinal BMP signaling is the primary cause of JPS. This in turn suggests a role for the BMP pathway in epithelial homeostasis. BMPs form a large subgroup of signaling cytokines within the TGF-ß superfamily. Originally identified as molecules inducing cartilage and bone formation, they now rival the Wnts as general regulators of development^ref. TGF-ß superfamily ligands signal through a common mechanism by bringing together type I and type II serine–threonine kinase receptors. This results in the phosphorylation of the type I receptor by the type II receptor and activation of the intracellular SMAD transcriptional regulators^ref. These fall into three classes: receptor-regulated SMADs (R-SMADs), common SMAD (co-SMADs), and inhibitory SMADs (I-SMADs). Upon receptor activation, R-SMADs become phosphorylated by type I receptors, resulting in association with the co-SMAD SMAD4 and in translocation of the complex to the nucleus (Fig. 3B). Once in the nucleus, the SMAD complex can interact with either co-activators or co-repressors of transcription to control target gene expression. BMP signaling is mediated through SMAD1, 5, and 8^ref. BMPs are expressed in the stroma of villi, whereas phosphorylated SMAD1, 5, and 8, indicative of active BMP signaling, are observed in the nuclei of the differentiated villus epithelial cells. This implies that constitutive BMP signaling occurs from the villus mesenchyme to the epithelium^ref. Most mutations in BMP pathway components are embryonic-lethal in mice, precluding a genetic assessment of a role for the BMP pathway in the gut^ref. However, inhibition of BMP signaling in the villus through the transgenic expression of the secreted BMP inhibitor noggin resulted in a JPS-like phenotype, including the late development of adenomatous polyps^ref. The stromal BMP signal apparently confines the postnatal formation of crypts to regions directly opposed to the intestinal wall. When BMP signaling is blocked, crypts appear de novo anywhere in the epithelium, leading to the characteristic JPS histology and ultimately to adenomas. A similar phenotype was observed in mice mutant for the Bmpr1a gene^ref. Vogelstein has coined the term "landscaper" for the molecular defect in JPS^ref, and although much remains to be learned about crypt initiation, it appears appropriate that the JPS-landscaper genes control spatial positioning of crypts in the intestinal epithelium. The Notch cascade represents a third developmental signaling pathway that plays a controlling role in intestinal homeostasis. Notch genes encode evolutionarily conserved single-transmembrane receptors, which regulate many cell fate decisions and differentiation processes. Mice and humans possess four Notch receptors, and these can be activated by transmembrane ligands of the delta and jagged families expressed on neighboring cells^ref. This initiates a cascade of proteolytic cleavages of the receptor close to and within the transmembrane domain. Ultimately, the intramembrane -secretase protease liberates NICD (Notch intracellular domain), which translocates to the nucleus and engages the transcription factor CSL {CBF1/RBPjk in vertebrates, suppressor of hairless [Su(H)] in Drosophila, and Lag-1 in C. elegans}, thereby activating transcription^ref. Some of the best-characterized Notch target genes encode members of the hairy-enhancer of split (Hes) family of transcriptional repressors, which are nuclear basic helix-loop-helix (bHLH) proteins. These HES family members regulate downstream genes, involved (at least in Drosophila) in the segregation of neuronal and epidermal lineages^{ref1, ref2}. Genetic evidence implies a role for several putative Notch target genes in the control of intestinal homeostasis. For example, Hes1 mutant mice die perinatally because of severe neurological defects, whereas the intestines of Hes1-/- fetuses contain increased numbers of secretory cells at the expense of adsorptive enterocytes^ref. The transcription factor gene Math1 is repressed by Hes1 in multiple organs, including the intestine^{ref1, ref2}. The intestines of Math1-deficient mice show a relatively normal crypt-villus architecture that is populated entirely by enterocytes, indicating that Math1 is required for all secretory cell lineages^ref. This phenotype is somewhat reciprocal to the phenotype observed in Hes1-/- mice. Taken together, these results suggest that Notch-mediated Hes1 expression regulates a binary decision between adsorptive and secretory cell fates whereas other bHLH proteins may refine these fate decisions. For example, mice deficient in the bHLH factor neurogenin-3 specifically lack enteroendocrine precursors^ref. BETA2/neuroD, a bHLH protein best known for its role in pancreatic differentiation, appears to further refine the enteroendocrine fate by controlling terminal differentiation of the enteroendocrine secretin- and cholecystokinin (CKK)-producing cells^ref. Additional indirect support for the control of intestinal cell fate by Notch stems from the use of -secretase inhibitors developed for the treatment of Alzheimer's disease^ref. The generation of NICD from Notch requires g-secretase^ref. Rodents treated with g-secretase inhibitors display increases in goblet cell numbers in the gut (viewed as an undesirable side effect), most probably through the inhibition of Notch signaling^{ref1, ref2}. The crypt-villus unit represents one of the simplest self-renewing entities in mammalian biology. Although a molecular understanding is still in its infancy, several principles are taking shape: First, regulatory signaling pathways that have emerged from the study of embryonic development of model organisms play key roles in this adult mammalian structure. Second, the malignant transformation of the intestinal epithelial cells does not rely on mutational changes in generic oncogenes or tumor suppressors. Rather, the transformation process appears to specifically subvert the physiological regulators of the epithelium. Third, structure and function of the crypt-villus unit are intricately linked. The epithelium is therefore preferably studied in its histological context, allowing marker analysis while preserving the positional information of individual cells. By contrast, the best-understood self-renewing tissue, the bone marrow, is usually treated as an unordered suspension of cells studied by flow cytometry outside the natural context. Nevertheless, this reductionist approach has yielded spectacular results. Elaborate cell culture systems have been established to study the hemopoietic system, often at the level of single primary cells^ref. Unfortunately, no such culture system exists yet for primary epithelial cells of the intestine. The insights that are emerging from the studies discussed in this review are painting a growing picture of the factors that control intestinal cell behavior in physiology as well as in cancer. Apparently, the transformation process uses crucial physiological regulators of normal intestinal epithelium as a strategy to open the most efficient road to cancer. Malignancies that arise in other self-renewing tissues may exploit similar strategies. In-depth insights into the molecular physiology of the self-renewal process of gut epithelium should ultimately allow the design of sophisticated modes of therapeutic interference in the diseased intestine.
As snakes, frogs, birds, and other wild creatures attest, digestive systems need flexibility to meet energy demands as well as the challenges of environment, diet, and predators. You haven't had a meal for so long that your stomach and intestines have atrophied. And when you finally do get something to eat, it's almost as big as you are. Yet you cram it into your mouth and hope that your gut can somehow cope with it. That's what life's like for many snakes: feast or famine. Other animals ride similar nutritional roller coasters. Birds travel thousands of kilometers without eating, then gorge themselves when they stop to refuel--often on a completely different type of food than they are accustomed to. Not a morsel of food or liquid passes the lips of a hibernating animal for months, yet their digestive systems kick in as soon as they greet the world again. How does the gut accommodate such extremes without shriveling up and dying or being completely overwhelmed by a sudden flood of nutrients? Those are questions that have given biologists a lot of food for thought. Most of us learned in our textbooks about a rather static digestive system, but the gut is a very dynamic organ. It can adjust to changing demands and energy supply, and those adjustments can be radical in the extreme. During the months between meals, the python's stomach and intestine atrophy. Yet once the snake begins to eat, it quickly revs up its digestive function : the first food to reach the gut--particularly proteins or their amino acids--stimulates a dramatic expansion of the gut lining. The intestine doubles in size, significantly increasing its absorptive surface area. New cells are added to the gut lining when the intestine shifts into high gear. That shift, especially the rapid reactivation of the stomach and the production of stomach acids, is quite energy-intensive, taxing the body's reserves. But actually the gut lining grows not because the number of cells increases but because blood pours into shrunken villi once a snake eats, expanding the surface area of the villi and flooding them with materials needed to digest the incoming meal, a less expensive mechanism; digestion can begin even when fat reserves are relatively low. And once digestion starts, the ingested food provides the energy needed to complete it. In snakes that eat irregularly, the intestines (lower left) and their fingerlike projections (black and white, left) shrink between meals but quickly expand (right) after eating.

Starck's new proposal draws on ultrasound measurements of blood flow to and within the gut lining, as well as histological studies that characterize physical changes in the lining. When snakes are fed with mice, their metabolic rates rise, their small intestines grow, and blood flow to the intestines triples. This blood flow was responsible for half the intestine's increase in size. Microscopic globs of fat absorbed from the gut further bloat the cells lining the intestine, accounting for the rest of the increase. Cells swell rather than divide, but blood has little to do with their expansion. Instead, the lining's villi absorb the digestive fluids from the gut itself. Electron microscopy has shown that each cell's microvilli also swell significantly, quadrupling in size within 24 hours. Even though increased blood flow is not the secret to the rapid growth of a snake gut, it is important to digestion. Animals typically divert blood to the gut during digestion, just as exercise results in increased circulation to muscles. Snakes go to extremes, increasing blood flow to the gut by about 10-fold compared to the 50% increase humans experience during digestion. The cardiac output is comparable to somebody going full-out in exercise and the python can sustain this additional blood flow for days--plenty of time for its intestinal muscles to work without fatigue at breaking down the skin, bones, and underlying tissue of its prey. It takes a lot of heart to pump all that blood. Indeed, the snake's heart actually grows once it eats, increasing 40% in mass in just 2 days. Athletes' hearts can also expand--but that growth happens over years. Even as they digest their food, snakes stockpile resources for their next great feast. In pythons, the stomach operates for 4 to 6 days, then begins to wind down, while the intestines keep going for at least another week to finish the job. As the intestine takes these extra days to process nutrients, it generates and banks cells for a subsequent supper. This is the key adaptive factor: a dormant gut with unused cells that can quickly restart functioning when food is available again. A similar phenomenon occurs in fasting rats. Even as they are reduced to breaking down their body's proteins--a desperate measure that can cause organs to waste away--their intestine begins to produce new cells, and programmed cell death in the lining stops. After a prolonged fast, the intestinal lining prepares itself for eventual refeeding. Other animals faced with widely spaced meals have also adapted their guts to keep some cells in their digestive system up and running during the lean times. Perhaps the most extreme examples are creatures that hibernate during the cold winter or their summer counterparts that burrow and become dormant to escape life-threatening heat or dryness, a strategy called estivation. For example, the guts of green-striped burrowing frogs, an Australian species whose estivation can last > 10 months, have been studied. Once it rains hard, the frogs surface--sometimes for just a week--and they must quickly stock up on food to help find mates and build up fat reserves. Within 3 months of estivation, the animals lose as much as 70% of their gut mass, and an additional 10% disappears by 9 months. The microvilli on cells of the frogs' intestinal lining also shrank. Australia's green-striped burrowing frog keeps a few gut cells up and running in preparation for a feeding frenzy when it surfaces. Overall, this gastrointestinal atrophy saves energy for the frogs. Nonetheless the gut of an estivating creature can still absorb nutrients, even though maintaining that readiness entails a significant energetic cost at a time when the frog has little energy to spare. But the cost is a worthwhile investment : frogs surfacing from estivation absorb nutrients 40% more efficiently than frogs that hadn't burrowed. Newly aroused frogs can maximize their digestive capability from the outset. Hibernating mammals called 13-lined ground squirrels also keep digestive capacity in reserve. To save energy as they hibernate, the animals' gut lining atrophies, and their intestines thin. Some cells undergo programmed cell death in response to fasting. But tissue damage is minimal as genes that promote survival and curtail cell death become active at the same time : microvilli remain intact on the surviving cells, and their density on each cell sometimes increases. In these microvilli, transporter proteins and digestive enzymes continue to be plentiful. Thus, during brief moments when the animals come out of their stupor during those quiet months, they can absorb nutrients still left in the gut. Indeed, when ntestinal tissue from hibernating animals was warmed so that it could function normally, gram for gram, the tissue worked more efficiently than did the intestines of the nonhibernating squirrels. This is likely a beneficial adaptation : squirrels emerging from hibernation could make the most of spring's low food supply and still have enough energy for breeding. Like hibernation, migration places unusual demands on the gut. Migrating birds, for example, devote extraordinary amounts of energy to flying, and they must be able to digest the different foods they encounter along the way. For many migrating birds, the way to cope with season-to-season differences in food quality and energy expenditure is to change gut size : the gut of the red knot, a bird species that migrates between Antarctica and Northeastern Canada and Greenland, can adjust to different diets. Red knots typically eat 2 types of food: relatively soft stuff such as shrimp, crabs, or spiders, and hard stuff--cockles, mussels, and other bivalves. The red knot's gizzard, the muscular extra stomach used to crunch shells, grows quickly when the bird switches from soft food to hard food. Over the next 3 weeks, the gizzards of red knots fed trout chow for years and then switched to small mussels grew by 4.9 grams; the red knots only weighed about 130 grams total. Overall, the birds gained 7.3 grams. The dietary changes experienced by migrating birds have apparently favored the evolution of intestinal plasticity. When ultrasound was used to see what happens to a red knot's gut during migration, researchers found that when the birds arrive at a stopover, their guts are much reduced. Less intestinal baggage apparently gives the birds a better shot at making it to their destination. When red knots make a pit stop along the Wadden Sea, their digestive systems quickly regain their ability to process food and absorb nutrients, albeit temporarily. The speed at which the gut comes back online is critical to the birds' ability to replenish the fat reserves they need to complete their journey. According to some physiologists, that ability should be limited by how fast the birds can catch their prey, but the gut's ability to process food is the limiting step, and that their food choice--and therefore their rate of consumption--is in large part dictated by the size of their gizzards. The faster gizzards can bulk up, the greater the birds' range of food choices. There are incredibly strong interactions between the type of food and type of digestive machinery. The researchers set up patches of food along the mudflats at the Wadden Sea stopover that differed in food quality. One had many good-sized mollusks, which are relatively tough to digest. The other had a sparse smattering of crabs, which are easier for the gizzard to process but gram for gram pack less nutritional value than the mollusks. They watched as radio-tagged birds foraged in these patches and used ultrasound to measure their gizzards. Red knots with large gizzards, which could digest the shelled food faster, favored the larger bivalves. Those with small gizzards--the majority of the migrating birds when they first arrived--had to forage almost exclusively in the other patch. As a result, they needed to spend more time--and wasted precious energy--looking for meals. Thus, the gizzard's size seems to drive the food choice and foraging strategy of the migrating red knot, and only if the gizzard grows fast enough will the migrants be able to lay in the stores they need for the final leg of their trip. Red knots that optimize gut size and function arrive with more energy reserves in their breeding grounds and thus [have an] advantage over others. In contrast to red knots, having a big gut seems to be the secret to success for some migrating birds. Consider Western Sandpipers, which migrate from Central America to Alaska. These birds actually increase the size of digestive organs for migration : the researchers attribute the difference between red knots and sandpipers to the species' contrasting migration habits. Red knots travel very long distances, fueling up just once during a monthlong stopover. Sandpipers hop from food stop to food stop, so they don't need to be as trim as red knots to get to their destinations. These gastrointestinal tales of famished snakes and ravenous frogs may have implications beyond explaining how animals adjust to the nutritional ups and downs of life in the wild.
