The small and large intestines are contiguous and occupy most of the abdominal cavity. Working in concert, and with remarkable efficiency, they are responsible for several complex functions including digestion and the absorption of nutrients, among them vitamins and trace elements. Other functions include fluid and electrolyte transport, excretion, and physical and immunologic defense mechanisms.
The intestines are morphologically adapted to serve these functions, with distinct regional and anatomic variations. The digestion and absorption of nutrients is almost solely restricted to the small intestine. Fluid and electrolyte transport occur along the entire length of small and large intestines, with most of it taking place in the small intestine.
The mucosal surface of the small intestine is covered by finger-like luminal projections, called villi, which amplify surface area for nutrient absorption. However, this remarkable adaptation unfortunately serves as a double-edged sword, providing a massive interface for possible antigenic interaction with the environment. This interface is modulated via the activity of the immunoendocrine system and the integrative functions of the enteric nervous system. The enteric nervous system is an independent nervous system within the wall of the digestive tract with the ability to generate and modulate essential gastrointestinal tract functions without input from the autonomic or central nervous system.
There is a growing understanding of the complex processes of nutrient digestion and absorption and the roles of hormones and neurotransmitters in intestinal motility regulation, as well as the vast field of enteric neuroimmunophysiology; these are all beyond the scope of this chapter. This chapter focuses on the morphology of the small and large intestines along with the physiologic roles of fluid and electrolyte transport.
Intestinal Anatomy
Development of the Intestines
The mature intestine develops during embryogenesis from all three germ layers: endoderm, mesoderm, and ectoderm. The endoderm gives rise to the simple columnar epithelial cell lining of the surface of the small and large intestines. Cells of the lamina propria and muscularis layers derive from the embryonic mesoderm. The enteric neurons derive from embryonic ectoderm, specifically from migrating neural crest cells. This schema is true for the esophagus, stomach, pancreas, and liver; organs of the digestive system are therefore ontogenically and functionally related. Development of the intestine is covered in detail in Chapter 1 .
Anatomy of the Small Intestine
The small intestine is a convoluted tubular organ, extending from the pylorus to the ileocecal valve, occupying the central and lower parts of the abdominal cavity. Mostly circumscribed by the large intestines, it is divided into three segments: duodenum, jejunum, and ileum. The average length of the small intestine is between 250 and 300 cm in the newborn, increasing to as much as 600 to 800 cm in the adult. The caliber of the small intestine gradually diminishes from its origin to its termination. The duodenum constitutes approximately the first 25 cm of the small intestine in adults; the remaining length is arbitrarily divided into the proximal two fifths, designated as the jejunum, and the distal three fifths, designated as the ileum. The transition from jejunum to ileum is arbitrary, because there are no histologic or gross anatomic demarcations between these segments. The duodenum is derived from the distal foregut during embryologic development. It is largely retroperitoneal. The proximal 2 to 5 cm of the duodenum is occasionally supported on a short mesentery, and the remainder lies firmly fixed in a retroperitoneal position, forming an incomplete circle around the head of the pancreas, where it is devoid of mesenteric cover. The duodenum emerges from this retroperitoneal position at the ligament of Treitz in the left upper quadrant. The duodenum is arbitrarily divided into four segments:
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The first portion of the duodenum, which begins at the pylorus and ends at the neck of the gallbladder, is the most mobile segment. This portion is also referred to as the duodenal bulb.
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The second portion, often referred to as the descending portion, descends from the level of the neck of the gallbladder along the right side of the vertebral column to the level of the third lumbar vertebra.
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The third, horizontal portion, courses over the lower border to the third lumbar vertebra, passing from right to left, with a slight inclination upward, lying just inferior to the origin of the superior mesenteric artery in front of the aorta.
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The fourth portion begins its ascending course immediately to the left of the aorta, up to the level of the second lumbar vertebra, where it makes a ventral turn, as it becomes the jejunum (duodenojejunal flexure or ligament of Treitz).