Sometimes, it's who's digesting you that determines how you digest. In general, long guts absorb more food and make digestion more efficient. But having a big belly, so to speak, can slow an organism down--and that's bad news in a world of predators. Demonstrating a link between a creature's gut size and its enemies, researchers have raised wood frog tadpoles under different conditions. They've set up tanks with all the ingredients of the tadpole's natural pond environment. In some, they put just tadpoles, anywhere from 20 to 160 per tank. In others, the researchers added a predator: immature dragonflies. These insects were kept in underwater cages, so the tadpoles were safe, but the dragonfly smell signaled danger. In the first experiment, which lasted a month, 10 tadpoles were removed from each tank several times, measured their sizes, and preserved the specimens. The preserved specimens was later dissected and gut lengths measured . The greater the competition for food--such as in tanks with 160 tadpoles--the longer the tadpoles' guts grew. In crowded conditions, if a tadpole is lucky enough to find food, it needs to extract as much energy as possible. A great way to increase digestive efficiency is to have longer intestines because it forces the food to spend more time traveling through them--the slow journey provides more opportunities for the gut lining to absorb nutrients. In the tanks with the caged dragonflies, however, the fear-provoking chemical cues emitted by the insect stunted gut growth. In the wild, tadpoles use their tails to dart away from dragonfly larvae, and the longer the tail, the better. But growing a long tail puts demands on the tadpole's resources, and gut length is sacrificed. The shorter gut may be poorer at processing food, but in dragonfly-infested waters, the tradeoff for a swifter escape is likely worth it. Animals can be amazingly sophisticated at fine-tuning their gut length to strike an effective balance between the two opposing forces of predation and competition
The adult human intestine is home to an almost inconceivable number of microorganisms. The size of the population—up to 100 trillion—far exceeds that of all other microbial communities associated with the body's surfaces and is 10 times greater than the total number of our somatic and germ cells^ref. Thus, it seems appropriate to view ourselves as a composite of many species and our genetic landscape as an amalgam of genes embedded in our Homo sapiens genome and in the genomes of our affiliated microbial partners (the microbiome). Our gut microbiota can be pictured as a microbial organ placed within a host organ: It is composed of different cell lineages with a capacity to communicate with one another and the host; it consumes, stores, and redistributes energy; it mediates physiologically important chemical transformations; and it can maintain and repair itself through self-replication. The gut microbiome, which may contain 100 times the number of genes in our genome, endows us with functional features that we have not had to evolve ourselves. Our relationship with components of this microbiota is often described as commensal (one partner benefits and the other is apparently unaffected) as opposed to mutualistic (both partners experience increased fitness). However, use of the term commensal generally reflects our lack of knowledge, or at least an agnostic (noncommittal) attitude about the contributions of most citizens of this microbial society to our own fitness or the fitness of other community members. The guts of ruminants and termites are well-studied examples of bioreactors "programmed" with anaerobic bacteria charged with the task of breaking down ingested polysaccharides, the most abundant biological polymer on our planet, and fermenting the resulting monosaccharide soup to short-chain fatty acids. In these mutualistic relationships, the hosts gain carbon and energy, and their microbes are provided with a rich buffet of glycans and a protected anoxic environment^ref. Our distal intestine is also an anaerobic bioreactor that harbors the majority of our gut microorganisms; they degrade a varied menu of otherwise indigestible polysaccharides, including plant-derived pectin, cellulose, hemicellulose, and resistant starches. Microbiologists from Louis Pasteur and Ilya Mechnikov to present-day scientists have emphasized the importance of understanding the contributions of this microbiota to human health (and disease). Experimental and computational tools are now in hand to comprehensively characterize the nature of microbial diversity in the gut, the genomic features of its keystone members, the operating principles that underlie the nutrient foraging and sharing behaviors of these organisms, the mechanisms that ensure the adaptability and robustness of this system, and the physiological benefits we accrue from this mutualistic relationship. This Review aims to illustrate these points and highlight some future challenges for the field. The adult human gastrointestinal (GI) tract contains all 3 domains of life—bacteria, archaea, and eukarya. Bacteria living in the human gut achieve the highest cell densities recorded for any ecosystem^ref. Nonetheless, diversity at the division level (superkingdom or deep evolutionary lineage) is among the lowest^ref; only 8 of the 55 known bacterial divisions have been identified to date (Fig. 1A), and of these, 5 are rare. The divisions that dominate—the Cytophaga-Flavobacterium-Bacteroides (CFB) (e.g., the genus Bacteroides) and the Firmicutes (e.g., the genera Clostridium and Eubacterium)—each comprise 30% of bacteria in feces and the mucus overlying the intestinal epithelium. Proteobacteria are common but usually not dominant^ref. In comparison, soil (the terrestrial biosphere's GI tract, where degradation of organic matter occurs) can contain 20 or more bacterial divisions^ref.

Fig. 1. Representation of the diversity of bacteria in the human intestine. (A) Phylogenetic tree of the domain bacteria based on 8903 representative 16S rRNA gene sequences. Wedges represent divisions (superkingdoms): Those numerically abundant in the human gut are red, rare divisions are green, and undetected are black. Wedge length is a measure of evolutionary distance from the common ancestor. (B) Phylogenetic tree of the CFB division based on 1561 sequences from GenBank (>900 nucleotides) and their ecological context. Wedges, major subgroups of CFB; symbols, source of the sequences [Earth, environmental; cow, ruminants; rodent, rat and/or mouse; person, human GI tract; others are termite, cockroach, worm (including hydrothermal), and pig]. Ratios are the number of sequences represented in the human gut relative to the total number in the subgroup; red, yellow, and black indicate majority, minority, and absence of sequences represented in human GI tract, respectively. (C) Phylogenetic (parsimony) tree of Bacteroides. Strains classified as B. thetaiotaomicron based on phenotype are in red; 16S rRNA analysis did not confirm this classification for all strains. Bacteroides spp. with sequenced genomes are in bold. Black circles indicate nodes with high (>70%) bootstrap support (41). Scale bars indicate the degree of diversity (evolutionary distance) within a division or subgroup [(A) and (B), respectively] in terms of the fraction of the 16S rRNA nucleotides that differ between member sequences; in (C), the evolutionary distance between organisms is read along branch lengths, where scale indicates number of changes in 16S rRNA nucleotide composition. Our knowledge of the composition of the adult gut microbiota stems from culture-based studies^ref, and more recently from culture-independent molecular phylogenetic approaches based on sequencing bacterial ribosomal RNA (16S rRNA) genes. Of the >200,000 rRNA gene sequences currently in GenBank, only 1822 are annotated as being derived from the human gut; 1689 represent uncultured bacteria. rRNA sequences can be clustered into relatedness groups based on their percent sequence identity. Cutoffs of 95 and 98% identity are used commonly to delimit genera and species, respectively. Although these values are somewhat arbitrary and the terms "genus" and "species" are not precisely defined for microbes, we use them here to frame a view of human gut microbial ecology. When the sequences (n = 495 greater than 900 base pairs) are clustered into species, and a diversity estimate model is applied, a value of 800 species is obtained. If the analysis is adjusted to estimate strain number (unique sequence types), a value of >7000 is obtained. Thus, the gut microbiota, which appears to be tremendously diverse at the strain and subspecies level, can be visualized as a grove of eight palm trees (divisions) with deeply divergent lineages represented by the fan(s) of closely related bacteria at the very top of each tree trunk.

Taxon richness estimates for bacteria in the human GI tract. Taxon richness estimates for varying levels of 16S rRNA sequence identity, ranging from below the "genus" level (95% identity), to the "species" level (98% identity), to the strain level (unique sequences). Estimates are based on sequences available in GenBank, annotated as derived from the human GI tract, after alignment and clustering into taxonomic units ranging from 80 to 100% identity
Diversity present in the GI tract appears to be the result of strong host selection and coevolution. For example, members of the CFB division that are predominantly associated with mammals appear to be the most derived (i.e., farthest away from the common ancestor of the division), indicating that they underwent accelerated evolution once they adopted a mutualistic lifestyle. Moreover, a survey of GenBank reveals that several sub-groups in CFB are distributed among different mammalian species, suggesting that the CFB-mammal symbiosis is ancient and that distinct subgroups coevolved with their hosts. The structure and composition of the gut microbiota reflect natural selection at two levels: at the microbial level, where lifestyle strategies (e.g., growth rate and substrate utilization patterns) affect the fitness of individual bacteria in a competitive ensemble; and at the host level, where suboptimal functionality of the microbial ensemble can reduce host fitness. Microbial consortia whose integrated activities result in a cost to the host will result in fewer hosts, thereby causing loss of their own habitat. Conversely, microbial consortia that promote host fitness will create more habitats. Thus, the diversity found within the human GI tract, namely, a few divisions represented by very tight clusters of related bacteria, may reflect strong host selection for specific bacteria whose emergent collective behavior is beneficial to the host. This hypothesis has 2 important implications: (i) A mechanism exists to promote cooperation, and (ii) the structure promotes functional stability of the gut ecosystem. To benefit the host, bacteria must be organized in a trophic structure (food web) that aids in breaking down nutrients and provides the host with energetic substrates. Cooperative behavior that imposes a cost to the individual while benefiting the community can emerge within groups of bacteria^ref and can be maintained by group selection as long as consortia are isolated and new consortia form periodically (e.g., new GI tracts). Furthermore, selection must act simultaneously at multiple levels of biological organization^ref. These criteria are met in the human GI tract where new acts of colonization occur at birth, with a small founding population of noncheaters from the mother, and selection occurs both at the microbial and host level. Diversity is generally thought to be desirable for ecosystem stability^ref. One important way diversity can confer resilience is through a wide repertoire of responses to stress [referred to as the insurance hypothesis^ref]. In man-made anaerobic bioreactors used to treat wastewater (a system analogous to the gut but where no host selection occurs), rates of substrate degradation can remain constant, whereas bacterial populations fluctuate chaotically as a result of blooms of subpopulations^ref. Functional redundancy in the microbial community ensures that key processes are unaffected by such changes in diversity^ref. By contrast, in the human gut, populations are remarkably stable within individuals^ref, implying that mechanisms exist to suppress blooms of subpopulations and/or to promote the abundance of desirable bacteria. A study of adult monozygotic twins living apart and their marital partners has emphasized the potential dominance of host genotype over diet in determining microbial composition of the gut bioreactor^ref. The role of the immune system in defining diversity and suppressing subpopulation blooms remains to be defined. One likely mediator of bacterial selection is secretory IgA^ref. The human gut is faced with a paradox: How can functional redundancy be maintained in a system with low diversity (few divisions of bacteria), and how can such a system with-stand selective sweeps in the form of, for example, phage attacks? [The estimated 1200 viral genotypes in human feces^ref suggest that phage attack is a powerful shaper of the gut's microbial genetic landscape^{ref1, ref2}]. Enough diversity of genome and transcriptome must be represented at the subspecies level to lend resilience to the gut ecosystem. Ecological studies of macroecosystems have shown that less diversity is required to maintain stability if individual species themselves have a wide repertoire of responses^ref. In the following section we discuss recent genome-based studies exploring how a presumed keystone bacterial species in our gut is able to adapt to (i) changing dietary conditions in ways that should stabilize the microbiota's food web and (ii) changing immune and phage selective pressures in ways that should stabilize the ecosystem. Bacteroides thetaiotaomicron is a prominent mutualist in the distal intestinal habitat of adult humans. It is a very successful glycophile whose prodigious capacity for digesting otherwise indigestible dietary polysaccharides is reflected in the fully sequenced 6.3-Mb genome of the type strain (ATCC 29148; originally isolated from the feces of a healthy adult human)^ref. Its "glycobiome" contains the largest ensemble of genes involved in acquiring and metabolizing carbohydrates yet reported for a sequenced bacterium, including 163 paralogs of 2 outer membrane proteins (SusC and SusD) that bind and import starch^ref, 226 predicted glycoside hydrolases, and 15 polysaccharide lyases^ref. By contrast, our 2.85-Gb genome only contains 98 known or putative glycoside hydrolases and is deficient in the enzyme activities required for degradation of xylan-, pectin-, and arabinose-containing polysaccharides that are common components of dietary fiber [we have one predicted enzyme versus 64 in B. thetaiotaomicron (table S1)]. The carbohydrate foraging behavior of B. thetaiotaomicron has been characterized during its residency in the distal intestines (ceca) of gnotobiotic mice colonized exclusively with this anaerobe^ref. Scanning electron microscopy studies of the intestines of mice maintained on a standard high-polysaccharide chow diet, containing xylose, galactose, arabinose, and glucose as its principal monosaccharide components, revealed communities of bacteria assembled on small undigested or partially digested food particles, shed elements of the mucus gel layer, and exfoliated epithelial lining cells. Whole-genome transcriptional profiling of B. thetaiotaomicron disclosed that this diet was associated with selective up-regulation of a subset of SusC and SusD paralogs, a subset of glycoside hydrolases (e.g., xylanases, arabinosidases, and pectate lyase), as well as genes encoding enzymes involved in delivering the products of mannose, galactose, and glucose to the glycolytic pathway and arabinose and xylose to the pentose phosphate pathway. In contrast, a simple sugar (glucose and sucrose) diet devoid of polysaccharides led to increased expression of a different subset of SusC and SusD paralogs, glycoside hydrolases involved in retrieving carbohydrates from mucus glycans, as well as enzymes that remove modifications that make these host glycans otherwise resistant to degradation (O-acetylation of sialic acids and sulfation of glycosoaminoglycans). These findings provide insights about how functional diversity and adaptability are achieved by a prominent member of the human colonic microbiota (Fig. 3). Dining occurs on particulate nutrient scaffolds (food particles, shed mucus, and/or exfoliated epithelial cells). For a bacterium such as B. thetaiotaomicron, which lacks adhesive organelles, seating at the "dining table" is determined in part by the repertoire of glycan-specific outer membrane–binding proteins it produces, and this repertoire is itself shaped by the menu of available glycans. Attachment to nutrient platforms helps avoid washout from the intestinal bioreactor, in much the same way as dense, well-settling, granular biofilms help oppose elimination from engineered (man-made) anaerobic upflow bioreactors^ref. Attachment also presumably increases the efficiency of oligo- and monosaccharide harvest by adaptively expressed bacterial glycoside hydrolases and their subsequent distribution to other members of the microbiota whose niche overlaps that of B. thetaiotaomicron. In this conceptualization, microbial nutrient metabolism along the length of the intestine is a summation of myriad selfish and syntrophic relationships expressed by inhabitants of these nutrient platforms. Diversity in these micro-habitats and mutualistic cooperation among their component species (including the degree to which sanctions must be applied against cheats) are reflections of a dynamic interplay between the available nutrient foundation and the degree of flexible foraging (niche breadth) expressed by microhabitat residents. Bacteroides spp., such as B. thetaiotaomicron, impart stability to the gut ecosystem by having the capacity to turn to host polysaccharides when dietary polysaccharides become scarce. The highly variable outer chain structures of mucus and epithelial cell surface glycans are influenced by host genotype and by microbial regulation of host glycosyltransferase gene expression. Coevolution of host glycan diversity and a large collection of microbial glycoside hydrolases that are regulated by nutrient availability provides insurance that the "system" (microbiota and host) can rapidly and efficiently respond to changes in the diet, and maximize energy harvest, without having to undergo substantial changes in species composition. Rather than minimizing genome size, a keystone species such as B. thetaiotaomicron has evolved an elaborate and sizable genome that can mobilize functionally diverse adaptive responses.

Lessons about adapative foraging for glycans obtained from B. thetaiotaomicron^ref. B. thetaiotaomicron does not have adhesive organelles. Without outer membrane polysaccharide-binding protein-mediated attachment to glycan-rich nutrient platforms, it is at risk for being washed out from the intestinal bioreactor. Substrate access is limited under these conditions^ref.Small nutrient platforms are composed of undigested or partially digested food particles (e.g., dietary fiber), shed host epithelial cells, and/or mucus fragments. These platform elements may be in dynamic equilibrium with one another and with the mucus layer overlying the intestinal epithelium. Microbial fermentation of otherwise indigestible polysaccharides in these platforms is made possible by induced expression of substrate-appropriate sets of bacterial polysaccharide-binding proteins and glycoside hydrolases^ref. Mesophilic methanogens drive carbohydrate utilization by removing products of fermentation (H₂ and CO₂ are converted to methane), thereby improving the overall efficiency of energy extraction from polysaccharides^ref. When dietary polysaccharides are scarce, B. thetaiotaomicron turns to host mucus by deploying a different set of polysaccharide binding proteins and glycoside hydrolases. This adaptive foraging reflects the coevolved functional versatility of B. thetaiotaomicron's glycobiome and the structural diversity of the host's mucus glycans.
Diet-associated changes in the glycan foraging behavior of B. thetaiotaomicron are also accompanied by changes in expression of its capsular polysaccharide synthesis loci (CPS), indicating that B. thetaiotaomicron is able to change its carbohydrate surface depending upon the nutrient (glycan) environment. This could be part of a strategy for evading an adaptive immune response. Whole-genome genotyping studies of B. thetaiotaomicron isolates, with the use of GeneChips designed from the sequenced genome of the type strain, disclose that their CPS loci differ, whereas their housekeeping genes are conserved. Because selective sweeps are most likely to come from the immune system and phages, both of which respond to surface structures, the associated genes are likely to be the most diverse in the genome. Accordingly, B. thetaiotaomicron has a remarkable apparatus for altering its genome content. The sequenced type strain contains a plasmid, 63 transposases, 43 integrases, and four homologs of a conjugative transposon^ref. Gene transfer and mutation mechanisms endow strains of bacterial species with the (genetic) versatility necessary to withstand selective sweeps that would eradicate more clonal populations^ref.