The biliary and pancreatic ducts drain into the second, descending portion of the duodenum. In most children, both ducts join approximately 1 to 2 cm from the outer margins of the duodenal wall, and thereafter traverse the posteromedial aspect of the duodenal wall, through the sphincter of Oddi, to empty into the lumen of the second part of the duodenum at the ampulla of Vater. In 5% to 10% of individuals, an accessory pancreatic duct also enters 1 to 2 cm proximal to the ampulla of Vater, as the duct of Santorini.
The jejunum and ileum are derived from the endodermal midgut. There is no distinct demarcation between them, but progressive structural differences are present from the proximal jejunum to the distal ileum. The jejunal wall is thicker and more vascular than the ileum, and diminishes in size with distal progression. The intestinal luminal diameter is also greatest in the jejunum, shrinking in diameter as it progresses distally.
The jejunum and ileum, attached to and loosely suspended from the posterior abdominal wall by the mesentery, are freely mobile, enabling each coil to accommodate easily to changes in form and position with propulsive peristaltic contractions.
The mesentery begins as an anterior reflection of the posterior peritoneum, attached to the posterior abdominal wall along a line extending from the left side of the lumbar vertebral bodies to the right sacroiliac joint, where it crosses over the duodenum along with other retroperitoneal structures, enveloping the jejunum, ileum, the jejunal and ileal branches of the superior mesenteric blood vessels, nerves, lacteals, lymph nodes, and a variable amount of fat. The mesentery is fan shaped, with the breadth greater in the middle than at its upper and lower ends. The entire length of the jejunum and the ileum hangs suspended in the mesentery, with the exception of the retroperitoneal terminal ileum and cecum.
The duodenum derives its arterial supply from the right gastric, supraduodenal, right gastroepiploic, and superior and inferior pancreaticoduodenal arteries, whereas the venous drainage is via the superior mesenteric, splenic, and portal veins. The jejunal and ileal branches of the superior mesenteric artery, which itself courses over the third portion of the duodenum, form the arterial arcade that supplies the jejunum and ileum. The main venous drainage of the jejunum and ileum is through the portal and superior mesenteric veins to the liver.
Lymphatic drainage, coursing through the mesentery from the villous lacteals and the lymph follicles, converges to the preaortic lymph nodes around the superior mesenteric and celiac arteries. Approximately 70% of the lymph passes via the intestinal trunk and about 25% via the thoracic duct to the main subclavian vein. The intestines are overall quite rich in lymphoid tissue; the Peyer’s patches are small aggregates of lymphoid tissue located along the antimesenteric border of the small intestine. They are most abundant in the region of the midileum to the ileocecal valve. The Peyer’s patches are more prominent during childhood and regress in size and number with advancing age.
The plicae circulares, which are crescentic luminal protrusions of the submucosa covered by mucosa, running almost circumferentially in a circular fashion along the inside diameter of the intestinal wall, are most prominent in the distal duodenum and proximal jejunum, decreasing in number and size with progression through the ileum. They are permanent structures and do not smooth out when the intestine is distended. Together with the continuous reduction in caliber and villus height, these anatomic differences amount to a fourfold reduction in the surface area per length occurring over the course of the small intestine from distal duodenum and jejunum to the ileum.
The junction of the small intestine with the large intestine is referred to as the ileocecal valve, partly because of its structural appearance in most individuals and partly because the end of the terminal ileum (being wedged into the wall of the cecum) functions as a flutter valve. The ileocecal valve (sphincter) opens when a peristaltic wave strong enough to overcome the resistance of the valve arrives at the terminal ileum. The cecum, in concert, will generate reflexive relaxation. Overdistension or peristaltic contraction of the cecum causes a reflexive contraction of the sphincter. This protective mechanism prevents overfilling of the cecum or cecoileal reflux. This is an important factor to be remembered by endoscopists when attempting to intubate the terminal ileum during colonoscopy. Reflexive contraction of the sphincter due to overdistension with air will often thwart successful intubation of the ileum.