Comparisons of mice raised without exposure to any microorganisms [germ-free (GF)] with those that have acquired a microbiota since birth [conventionally raised (CONV-R)] have led to the identification of numerous effects of indigenous microbes on host biology, including energy balance. Young adult CONV-R animals have 40% more total body fat than their GF counterparts fed the same polysaccharide-rich diet, even though CONV-R animals consume less chow per day^ref. This observation might seem paradoxical at first but can be explained by the fact that the gut microbiota allows energy to be salvaged from otherwise indigestible dietary polysaccharides^ref. "Conventionalization" of adult GF mice with cecal contents harvested from CONV-R donors increases body fat content to levels equivalent to those of CONV-R animals^ref. The increase reflects adipocyte hypertrophy rather than hyperplasia and is notable for its rapidity and sustainability^ref. The mutualistic nature of the host-bacterial relationship is underscored by mechanisms that underlie this fat-storage phenotype. Colonization increases glucose uptake in the host intestine and produces substantial elevations in serum glucose and insulin^ref, both of which stimulate hepatic lipogenesis through their effects on two basic helix-loop-helix/leucine zipper transcription factors—ChREBP and SREBP-1c^{ref1, ref2, ref3}. Short-chain fatty acids, generated by microbial fermentation, also induce lipogenesis^ref. Triglycerides exported by the liver into the circulation are taken up by adipocytes through a lipoprotein lipase (LPL)–mediated process. The microbiota suppresses intestinal epithelial expression of a circulating LPL inhibitor, fasting-induced adipose factor (Fiaf, also known as angiopoietin-like protein-4)^ref. Comparisons of GF and conventionalized wild-type and Fiaf ^–/– mice established Fiaf as a physiologically important regulator of LPL activity in vivo and a key modulator of the microbiota-induced increase in fat storage^ref. The caloric density of food items is portrayed as a fixed value on package labels. However, it seems reasonable to postulate that caloric value varies between individual "consumers" according to the composition and operation (e.g., transit time) of their intestinal bioreactors, and that the microbiota influences their energy balance. Relatively high-efficiency bioreactors would promote energy storage (obesity), whereas lower efficiency reactors would promote leanness (efficiency is defined in this case as the energy-harvesting and storage-promoting potential of an individual's microbiota relative to the ingested diet). The idea that individual variations in bioreactor efficiencies may be a significant variable in the energy balance equation is supported by several observations. First, individual variations in the composition of the microbiota occur and are influenced by host genotype^ref. Second, small but chronic differences between energy intake and expenditure can, in principle, produce major changes in body composition [e.g., if energy balance is +12 kcal/day, >0.45 kg of fat could be gained per year if there are no compensatory responses by the host; this is the average weight increase experienced by Americans from age 25 to 55^ref]. Third, the microbiota is a substantial consumer of energy. One group estimated that individuals on a "British Diet" must ferment 50 to 65 g of hexose sugars daily to obtain the energy required to replace the 15 to 20 g (dry weight) of bacteria they excrete per day^ref. These considerations emphasize the need to assess the representation of species with large capacities for processing dietary polysaccharides, such as Bacteroides, in lean versus morbidly obese individuals, and in cohorts of obese individuals before, during, and after weight reduction achieved by high-polysaccharide/low-fat versus high-fat/low-polysaccharide diets [or by bariatric (gastric bypass) surgery]. The results, coupled with coincident assessments of energy extraction from the diet, should provide a proof-of-concept test of whether differences in the composition of the microbiota are associated with differences in gut bioreactor efficiency (and predisposition to obesity). Lessons that have been learned by environmental engineers who study how to optimize the efficiency of man-made anaerobic bioreactors suggest that these enumeration studies should also include members of archaea. Thermodynamics dictates that the energy obtained from substrate conversions will be higher if low concentrations of products are maintained^{ref1, ref2}. In the human gut, methanogenic archaea provide the last microbial link in the metabolic chain of polysaccharide processing. Bacteria degrade polysaccharides to short-chain fatty acids, CO₂, and hydrogen gas. Methanogens lower the partial pressure of hydrogen by generating methane, and thereby may increase microbial fermentation rates. Defining the representation of mesophilic methanogens in the colonic microbiota of individuals, sequencing their genomes [as we are currently doing with Methanobrevibacter smithii, a prevalent isolate from the human colon^ref], and characterizing archaeal-bacterial syntrophy in simplified gnotobiotic mouse models consuming different diets should provide a starting point for defining the role of archaea in shaping the functional diversity, stability, and beneficial contributions of our distal gut microbiota. Devising ways for manipulating archaeal populations may provide a novel way for intentionally altering our energy balance. A comprehensive 16S rRNA sequence–based (bacterial and archaeal) enumeration of the microbiotas of selected humans, representing different ethnic groups, living in similar or distinct milieus, would provide an invaluable database for studying normal and diseased populations^ref. The concept of using the microbiota as a biomarker of impending or fully manifest diseases within or outside of the GI tract and for monitoring responses to therapeutic interventions needs to be explored. Several groups are embarking on meta-genome sequencing projects to define gene content in the human gut microbiome. If we view ourselves as being a composite of many species, this represents a logical continuation of the Human Genome Project. A complementary approach to metagenomic analysis is to determine genome-level diversity among bacterial populations belonging to a specific genus or species residing within a defined gut habitat of a single individual or a few individuals. Members of Bacteroides provide a natural experiment for examining the impact of habitat on genome content since they have yet to be encountered in any environment other than animal GI tracts. Figure 1C illustrates how a collection of just 29 isolates phenotyped as B. thetaiotaomicron provided a broad range of 16S rRNA sequences, including several new species. We are close to producing finished genome sequences for two prominent members of the colonic microbiota, B. vulgatus and B. distasonis^ref. B. fragilis, a less prominent member, has recently been sequenced^{ref1, ref2}. The results will allow us to ask how evolutionary history relates to genome content and what constitutes a minimal Bacteroides genome. We also need to obtain a direct view of how the metabolites originating from the microbiome influence host physiology. This will be a formidable task, requiring new techniques for measuring metabolites generated by single and defined collections of symbionts during growth under defined nutrient conditions in single-vessel chemostats, in more elaborate mechanical models of the human gut, and in vivo after colonization of specified habitats of the intestines of gnotobiotic mice. The results should help formulate and direct hypothesis-based investigations of the microbiota's "metabolome" in humans. Databases that connect molecular data with ecosystem parameters are still rare^ref. A human intestinal microbiome database is needed to organize genomic, transcriptomic, and metabolomic data obtained from this complex natural microbial community, and would provide a substrate for generating testable hypotheses. Finally, just as microbiotas have coevolved with their animal hosts, this field must coevolve with its academic hosts and their ability to devise innovative ways of assembling interactive interdisciplinary research groups necessary to advance our understanding.
There is no doubt that food intake in humans is influenced by emotional factors, social cues, and learned behavior. These influences overlay highly conserved systems within the brain that sense and integrate signals reflecting overall energy stores, recent energy intake, and presence of specific classes of nutrients. The hypothalamus, especially the arcuate nucleus, is relatively accessible to circulating factors and also receives inputs from other areas of the brain. Here, signals are received that relate to total energy stores in fat and to immediate changes in energy availability, including nutrients within the gut. These 2 categories of signals are not exclusive, because signals relating to long-term energy stores, including insulin and leptin, can modulate responses to short-term nutritional inputs. The hypothalamus integrates these peripheral and central signals and exerts homeostatic control over food intake, levels of physical activity, basal energy expenditure, and endocrine systems, including those that determine reproductive competence.

Fig. 1. The brain integrates long-term energy balance. Peripheral signals relating to long-term energy stores are produced by adipose tissue (leptin) and the pancreas (insulin). Feedback relating to recent nutritional state takes the form of absorbed nutrients, neuronal signals, and gut peptides. Neuronal pathways, primarily by way of the vagus nerve, relate information about stomach distention and chemical and hormonal milieu in the upper small bowel to the NTS within the dorsal vagal complex (DVC). Hormones released by the gut have incretin-, hunger-, and satiety-stimulating actions. The incretin hormones GLP-1, GIP, and potentially OXM improve the response of the endocrine pancreas to absorbed nutrients. GLP-1 and OXM also reduce food intake. Ghrelin is released by the stomach and stimulates appetite. Gut hormones stimulating satiety include CCK released from the gut to feedback by way of vagus nerves. OXM and PYY are released from the lower gastrointestinal tract and PP is released from the islets of Langerhans

Fig. 2. Simplified representation of potential action of gut peptides on the hypothalamus. Access circulating agents into the arcuate nucleus of the hypothalamus is facilitated by a relaxed blood-brain barrier. Primary neurons in the arcuate nucleus contain multiple peptide neuromodulators. Appetite-inhibiting neurons (red) contain pro-opiomelanocortin (POMC) peptides such as  melanocyte-stimulating hormone (MSH), which acts on melanocortin receptors (MC3 and MC4) and cocaine- and amphetamine-stimulated transcript peptide (CART), whose receptor is unknown. Appetite-stimulating neurons in the arcuate nucleus (green) contain neuropeptide Y (NPY), which acts on Y receptors (Y1 and Y5), and agouti-related peptide (AgRP), which is an antagonist of MC3/4 receptor activity. Integration of peripheral signals within the brain involves interplay between the hypothalamus and hindbrain structures including the NTS, which receives vagal afferent inputs. Inputs from the cortex, amygdala, and brainstem nuclei are integrated as well, with resultant effects on meal size and frequency, gut handling of ingested food, and energy expenditure. , direct stimulatory; ---|, direct inhibitory; - - ->, indirect pathways
Short-term eating behavior is also controlled by the hindbrain. The nucleus of the tractus solitarius (NTS) receives input from vagus nerve afferents, whereas the area postrema is a target for circulating factors such as amylin and glucagon-like peptide 1 (GLP-1)^ref. Classical studies show that when higher inputs are surgically interrupted, the hindbrain can regulate food intake in response to peripheral signals^ref.
Signals of Long-Term Energy Balance
Insulin, produced by pancreatic ß cells, is vital for regulating the storage of absorbed nutrients and also acts as an adiposity signal to the brain for the regulation of energy balance^ref. Mechanisms exist for transporting insulin across the blood-brain barrier and insulin receptors are expressed in appetite-controlling areas of the brain. Administration of insulin to the brain not only reduces appetite in rodents and subhuman primates but also potentiates satiety factors such as cholecystokinin (CCK). Clinically, insulin deficiency is associated with hyperphagia in uncontrolled type 1 diabetes, and intrahypothalamic administration of antibodies to insulin or neuronal disruption of insulin receptors modestly increases food intake and body weight in rodents^ref.
Leptin is an adipocyte-derived factor, or adipokine, that is the dominant long-term signal informing the brain of adipose energy reserves^ref. Similar to insulin, leptin is transported across the blood-brain barrier, where it binds to specific receptors on appetite-modulating neurons, most notably but not exclusively in the arcuate nucleus^ref. The long form of the leptin receptor activates Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling among several other signal transduction pathways.
Leptin-deficient ob/ob mice and both db/db mice and Zucker fa/fa rats that lack functional leptin receptors are hyperphagic and obese. Apart from promoting hunger, leptin deficiency reduces energy expenditure and fecundity^ref. Exogenous leptin reverses obesity caused by its absence in mice and humans^{ref1, ref2}; however, absolute leptin deficiency is an uncommon cause of human obesity. Instead, leptin resistance results from defects in transport across the blood-brain barrier or impaired intracellular signaling. Suppressor of cytokine signaling 3 (SOCS3) is an intracellular protein that acts to limit leptin signaling and is an important mediator of leptin resistance. Although lack of SOCS3 is embryonically lethal, mice with haploinsufficiency of SOCS3 have enhanced leptin sensitivity and are protected against diet-induced obesity and its metabolic consequences^ref. Because SOCS3 also limits insulin signaling, its expression provides a potentially important point of interaction between insulin and leptin pathways that may be important in the pathogenesis of the metabolic syndrome^ref. Protein tyrosine phosphatase-1b is another factor implicated through both gain- and loss-of-function experiments as a key regulator of insulin and leptin signaling^ref.
Leptin is also produced in the stomach, where it may have local paracrine functions. Its synthesis in the stomach is regulated by nutritional state and other gut hormones^ref, but no physiological role of gut-derived leptin in appetite regulation has been established.
The Enteric Nervous System and Energy Balance
The enteric nervous system is implicated in every aspect of gut function. Mastication and defecation are under higher control, but the nervous system also exerts influence on gastric and pancreatic exocrine secretion, motility, blood supply, and secretion of gut hormones. Local signaling occurs within and between submucosal and myenteric plexuses, whereas afferent signals from the gut to the brain are carried in vagal and splanchnic nerve pathways. Vagal afferents respond to specific luminal chemical stimuli, physiological levels of distention or nutrients in the portal circulation, whereas splanchnic afferents convey information regarding noxious stimuli.
Vagal afferents originate from numerous areas within the abdominal viscera (Fig. 1) and different stimuli may be associated with different patterns of nerve firing. Responses to physical and chemical stimuli may be modulated by CCK, suggesting a degree of peripheral signal integration^ref. In the brain, c-fos–like immunoreactivity (CFLI), a marker of neuronal activation, increases in the area postrema and the NTS after feeding but not sham feeding. Specific patterns of CFLI in the NTS can be induced by balloon mimicry of gastric distention^ref or duodenal infusions of nutrients. The importance of vagal afferents for meal termination is demonstrated by surgical or chemical interruptions that prevent suppression of meal size by gastric load, suppression of sham feeding by infusion of nutrients into the gut lumen, and satiety effects of exogenous CCK during real and sham feeding.
Humoral Messengers of Gut Function
The gut is a source of numerous peptides, many of which can alter appetite. These peptides have numerous targets, including gastrointestinal exocrine glands, smooth muscle, afferent nerve terminals, and the brain. Single enteroendocrine cells appear set adrift in the gut, in contrast to the archipelago of islets within the pancreas. Yet this belies the true integration of these cells into both humoral and neural systems. These highly specialized cells within the stomach, proximal small intestine, distal ileum, and colon are polarized with their apical poles at the gut lumen "tasting" the nutritional milieu within the gut.
Secretion of gut hormones is regulated by receptors that sense specific chemical signals. The previously orphan G protein–coupled receptor (GPCR) GPR 120 is stimulated by free fatty acids (FFA) in vitro and is expressed abundantly in GLP-1–containing cells of the distal gastrointestinal tract, which release their contents in response to luminal FFA^ref. Sensing of circulating FFA by ß cells may occur by a similar mechanism involving the family of GPR 40 to GPR 43 to directly stimulate insulin release, complementing the incretin effect of GLP-1. GPCRs of the T2 receptor family, which sense bitter taste on the tongue, are also expressed in the stomach and duodenum and have been postulated to play a role in sensing luminal contents^ref. There is also evidence that the extracellular calcium-sensing receptor is located within the gut, where it acts as a sensor for aromatic amino acids in foodstuffs^ref. The fatty acid oleylethanolamide (OEA) is a ligand for peroxisome proliferator-activated receptor  (PPAR), which specifically reduces food intake by means of a vagal mechanism^ref.
Metabolic signals also play a role in stimulus-secretion coupling of enteroendocrine cells. For example, glucose stimulates secretion of GLP-1 in vitro by a mechanism involving adenosine 5'-triphosphate (ATP)–sensitive potassium channels, closure of which depolarizes the cell in a mechanism analogous to the ß cell^ref. It also appears that carbohydrate-sensing mechanisms exist that act independently of intracellular glucose metabolism^ref.
Multiple peptides may be produced and packaged in secretory granules within single cell types, whereas single peptides may have numerous effects (Fig. 1). Differential processing by prohormone convertases and other posttranslational modifications, such as acylation or sulfation, further increase the repertoire of possible signaling molecules. Likewise, multiple receptor types direct distinct physiological effects that depend on the availability of the cognate receptor in a particular cell type. In addition, many gut peptides are expressed in the brain, where they function distinctly as neuromodulators. There is a complex interplay between hypothalamic and brainstem systems; hypothalamic areas such as the paraventricular nucleus have reciprocal projections with the NTS. Hence, the anorectic effects of central leptin and peripheral CCK potentiate each other. This apparent redundancy of enteroendocrine function safeguards energy intake and allows integrated responses to signals from a variety of nutrient sources.
Satiety Peptides from the Gut
CCK is the prototypical satiety hormone, produced by mucosal enteroendocrine cells of the duodenum and jejunum and secreted in response to the presence of food within the gut lumen. Multiple biologically active forms of CCK coordinate postprandial gall bladder contraction and pancreatic secretion with gastric emptying and gut motility. Reduction in meal size is mediated by CCK1 receptors, which preferentially bind sulfated CCK on vagal afferent neurons; hence, vagotomy reduces the effect of CCK on satiety^ref. Gastric emptying is also inhibited by CCK1 receptors on the pyloric sphincter, which may contribute to satiety. Infusion of CCK in human subjects suppresses food intake and causes earlier meal termination^ref, and by contrast, infusion of a CCK1 antagonist increases caloric intake^ref.
Preproglucagon gene product yields 2 important satiety peptides, GLP-1 and oxyntomodulin (OXM). Both are released from L cells in response to nutrients in the form of FFA or carbohydrate. GLP-1(7–36) amide inhibits gastric acid secretion and emptying and stimulates the endocrine pancreas with postprandial insulin release, inhibition of glucagon secretion, and, in some species, ß-cell neogenesis^{ref1, ref2}. Circulating GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV), leading to a circulating half-life of only 2 min^ref. Long-acting DPP-IV–resistant GLP-1 agonists reduce food intake and induce weight loss when given peripherally to rats^ref. GLP-1 receptors are present in the brain, and in rats, the blockade of endogenous GLP-1 by intracerebroventricular infusion of the specific GLP-1 antagonist exendin(9–39) increases food intake and causes obesity^ref, although knockout of the GLP-1 receptor does not in mice^ref. The effect of GLP-1 on human weight is inconsistent, but a meta-analysis of studies reveals that GLP-1 treatment brings about a small reduction in food intake^ref.
OXM potently inhibits food intake when administered to rodents^ref and suppresses appetite in humans^ref by means of GLP-1–like receptors. Surprisingly, the areas of the brain stimulated by OXM and GLP-1 differ: GLP-1 activates cells in the brainstem^ref and other central autonomic control sites^ref, whereas OXM-mediated increase in CFLI is limited to the arcuate nucleus^ref. Moreover, injection of exendin(9–39) into the arcuate nucleus inhibits the effect of peripherally administered OXM but not GLP-1^ref, and studies examining mice deficient in the GLP-1 receptor suggest that these two peptides differentially regulate food intake and energy expenditure^ref. Preproglucagon also yields GLP-2 and glucagon. Although a role of GLP-2 in appetite regulation has yet to be established, administration into the brain reduces feeding in rats, possibly by means of GLP-1 receptors. GLP-2 has not been discovered to have any effect on appetite or food intake in humans^ref.
Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin hormone. Similar to GLP-1, GIP is rapidly inactivated by DPP-IV. Whereas the insulinotropic effect of GIP is diminished with diabetes, GLP-1 continues to stimulate insulin secretion even in advanced stages of the disease. Release of GIP from the duodenal K cells is stimulated primarily by ingested fat such that mice fed a high-fat diet have elevated GIP levels. Notably, food intake is not affected by centrally administered GIP^ref and knockout of the receptor protects against obesity in diet-induced and ob/ob mice in the absence of changes in food intake by increasing energy expenditure^ref. This peptide has multiple effects on adipocytes, including enhancement of insulin-stimulated glucose transport and stimulation of fatty acid synthesis and incorporation into triglycerides. Further work is needed to clarify the mechanism by which GIP promotes efficient storage of ingested energy as fat. Inhibition of this system may provide a useful anti-obesity therapeutic strategy.
The PP-fold peptide family includes neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP). All are produced as 36–amino acid, tyrosine-containing peptides and are recognized by a family of receptors. NPY, produced in the arcuate nucleus, is the most potent short-term stimulus for appetite. PYY is produced in enteroendocrine cells in the ileum and colon and is secreted after a meal, acting as an "ileal brake" to delay gastric emptying. In the brain, PYY(3–36) preferentially binds to presynaptic Y2 receptors within the hypothalamus to inhibit NPY neurons, release inhibition of proopiomelanocortin neurons, and depress feeding. The anorectic effect of PYY in rodents is controversial, but recent findings in nonhuman primates suggest that intramuscular administration of PYY(3–36) is associated with modestly reduced food intake^ref. In humans, intravenous infusion of physiological levels of PYY(3–36) does reduce caloric intake in normal weight^ref and obese subjects^ref. Malabsorptive states and diarrhea substantially increase circulating PYY.
Pancreatic polypeptide is released from specific pancreatic islet cells, primarily under nutrient control^ref, to act on Y4 and Y5 receptors in the brain and peripherally to alter exocrine pancreatic and biliary function, gastric acid secretion, and gut motility. Chronic peripheral administration of PP reduces food intake in lean and obese mice^ref, but central administration increases food intake. This disparity, also seen with PYY, may be caused by differential stimulation of Y4 receptors in the area postrema (which reduce food intake) and Y5 receptors expressed elsewhere in the brain (which increase food intake). In humans, PP reduces appetite and food intake without affecting gastric emptying ^ref.
It is clear that the field has a robust capacity to identify gut-derived factors that acutely suppress food intake in one or more experimental paradigms. Although interest in this area continues to grow, the true challenge will be to integrate the action of these multiple gut hormones. Both genetic and pharmacological approaches will be necessary to elucidate the relative importance of these numerous satiety factors to physiology, pathology, and potential therapeutics.
A Gut Peptide That Stimulates Hunger
Ghrelin is a 28–amino acid acylated hormone with appetite-stimulating and growth hormone–releasing activities mediated by the growth hormone secretagogue receptor^ref. Cells that synthesize ghrelin are located throughout the gastrointestinal tract, at highest density in the fundus of the stomach. Plasma levels of ghrelin rise during fasting and immediately before meals and fall within an hour of food intake, suggesting a role in meal initiation^ref.
In the arcuate nucleus of the hypothalamus, ghrelin activates neurons expressing NPY^ref. Stimulation of gastric vagal afferents^ref and direct ghrelin action on the dorsal vagal complex^ref also appear to mediate ghrelin signaling. However, the role of ghrelin in obesity is open to question, as ghrelin levels tend to be low in obese humans, only increasing after dietary weight loss^ref, and initial reports suggest that deletion of ghrelin ^ref or its receptor^ref does not impair food intake or substantially alter body weight. Given that intravenous administration of ghrelin increases appetite and food intake in volunteers of normal weight and increases food intake of patients with cancer-related anorexia by over 30%^ref, ghrelin or the activation of its receptor may find a use in the treatment of anorexia.
Loss of appetite and cachexia may occur in many gastrointestinal disorders, including hepatopancreaticobiliary disorders, celiac disease, gastrointestinal infections and infestations, radiation enteritis, and intestinal resection. Changes in the endocrine milieu have been reported in malabsorptive states^ref. The future availability of peptide and small molecule antagonists of gut-peptide receptors will permit testing the hypothesis that such appetite loss may be due to altered secretion of gut-derived satiety factors.
Other Peptides of Visceral Origin Potentially Linked to Energy Balance
Amylin (islet amyloid polypeptide) is a 37–amino acid peptide cosecreted with insulin by pancreatic ß cells^ref. In animal studies, synthetic amylin analogs delay gastric emptying and decrease food intake^ref, an effect mediated by the area postrema in rats. Studies in humans involving an amylin analog, pramlintide, have produced weight loss in diabetic populations^ref. The bombesin homologs, gastrin-releasing peptide and neuromedin B, reduce meal size in several species, including humans^ref.
Enterostatin is a pentapeptide cleaved from procolipase released by the exocrine pancreas. Peripheral and central administration reduce food intake in rats and alter food preference away from fatty foodstuffs, but in humans, recent metabolic studies have failed to show an effect of oral enterostatin on food intake, appetite, energy expenditure, or body weight^ref.
A Special Role for Visceral Fat in Obesity and Energy Balance?
Deposition of fat within the abdomen, so-called visceral adiposity, confers greater risk of metabolic and cardiovascular complications than does adipose accumulation elsewhere. The mechanistic basis for this association has stimulated much interest. Whereas adipose tissue was viewed as a means of storage and release of energy in response to shifts between fed and starved states, the adipocyte is now recognized as a bona fide endocrine cell. Adipocyte hormones influence appetite, glucose homeostasis, vascular function, and even reproductive competence, among other functions^ref. It is likely that adiposity within the abdomen is metabolically harmful both because of its unique anatomical relation to the hepatic portal circulation and because of the specific endocrine features of this adipose depot. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory actions that is suppressed in obesity in parallel to reduced insulin sensitivity^ref. By contrast, resistin, a 108–amino acid peptide hormone that is expressed in adipocytes in rodents and in macrophages in humans is induced in obesity and leads to insulin resistance^ref. The induction of resistin by cytokines may be a link between obesity and inflammatory states resulting in insulin resistance^ref. Visfatin is a newly discovered adipokine expressed at high levels in visceral fat that has the notable property of activating the insulin receptor by binding at a site distinct from that recognizing insulin. Visfatin stimulates glucose uptake by adipocyte and muscle cells in vitro and decreases blood glucose levels in mice^ref. It is a paradox that an insulinomimetic factor is produced by visceral fat in a state of insulin resistance. Further studies will be required to elucidate a physiologic role for visfatin and whether resistance to its action is seen in insulin-resistant states.
Obese Zucker rats overexpress the glucocorticoid reactivating enzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in adipose depots, presenting the possibility of "Cushing's disease of the omentum" resulting from local overproduction of cortisol in humans. Mice overexpressing 11ß-HSD1 in fat are hyperphagic, have visceral obesity, and develop insulin-resistant diabetes and hypertension^ref. Conversely, mice with global deletion of 11ß-HSD1 are protected from diet-induced obesity and related hyperglycemia. In humans, increased 11ß-HSD1 expression and activity has been reported in adipose tissue in some but not all studies.