Anatomy of the Large Intestine
The large intestine commences at the cecum as a blind pouch below the termination of the small intestine. It hooks around, usually encircling the convolutions of the small intestine, and terminates at the rectum. From proximal to distal (oral to anal), the large intestine consists of the following segments:
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Cecum and vermiform appendix
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Colon, which in turn is composed of four sections—ascending, transverse, descending, and sigmoid colon
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Rectum
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Anal canal
The colon is approximately 60 cm long in the newborn, increasing to approximately 150 cm in the adult. The caliber of the large intestine is greatest at the cecum and gradually diminishes as it approaches the rectum, where it balloons out considerably in size just above the anal canal. The colonic wall remains constant in thickness throughout its entire length and lacks the villi that are a hallmark of the small intestine. The colon, in part, functions as a receptacle and reservoir for fecal matter; periodic high-amplitude contractions propel the contents caudally. Absorption of fluids and electrolytes, which is its main function, takes place along the entire length. The colon is easily distinguished from the small intestine by several distinctive characteristic features:
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It lacks villi.
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It is larger in caliber.
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Its outer longitudinal muscular layer is congregated into three distinct longitudinal bands, or teniae coli, extending from the cecum to the rectum.
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It has a characteristic sacculated and puckered appearance due to outpouchings (termed haustra) of its walls. The luminal surface is interrupted by intermittent creases (called plicae semilunares) that can be visualized on colonoscopy as irregular folds in the luminal surface.
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Fatty projections of the mesentery and the serosa (termed appendices epiploicae) are found scattered over the free surface of the entire large intestine, with the exception of the cecum, vermiform appendix, and rectum.
Extending as a reflection of the peritoneal lining, the mesentery envelops the colon just as it does the small intestine. The transverse colon and sigmoid colon hang fully suspended by the mesentery, whereas only a portion of the cecum is fully suspended. The ascending and descending colon are retroperitoneal. The prominent mesentery of the transverse colon is termed the transverse mesocolon, and the appendix is anchored by a short and well-defined mesentery referred to as the mesoappendix.
Originating from the midgut, the proximal colon, cecum, ascending colon, and proximal two thirds of the transverse colon all derive their blood supply from the superior mesenteric artery. The inferior mesenteric artery supplies the remaining one-third of the transverse colon, descending colon, sigmoid colon, and rectum. In addition to the blood supply from the inferior mesenteric artery, the rectum and anal canal also receive blood from the internal iliac and median sacral arteries. The superior and inferior mesenteric veins drain the same regions of the large intestine supplied by the corresponding arteries. With the exception of the lower half of the anal canal, the large intestine derives its nerve supply from the parasympathetic and sympathetic systems. The nerve distribution pattern closely mimics the arterial supply. The proximal colon receives its sympathetic neuronal innervation from the celiac and superior mesenteric ganglia, whereas the parasympathetic supply is from the vagus nerve. In each case, the nerves are distributed to the proximal colon in plexuses around the branches of the superior mesenteric artery. The distal colon receives its sympathetic nerve supply via branches from the lumbar segments of the sympathetic trunk, and the parasympathetic nerves originate from the pelvic splanchnic nerves. The lymphatic drainage of the large intestine courses through the mesentery in proximity to the arterial and venous supplies. First draining through groups of small pericolic nodes along the right and middle colic arteries, lymph flow from the colon drains into intermediate nodes located within the mesentery. The lymph ultimately terminates in the large colic preaortic nodes surrounding the superior and inferior mesenteric arteries. The rectum and anal canal drain into the inferior mesenteric and iliac nodes via perirectal nodes, which lie in close apposition to the rectal walls.
As stated previously, the primary function of the large intestine is water and electrolyte absorption; however, the large intestine is capable of absorbing small quantities of short-chain fatty acids (SCFAs), which are by-products of the anaerobic bacterial fermentation of polysaccharides. The SCFAs absorbed by the colon contribute only about 7% of overall total body energy requirements, with slightly higher amounts being contributed during infancy. More importantly, the colonic epithelium depends on the luminal SCFAs for their energy supply, as evidenced by the development of diversion colitis after surgical diversion of the fecal stream and resolution of the colitis with colonic instillation of n -butyric acid.