Thanks to dentists, "open wide" has become a command to fear. A century ago, dental practitioners depended on a shot of whiskey and pliers to treat toothaches and sore gums. Today's dentists have laser drills and Novocain, but they haven't completely shed the aura of pain. In the near future, however, the tools of choice may be less scary: a DNA test followed by a chaser of "good" bacteria, for example. Over the past 40 years, oral biologists have been taking stock of the vast microbial communities thriving on and around teeth, gums, and the tongue. It's been known for quite some time that bacteria that normally reside in the mouth can escape to other parts of the body and cause problems. There's a well-substantiated link between one oral pathogen and heart problems, for example. And last year, tests in mice lent support to the theory that a common mouth bacterium can slip into the bloodstream of pregnant women and infect their uterus and placenta, eventually causing premature births. But poor oral health also causes harm directly. 3 out of 10 people over 65 have lost all their teeth. In the United States, half of all adults have either gum disease or tooth decay; Americans spend more than $60 billion a year to treat tooth decay alone. Indeed, cavities are the single most common chronic disease of childhood, with a rate five times greater than that seen for the next most prevalent disease, asthma. Adding insult to injury, about one-third of the general population also suffers from halitosis, better known as bad breath. A lot of those problems can be traced to the mouth's microbes, say oral biologists. In healthy mouths, "good" bacteria and other microbes compete with nefarious cousins and keep them in check. But if conditions change, pathogenic microbes can gang up against the beneficial species and gain control of the mouth's surfaces. Bleeding gums, cavities, and bad breath can result. By comparing healthy mouths to unhealthy ones, researchers are now rooting out the problematic microorganisms, which include bacteria, viruses, fungi, and even archaea. In addition, efforts to sequence the genes, if not the whole genomes, of oral microbes are helping identify the villains in the mouth and how they trigger disease. We've been able to get a better understanding of the variety and scale of the microorganisms that are present. The new research clearly shows that the mouth is a complex ecosystem. Some microbial species are pioneers, producing proteins that serve as welcome mats to later colonizers. It's also become evident that in the mouth, microbes gang up to cause troubles. Unlike other infectious diseases, we are looking at infections that are caused by more than one organism. The study of oral bacteria goes back almost 400 years. When Dutch glassmaker Antony van Leeuwenhoek began using microscopes to study the human body, the microbial world of the mouth opened up to him. He examined samples of plaque from his own teeth and made some of the first drawings of what we now call bacteria. His notes set the stage for oral microbiology.He pointed out the nature of the diversity in the mouth. Since then, there's always been a sense that the community is what matters; the community is capable of doing things that individual species cannot. Still, it didn't hit home that many oral problems came from microbes until the 1960s, when Sigmund Socransky of the Forsyth Institute in Boston, Massachusetts, discovered bacteria buried in the gums of people with trench mouth. Soon afterward he and Forsyth's Anne Haffajee found that the population of microbes associated with plaque-encrusted teeth changes with the severity of the disease, indicating that more than one microbe is involved. It also became clear that bacteria grow in thin layers--called biofilms--on the mouth's surfaces. Studying these biofilms, however, was problematic. Researchers would try to use a cheek swab or tooth scraping to grow oral microorganisms in the lab, but only about half the microbial species took hold, leaving a knowledge gap. In the early 1990s, Socransky and colleagues developed a method, called checkerboard DNA-DNA hybridization, that greatly sped up the characterization of the bacterial community in an individual's mouth. Instead of being limited to analyzing 100 samples per year, they could look for 40 bacteria in 28 samples simultaneously. Since then, oral biologists have added another tool to their repertoire; they've been identifying oral bacteria that have yet to be cultured by differences in the gene for 16S, a ribosomal RNA subunit. Using this latter approach, extensive databases of 16S gene sequences collected from different parts of the mouth have been built. Each sequence represents a different microorganism. Collectively speaking, there are over 700 species in the human oral cavity, of which over half cannot yet be grown. With a microarray with all the 16S genetic sequences on it you can quickly assess the microbial profiles of each mouth. To a microbe, the mouth is a planet full of different surfaces and environmental conditions. Not surprisingly then, oral microbes have their favorite homes--teeth or the tongue, for example. In each case, if you can figure out which organisms should be present during health, that may lead us down the road to find some way of trying to encourage those to survive. Like the microbes they study, oral biologists tend to specialize in particular areas of the mouth and the diseases arising there. Some researchers analyze microbial invasions of teeth. That's the site of perhaps the most studied mouth microbe, Streptococcus mutans. This bacterium colonizes the teeth of almost every child and feeds off sugar in the mouth, generating lactic acid that destroys tooth enamel and leads to lesions known as caries or cavities. It's the microbes that reside in the deepest part of the narrow crevice between the gums and the base of the tooth that are of great interest. In a healthy mouth, there's a tight fit between the tooth and the gum collar. But if disease sets in, the crevice widens and deepens, gums swell and bleed, and teeth loosen. Some of these more troublesome microbes are archaea, members of a group of microbes best known for thriving in extreme conditions. The researchers initially found these archaea in a third of 58 people with diseased crevices but not in individuals with healthy mouths. The more severe the disease, the larger the archaea population--and that population shrank with treatments that lessened gum disease. Oral disease involves all sorts of organisms that we've never thought of. Paster's chosen territory is the tongue. He's pinpointed 92 groups of microorganisms living there and is homing in on species that may create bad breath. In early 2003, Paster and his colleagues compared data from six people with bad breath to five without it. There were key differences in the microbial milieu of the two groups' mouths. Three bacterial species thrived in the healthy mouths but not in the six mouths with bad breath. Paster's team also identified a half-dozen microorganisms on foul-smelling tongues that were not found on the sweet-smelling ones. In an experiment whose data have yet to be published, they have confirmed that the tongue's microbial makeup is important in halitosis. The investigators tracked the microbial communities on the tongues of 33 people with halitosis before and after their bad breath was eliminated through daily scraping of the tongue and use of mouthwash and toothpaste containing zinc. As halitosis lessened, the tongue's microbial communities changed. Sometimes a microbe in one oral setting helps other microbes establish themselves elsewhere. Take the gram-positive bacterium called S. gordonii. These microbes settle on the saliva film coating teeth early in life by recognizing certain saliva proteins, which they proceed to break down and use as nutrients. In turn, surface proteins of the streptococci attract other bacteria, such as the pathogen Porphyromonas gingivalis. It attaches to the streptococci to get a toehold at the tooth-gum interface. But in a matter of minutes, it moves on to invade the gum's epithelial cells. To help understand how P. gingivalis colonizes the gums, Lamont has recently chronicled the pathogen's changing repertoire of proteins. Using a series of analytical techniques, including tandem mass spectrometry, capillary high performance liquid chromatography, and two-dimensional gel electrophoresis, he and his colleagues documented that the bacterium made about 220 new proteins when it encountered gum epithelial cells. Many of them are surface proteins that likely establish a nutrient pipeline from the host or protect the bacteria from immune responses. Although the genomes of dozens of microbes are now in the public databases, the sequencing of oral bacteria is just ramping up. Thus far, researchers have sequenced seven species that settle in the mouth, and a half-dozen more are in the pipeline, says Dennis Mangan, a microbiologist at the National Institute of Dental and Craniofacial Re-search (NIDCR) in Bethesda, Maryland, which supports the sequencing projects. And in late December 2004, NIDCR started a 3-year study with Relman and The Institute for Genomic Research in Rockville, Maryland, to catalog all the microbial genes in the mouth. For this project, Gary Armitage of the University of California, San Francisco, will collect DNA samples from seven sites in the mouth--the teeth, gums, tongue, palate, cheek, and so on--from a mix of people in different states of oral health. He and his colleagues estimate that the project will identify about 40,000 genes by its conclusion. "We will have a good handle on those organisms that are associated with health and those organisms that are associated with disease, and what genes are prevalent in disease," says Lepp. With that knowledge, researchers may be able to pinpoint weaknesses in pathogenic oral microbes or learn how to boost the mouth's response to microbial attacks. That might ultimately lead to mouthwashes that inhibit just bad mouth microbes instead of good and bad alike, or to drugs that disable the surface proteins microbes use to infect the mouth. Armed with the growing understanding of the mouth microbial ecosystem, one company, Oragenics Inc. in Alachua, Florida, has already taken steps to pit bacteria against bacteria in the battle for healthy teeth. The approach, called replacement therapy, would use genetically modified S. mutans bacteria to supplant normal cavity-causing ones; the altered germs don't make lactic acid. The company's microbe-laden mouthwash has been controversial, however, and the Food and Drug Administration put the first clinical trials of it on hold because of concerns that the researchers couldn't guarantee that, should something go wrong, they could get rid of the microbes once in the mouth. But in December 2004, Oragenics got approval to continue the trial with denture wearers whose dentures--and bacteria--could be removed if a problem occurs. It may be years before Oragenics's cavity-fighting bacterium makes it into dental practice. And it's not clear how popular this particular approach will be. But Mangan is convinced that all the work characterizing the mouth's microbial communities will eventually have a big payoff. "[It's] going to point to ways to control the numbers and the species of bacteria there, particularly the dangerous ones," he says. That could make cavities, gum disease, and bad breath a thing of the past--and bring a healthy smile to the mouths of many people. The gastrointestinal tract is the site where the divergent needs of nutrient absorption and host defense collide: The former requires a large surface area and a thin epithelium that has the potential to compromise host defense. Many infectious diseases involve the gut, and the investment by the gut in protecting itself is evident in the abundant lymphoid tissue and immune cells it harbors. In westernized countries, most infectious diseases of the gut are largely under control, yet gastrointestinal food allergies and idiopathic inflammatory conditions have dramatically increased; in other words, we now have inflammation without infection. Although the reason for this remains unknown, a prevailing notion is that the absence of overt gut infection has upset the balance between the normal bacteria that colonize the healthy gut and the mucosal immune system. The primary cellular barrier of the gut in preventing antigens encountering the immune system is the single layer of gut epithelium, the surface area of which is expanded to the order of 400 m², largely because it is formed into millions of fingerlike villi in the small bowel. Each epithelial cell maintains intimate association with its neighbors and seals the surface of the gut with tight junctions. In the upper bowel, the bulk of the antigen exposure comes from diet, whereas in the ileum and colon, the additional antigenic load of an abundant and highly complex commensal microflora exists. Nevertheless, the gut epithelial barrier does not completely prevent lumenal antigens from entering the tissues. Thus, intact food proteins can be detected in plasma^ref, and a few gut bacteria can be detected in the mesenteric lymph nodes draining the gut of healthy animals^ref. Antigens can cross the epithelial surface through breaks in tight junctions, perhaps at villus tips where epithelial cells are shed, or through the follicle-associated epithelium (FAE) that overlies the organized lymphoid tissues of the intestinal wall^ref. Peyer's patches (PP) in the small bowel are aggregates of lymphoid tissue numbering 200 in the average adult, although tens of thousands of much smaller individual follicles also line the small bowel and colon. FAE contains specialized epithelial cells termed M cells whose function is to transport lumenal antigens into the dome area of the follicle^ref (Fig. 1). Antigen-presenting dendritic cells (DC) also send processes between gut epithelial cells without disturbing tight junction integrity and sample commensal and pathogenic gut bacteria^{ref1, ref2}. The gut epithelial barrier therefore represents a highly dynamic structure that limits, but does not exclude, antigens from entering the tissues, whereas the immune system constantly samples gut antigens through the FAE and DC processes.

 Fig. 1. The gut makes a huge investment in maintaining an extensive and highly active immune system. The epithelium overlying organized gut-associated lymphoid tissue (GALT) contains specialized M cells that constantly transport gut bacteria and antigens from the gut lumen into the lymphoid tissue. DC in the LP reach through epithelial cells and also sample gut bacteria. The epithelium is filled with CD8⁺ T cells, and the LP contains many CD4 T cells, macrophages, and IgA antibody–producing plasma cells. Potentially tissue-damaging T cell responses may be inhibited by immunosuppressive cytokines and regulatory T cells.
Interaction of commensals with gut epithelium. The gut epithelium itself can also directly sense commensal bacteria and pathogens; integral to this are the mammalian pattern recognition receptors (PRRs), which recognize conserved structures of bacteria and viruses and generally activate pro-inflammatory pathways alerting the host to infection^ref. 2 different classes of PRRs are involved. The Toll-like receptors (TLRs) are usually associated with cell membranes and have an external leucine-rich repeat (LRR) recognition domain and an intracellular interleukin-1 receptor (IL-1R)–like signaling domain^ref. The nucleotide-binding oligomerization domain (Nod) molecules, Nod1 and Nod2, are present in the cytosol of epithelial cells and immune cells. These proteins also have LRRs at the C terminus, a Nod domain, and CARD domains at the N terminus^ref. There is abundant evidence that signaling through Nod or TLR activates transcription factor NF-kB, leading to pro-inflammatory gene expression^{ref1, ref2} TLR1 to TLR9 and Nod1 and Nod2 are each expressed by gut epithelial cells^{ref1, ref2}. Nod1 and Nod2 recognize slightly different muropeptide motifs derived from bacterial peptidoglycans^ref, which suggests that they sense intracellular infection or attempted bacterial subversion of epithelial cells^ref. TLRs recognize many different components of bacteria and viruses. For example, TLR4 recognizes lipopolysaccharide from the Gram-negative bacterial cell wall, and TLR5 recognizes bacterial flagellin^{ref1, ref2}. An unresolved question is how the gut distinguishes between pathogens and commensal bacteria. One means by which inappropriate responses to innate signals from commensals may be achieved is through the compartmentalization of TLRs to the basolateral aspects of epithelial cells or inside epithelial cells^{ref1, ref2}. Mutualism also appears to exist between the commensal flora and the gut epithelium to maintain epithelial integrity. For example, recognition of TLR2 or TLR9 ligands by epithelial cells increases gut barrier function^{ref1, ref2}. The normal flora also induces cytoprotective proteins hsp25 and hsp72 in colonic epithelial cells^ref. Mice deficient in MyD88, the adapter molecule essential for TLR signaling, fail to express epithelial hsp25 and hsp72^ref and are highly susceptible to experimental inflammatory bowel disease (IBD) initiated by dextran sodium sulfate, which suggests that through TLR signaling, the bacterial flora may help protect the gut epithelium from nonspecific damage. Nonpathogenic microorganisms in the gut have also been shown to regulate inflammation negatively in other ways^{ref1, ref2}. For example, avirulent Salmonella inhibits activation of NF-kB in epithelial cells by blocking polyubiquitination of phosphorylated IB^ref. Overall, there is good evidence that the normal commensal flora exerts an anti-inflammatory influence and protects epithelial cells from toxic insult. Epithelial pro-inflammatory responses to the commensal flora exist in vitro^{ref1, ref2}, but most individuals maintain an abundant intestinal flora without incurring disease. Interactions of commensals with the mucosal immune system. Healthy individuals possess an abundant and highly active gut immune system that is tightly regulated to prevent excessive immune responses to foods and gut bacteria (Fig. 1)^{ref1, ref2}. A major difference between the systemic and mucosal immune system is the anatomical separation of the inductive sites of mucosal immunity in the organized lymphoid tissue, such as PP, from the effector sites in the lamina propria (LP) and epithelium (Fig. 1)^ref. When T and B cells are activated in PP, they express the 4ß7 integrin and migrate to the blood^ref. Gut-specific homing is achieved by expression of the ligand for a₄ß₇, MADCAM-1, on gut endothelial cells, which allows PP-derived cells to migrate through blood vessels into the LP^ref. Chemokines produced by either colon or small bowel epithelial cells fine-tune the localization of lymphocytes to these tissues^ref. The LP is filled with antibody-producing plasma cells that secrete between 3 and 5 g of the IgA immunoglobulin isotype into the gut lumen each day^ref. Numerous other immune cells also reside in the gut LP, including large numbers of CD4+ T cells (T. T. MacDonald, G. Monteleone, in Mucosal Immunology, J. Mestecky, J. Bienenstock, M. Lamm, W. Strober, J. McGhee, L. Mayer, Eds. (Elsevier, San Diego, CA, ed. 3, 2005), pp. 407–413), macrophages, DC, mast cells, and eosinophils^ref. The gut epithelium also contains abundant intraepithelial lymphocytes (IEL)^ref, an intriguing population made up mostly of CD8⁺ T cells. Compared with other tissues, IEL are enriched in T cells expressing the  T cell receptor and often express the homodimeric form of the CD8 coreceptor^ref. The exact function of IEL is not known, although it has been suggested that they may play a role in epithelial tumor surveillance, protection against epithelial pathogens, or promotion of healing of the gut after injury^{ref1, ref2}. The presence of an extensive and activated intestinal immune system depends on the commensal flora. Thus, mice bred under germ-free conditions possess small, underdeveloped PP lacking germinal centers, few IgA plasma cells and CD4 cells in the LP, and reduced numbers of IEL. Furthermore, reconstitution of germ-free mice with a microbial flora is sufficient to restore the mucosal immune system^{ref1, ref2}.  The relationship between the immune system and the commensal flora is a precarious one, and perturbations in immune or epithelial homeostasis can lead to gut inflammation. In this situation, the commensal flora appears to act as a surrogate bacterial pathogen, and it is thought that lifelong inflammation ensues because the host response is incapable of eliminating the flora. Chronic inflammatory bowel disease in humans. Two main types of IBD exist: Crohn's disease and ulcerative colitis (UC)^ref. Patients suffer from chronic diarrhea and weight loss, abdominal pain, fever, and fatigue. Extra-intestinal manifestations can also occur, including skin ulcers, arthritis, and bile-duct inflammation, the last especially in UC. Both UC and Crohn's disease are characterized by mucosal ulceration, which is patchy in Crohn's disease but continuous in UC (Fig. 2). In Crohn's disease, ulcers penetrate into the gut wall, and fistulous tracts may develop between loops of bowel or to the skin. The downstream effector pathways that drive tissue injury are similar to those in immune-mediated diseases in other organs. Thus, excess immune activation leads to an influx of inflammatory cells from the blood and to increased concentrations of cytokines, free radicals, and lipid mediators. There is also massive overexpression of matrix-degrading enzymes, the matrix metalloproteinases, by fibroblasts, which are ultimately responsible for ulceration and fistulae (T. T. MacDonald, S. L. Pender, in Kirsner's Inflammatory Bowel Disease, R. B. Sartor, W. J. Sandborn, Eds. (Saunders, London, 2004), pp. 163–178).

 Fig. 2. Histological appearance of (A) normal colon, (B) Crohn's disease, and (C) ulcerative colitis. The normal colon contains glands filled with mucus-producing goblet cells. The image contains a small lymphoid follicle with FAE on the left. In the low-power image of Crohn's disease, the massive mucosal thickening and distortion of the glands is evident, there is a massive lymphoid infiltrate, and an ulcer penetrates through the mucosa from the lumen into the submucosa. In ulcerative colitis, the mucosa is also massively thickened and filled with inflammatory cells. Numerous neutrophil-filled crypt abscesses are present

	Crohn's disease	Ulcerative colitis	Celiac disease
Incidence	Presently 10-200/100,000 per year. Increased 8 to 10-fold since 1960s.	10-20/100,000 per year. Incidence stable since 1960s.	Around 0.5% of the European and North American population
Distribution	A disease of westernized societies, with the highest incidence in northern Europe. Excess of cases in urban compared with rural environments.	UC is seen world-wide and appears to show no relation with westernization or affluence.	Restricted to regions of the world where wheat, barley, and rye are a major part of the diet
Cause	Probably an excessive cell-mediated immune response to antigens of the normal bacterial flora.	Unknown, but perhaps an organ-specific autoimmune disease.	An excessive cell-mediated immune response to the storage proteins of wheat, barley, and rye (gluten) in individuals with HLA-DQ2 or HLA-DQ8 haplotypes.
Site of disease	Can affect any part of the gut from mouth to anus, but most commonly occurs in the ileum and colon. The lesions are characteristically patchy, with areas of normal mucosa between ulcers (skip lesions). Some extra-intestinal involvement.	UC first occurs in the rectum and, as disease progresses, lesions become more proximal. Inflammation is continuous and is restricted to colon.	Upper small intestine—the duodenum and jejunum
Inflammatory response	Inflammation consists mainly of T cells and macrophages. Granulomas are seen in just over half the cases. Inflammatory cells are present throughout the gut wall, and deep fissuring ulcers can lead to fistulae. Fibrosis of the external muscle layers frequently occurs.	Inflammation is restricted to the mucosa. Neutrophils are the major infiltrating inflammatory cells. These form crypt abscesses and damage the epithelium. There is loss of mucus-secreting goblet cells.	Inflammation restricted to the mucosa. There is a marked mono-nuclear infiltrate into the lamina propria and an increase in the density of intraepithelial lymphocytes, which results in a transformation of mucosal structure from a situation of long villi and short crypts to the flat mucosa, with short or absent villi.
Other features	Smoking is a risk factor for Crohn's disease	Smoking appears to protect against the development of UC, as does appendectomy	Celiac patients show an increased prevalence of autoimmune diseases
Treatment	Corticosteroids, azathioprine, antibody to TNF	Corticosteroids, azathioprine, aminosalicylates	Gluten-free diet

Crohn's disease bears the immunological stigmata of an exaggerated CD4 T helper cell type I response. Thus, intestinal CD4 T cells isolated from Crohn's patients produce large amounts of the T_h1 signature cytokine interferon-g^ref and display marked overexpression of the T_h1 cell–specific transcription factor, T-bet^ref. Mucosal macrophages from Crohn's patients also produce large amounts of the T_h1-inducing cytokines IL-12^ref and IL-18^ref. T_h1 cell resistance to apoptosis and increased cell cycling in Crohn's disease inflammation appear to be sustained by cytokines^{ref1, ref2}. Blocking the pathways that confer resistance of T_h1 cells to apoptotic stimuli and the use of drugs that enhance mucosal T cell death, such as the immunosuppressive agent azathioprine or the antibody to TNF, Infliximab, are effective in down-modulating intestinal inflammation^{ref1, ref2, ref3}. Identifying the particular antigen(s) that drive the T_h1 inflammatory response in the face of the myriad of potential antigens in the gut has proven difficult. Nevertheless, the likelihood is that bacterial antigens are involved, because stimulation of mucosal CD4 cells from Crohn's disease patients with extracts of their own commensal flora can induce interferon-g production^ref, and in murine colitis, flagellin from commensal bacteria also activates mesenteric lymph node CD4 cells^ref. Clinical observations also support a role for antigens derived from the commensal flora. Thus, for example, the antibiotic metronidazole is of therapeutic benefit in Crohn's disease of the distal colon^ref. Gut inflammation induced by the commensal flora: Evidence from animal models. The more than 30 models of IBD in rodents fall into four major groups: colitis that develops spontaneously, chemically induced colitis, colitis that develops from defects in epithelial barrier function, and colitis in mice in which the immune system has been genetically manipulated or regulatory cell function has been disrupted^ref. In a number of these models, the absence of commensal bacteria under germ-free conditions leads to an absence of or reduction in disease (R. B. Sartor, in Kirsner's Inflammatory Bowel Disease, R. B. Sartor, W. J. Sandborn, Eds. (Saunders, London, 2004), pp. 138–162). Consistent with evidence from human IBD, there is evidence in some models that CD4 T cell lines reactive to enteric bacterial antigens can cause colitis^ref, although no individual component of the flora has been yet identified as being specifically important. Nevertheless, in some models, particular bacteria species have been shown to cause disease^ref. For example, in HLA-B27 transgenic rats, monoassociation with Bacteroides vulgatus induces colitis, while Escherichia coli elicit no lesions. In IL-10–deficient mice, although B. vulgatus does not induce colitis, commensal E. coli can induce disease^ref. These models have been enormously important in demonstrating that immune responses to the flora can cause IBD, as well as the numerous pathways that can lead to chronic gut inflammation^ref. Crohn's disease susceptibility genes and their relation to innate immunity and intestinal permeability. Crohn's disease and UC represent complex genetic diseases but also tend to run in families. Genome-wide mapping has identified Crohn's disease susceptibility loci on chromosomes 1, 5, 6, 12, 14, 16, and 19^ref. In 2001, 2 groups mapped the locus on chromosome 16 to Nod2^{ref1, ref2}. 3 major polymorphisms have been specifically associated with 15% of Crohn's disease cases (Arg702Trp, Gly908Arg, and Leu1007fsinsC), and all are in, or around, the LRR region of the protein required for recognition of bacterial muramyl dipeptide (MDP). Individuals who carry two copies of the risk alleles have a 20- to 40-fold increase in their risk of developing Crohn's disease. About 8 to 17% of Crohn's patients carry two copies of the major risk-associated alleles, compared with 1% of the general population. Interestingly, Nod2 has not been found to be associated with Crohn's disease in Japan^ref, again highlighting the complex nature of this disease. Nod2 is expressed in the cytosol of gut epithelial cells, macrophages, and DC^ref. After ligand binding, Nod2 oligomerizes and recruits RICK/RIP, which leads to phosphorylation and degradation of IB and activation of NF-kB^ref. A consequence of mutations in Nod2 may therefore be a decreased ability to kill gut bacteria^ref. Consistent with this, monocytes from patients with common Crohn's disease mutations show defective activation of NF-kB and IL-8 secretion when stimulated with MDP^ref. Interestingly, Nod2-deficient mice do not develop spontaneous gut inflammation^{ref1, ref2}, and their macrophages show normal NF-kB activation and pro-inflammatory cytokine production to ligands for TLR3, 4, and 9. However, they secrete large amounts of IL-12 in response to TLR2 ligands^ref. Concomitant activation through Nod2 inhibits TLR2 induction of IL-12 in cells from wild-type mice but has no effect in Nod2-deficient mice, suggesting that enhanced IL-12 production in Crohn's disease may be due to a failure of Nod2 to negatively regulate TLR2 signaling, which then facilitates a T_h1 response through IL-12. It is not known whether Nod2-mediated negative regulation of TLR2 signaling occurs in Crohn's patients bearing the common mutations. In other studies, macrophages from mice engineered to express the 3020insC Nod2 mutation show increased activation of NF-B and increased IL-1ß and IL-6 production when activated with MDP, which suggests that Nod2 mutations may, in some situations, lead to a gain of function and increased pro-inflammatory cytokine production^ref. Nod2-deficient mice are also unusually susceptible to intestinal infection with the pathogen Listeria monocytogenes^ref and have been found to be deficient in cryptdin 4 and 10, bacteriacidal defensins produced by Paneth cells found in small intestinal crypts^ref. In the human gut, Nod2 is highly expressed in Paneth cells^ref, and reduced defensin expression has been reported in Crohn's patients with Nod2 mutations^ref. Nod2 mutations may thus also predispose to Crohn's disease indirectly by reducing defensin-mediated innate antimicrobial immunity. 2 other genes associated with Crohn's disease have been identified. The first of these, located on 5q31, encodes the organic cation transporter (OCTN) genes, and mutations at these loci affect the ability of the transporters to pump xenobotics and amino acids across cell membranes^ref. In the gut, these genes are expressed in epithelial cells, macrophages, and T cells, correlating closely with their potential function in IBD. The second gene is located on 10q23 and encodes the guanylate kinase DLG5^ref. The mutation in this gene involves a single amino acid substitution that is thought to impair the ability of DLG5 to maintain epithelial polarity. Both genes may be important in epithelial permeability, and disruption of this function could lead to inappropriate exposure of the mucosal immune system to bacterial products. The other major antigenic challenge facing the gut derives from ingested food antigens. Under normal circumstances, oral administration of protein antigens induces systemic unresponsiveness when the same antigen is given parenterally (a phenomenon known as oral tolerance). In animal models, oral tolerance appears to be a specific consequence of the immune environment in the gut, which favors the generation of T regulatory cells^ref. In recent years, food allergy has become increasingly common, and although there has been little progress in understanding host mechanisms involved at the molecular level, there has been great progress in clinical management^ref. In contrast to the lack of progress in understanding food allergy, huge progress has been made in understanding celiac disease. This condition occurs in some genetically susceptible individuals after the ingestion of cereal products, including those from wheat, barley, or rye, and the disease is treated by adherence to a gluten-free diet (Table 1). Many celiacs are undiagnosed (silent celiacs); the disease may affect as many as 0.5 to 1% of the European and North American population. Celiac disease shows classical morphological changes to the mucosa of the upper bowel, with long crypts and partial or complete atrophy of villi. Celiac disease involves four components: gluten; T cells; the major histocompatability complex locus HLA-DQ; and the endogenous enzyme, tissue transglutaminase (tTG). The past 10 years have seen a huge increase in our understanding of the immunology of celiac disease and how the interplay among these 4 components produces enteropathy. The original gluten-specific T cell clones isolated from intestinal biopsies of celiac patients were found to respond to a peptic/tryptic digest of gluten restricted by HLA-DQ2^ref. The peptide anchor positions of HLA-DQ2 preferentially bind negatively charged amino acids^ref, yet gluten, which is very proline and glutamine rich, has very few such residues. A key observation in helping resolve this was that tTG, which is expressed ubiquitously in the gut, can deamidate glutamine to glutamic acid, producing the negatively charged residues necessary for efficient binding to DQ2 and for T cell activation^ref. In theory, the identification of the immunogenic peptides in gluten would allow the derivation of genetically modified cultivars of wheat that would not cause disease. A polypeptide of 2 gliadin (residues 57 to 89) appears to survive digestion in the gut^ref. Interestingly, this polypeptide contains three concatemerized epitopes that are recognized by T cells from celiac patients and can be deamidated by tTG; removing this polypeptide could, theoretically, make gluten much less able to activate T cells. However, the in vivo situation is complex because T cell clones have been identified, especially from celiac children, which recognize epitopes of high molecular weight glutenins and diverse gliadin epitopes^{ref1, ref2}. It may therefore not be possible to remove all disease-inducing T cell epitopes from wheat. An alternative approach may be to modify gluten epitopes so that they tolerize T cells^ref. A polypeptide of A-gliadin (residues 31 to 49) produces rapid villus atrophy when infused into the gut of celiac patients^ref, but of the many T cell lines and clones made against gluten peptides, only a single T cell line clone has been identified that recognizes peptide 31-49^ref. However, if a similar peptide, 31-43, is added to ex vivo cultured biopsies from celiac patients, within hours there is a rapid increase in HLA-DR mRNA, an increase in the number of macrophages making IL-15, and phosphorylation of p38 MAPK^ref, which suggests T cell–independent innate immune activation by gluten. A number of potential pathways exist to explain the effector mechanisms that cause the pathology in celiac disease. One of the primary pathways is thought to involve the major histocompatibility complex class I chain–related gene (MICA), which is a dominant ligand for the NKG2D-activating receptor on human NK cells and CD8 T cells. The addition of peptide 31-49 to biopsies of treated celiac disease patients increases MICA on epithelial cells, which can be blocked by antibody to IL-15 and recapitulated by recombinant IL-15^ref. NKG2D is expressed on the majority of IEL, and MICA epithelial cells have been shown to be killed by NKG2D + IEL^{ref1, ref2}. It is possible therefore that+some peptides of gliadin may activate gut macrophages to produce IL-15, which then increases MICA on epithelial cells and arms IEL to kill MICA⁺ epithelial cells. Celiac disease is also marked by a significant increase in the numbers of  cells, yet their possible role in this condition is not established.  Recent years have seen the identification and characterization of dedicated regulatory T cells, in both mice and humans, that have the ability to profoundly suppress a variety of immune responses^{ref1, ref2}. These regulatory T cells have been shown to be able to significantly control gut inflammation in mouse models of IBD^ref and appear to mediate their effects through the cytokines IL-10 and TGFß₁^ref. Other work has shown that such cells with specificity for gut bacteria can also inhibit colitis^ref. It is still not clear whether there is active suppression of T cell responses to the flora in normal mice, because systemic injection of antigens cloned from commensal flora results in a vigorous T cell response, suggesting ignorance rather than specific immune tolerance. Compared with their characterization in the mouse, relatively little is known about regulatory T cells in the human gut^ref. However, the potential for regulatory T cells to suppress IBD in humans through the production of immunosuppressive TGFß is theoretically limited, because inflammatory cells in IBD lesions express high levels of Smad7, which prevents TGFß signaling and immune down-regulation^ref. Nevertheless, the possible role of T regulatory cells in controlling immune responses to bacterial flora in both mice and humans is a question that needs further investigation. An understanding of how the gut remains disease free in the face of constant immune challenge may involve the separation of the inductive sites in the PP from the effector sites in the rest of the mucosa (Fig. 3)^ref. Because T cells in the PP may potentially respond to all gut antigens, the problem of activated cells accumulating in the PP is solved by T cells leaving and migrating to the LP. If the T cell has specificity for a pathogen invading the mucosal tissues, antigen-driven cell-mediated immunity in the LP would ensue. However, if the T cell had responded to an antigen from a commensal or a food antigen, in a healthy individual, the epithelial barrier would help prevent the antigen from entering the LP. The few commensal organisms that do cross the barrier will be phagocytosed and killed by macrophages without provoking pro-inflammatory cytokine production^ref, and in the absence of reactivation the T cells would die by apoptosis.

Fig. 3. Increased epithelial permeability may be important in the development of chronic gut T cell–mediated inflammation. CD4 T cells activated by gut antigens in Peyer's patches migrate to the LP. In healthy individuals, these cells die by apoptosis. Increased epithelial permeability may allow sufficient antigen to enter the LP to trigger T cell activation, breaking tolerance mediated by immunosuppressive cytokines and perhaps T regulatory cells. Pro-inflammatory cytokines then further increase epithelial permeability, setting up a vicious cycle of chronic inflammation
If this notion is correct, then situations in which the normal flora either enters in increased numbers or persists in the LP should lead to T cell activation and Crohn's-like disease. To support this notion, children with genetic defects that lead to impaired killing of commensal bacteria by phagocytes can develop a condition virtually indistinguishable from Crohn's disease^{ref1, ref2}. Furthermore, some healthy relatives of Crohn's patients have increased intestinal permeability^ref, which suggests that genetically determined epithelial permeability is an important contributing factor in the development of disease. Chimeric mice with patchy increases in small intestinal epithelial permeability also develop spontaneous transmural Crohn's-like inflammation^ref. Considered together, such data suggest that a major determinant in the initiation of mucosal inflammation is the ability of antigen to enter into the LP and trigger T cell activation. In the evolutionary battle against infectious disease, the immune system cannot afford to err on the side of caution, because failure to mount effective and vigorous immune responses will be exploited by pathogens. This is best exemplified by celiac disease, in which the high prevalence of HLA-DQ2 in the general population suggests an evolutionary advantage of this allele against infection, even in the face of the negative effects of the coincidental affinity of gluten peptides for HLA-DQ2 to cause celiac disease. With this in mind, it is probably unrealistic to prevent chronic inflammatory diseases, especially in the gut, so attention has to be paid to new treatments based on understanding disease at the molecular level. Great advances have already been made, with the best to date being the therapeutic antibody to TNF, Infliximab, in Crohn's disease. At the same time, in the gut there is a silent partner whose influence on the host immune response is only beginning to be appreciated, namely the commensal flora. There are clear indications that the flora is beneficial but also has the potential to be harmful, and increasing knowledge of how the flora interacts with the immune system should allow exploitation of the former and minimization of the latter.
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