Cecum
The cecum exists as a large pouchlike cul-de-sac in the right iliac fossa and feeds the ascending colon. Its diameter is greater than its length; the adult cecum measures approximately 6 cm in length and 7.5 cm in width. The ileocecal valve, opening into the posteromedial wall of the cecum at its defined proximal end, passes through the wall in a perpendicular manner pointing slightly downward. The superior and inferior folds of the ileocecal valve formed by the protrusion of the ileum are arranged in an elliptical manner, forming the orifice of the ileocecal valve. This arrangement allows the valve to function as a sphincter. The appendiceal orifice lies about 2.5 cm inferior to the ileocecal valve. Being supported by a distinct mesentery, the cecum, appendix, and last segment of the ileum are mobile. This mobility accounts for the observed positional variability of these structures within the right lower abdominal quadrant and the rare predisposition for developing a cecal volvulus.
Vermiform Appendix
The adjective vermiform literally means “worm-like” and describes the narrow, elongated shape of the appendix. The appendix descends inferiorly as a small finger-sized tubular appendage of the cecum. It is typically anywhere between 2 and 20 cm long, being longest in childhood. It generally shrinks during development and throughout adult life. The appendiceal wall is composed of all layers typical of the intestine. Its outer layer and that of the cecum are circumferential, and the teniae coli are not apparent until the level of the ileocecal valve. The appendix, once regarded as a vestigial organ, is now recognized as an important component of the mammalian mucosal immune system, particularly B lymphocyte–mediated immune responses and extrathymically derived T lymphocytes. It shares functional similarities with the pharyngeal tonsils and Peyer’s patches. The vermiform appendix may vary greatly in location and be situated either dependently below the distal cecal pouch or behind the cecum, anteriorly or posteriorly to the ileum in a retroperitoneal manner.
Ascending Colon
Originating at the level of the ileocecal valve, the ascending colon is narrower than the cecum. It ascends in a cephalad manner to the inferior surface of the posterior lobe of the liver, where it angulates sharply inward and slightly forward, forming the hepatic flexure. It measures about 20 cm in length in the adult and is situated retroperitoneally in about 75% of individuals.
Transverse Colon
The ascending colon emerges from its retroperitoneal position, coursing anteriorly and medially to become the transverse colon. It becomes fully enveloped in mesentery (transverse mesocolon) and dips down to a variable extent toward the pelvis as it crosses the abdomen medially to the left upper abdominal quadrant. Here it curves acutely on itself, forming the splenic flexure. A thickened reflection of the peritoneum, termed the phrenicocolic ligament, anchors the splenic flexure, suspending it superior to the hepatic flexure. The transverse colon lies anterior to the stomach and the small intestine throughout its course, and it measures approximately 40 to 50 cm in adult length.
Descending Colon
The descending colon emerges from the splenic flexure, continuing downward and posteriorly to take up a retroperitoneal position, with only a partial peritoneal cover on its anterior surface in about 65% of individuals. It measures approximately 25 to 45 cm in adult length, extending from the splenic flexure to the level of the left iliac crest.
Sigmoid Colon
The sigmoid colon begins at the pelvic brim, where it is continuous with the descending colon as it emerges from a retroperitoneal position. The sigmoid colon forms a loop that varies greatly in length, averaging about 40 cm in an adult. It is surrounded and supported by a mesentery termed the sigmoid mesocolon, longest at the center of the loop, then shortening and disappearing as it approaches the rectum. Thus, the sigmoid colon is somewhat fixed at its junctions with descending colon and rectum, respectively. Enjoying a great range of mobility in its central region, it is predisposed to volvulus depending on the length of its mesocolon and/or the degree of distension. The sharpest angulations of the loop occur as the sigmoid turns downward to join the rectum.
Rectum
The rectum extends from the sigmoid colon at the level of the third sacral vertebra following the sacral curvature to the anal canal distally. It initially passes downward and posteriorly, and then directly downward before finally passing downward and anteriorly to join the anus. It measures approximately 12 to 15 cm in length in the adult. The peritoneum is reflected anteriorly at the rectosigmoid junction in most individuals; hence, the entire rectum lies below the peritoneum in close relationship with structures within the pelvis. The anorectal junction usually lies 2 to 3 cm in front of and just below the tip of the coccyx. The rectum is narrowest at its junction with the sigmoid, expanding out into the rectal ampulla at its lower end just before joining the anus. Unlike the sigmoid, the rectum lacks sacculations, appendices epiploicae, and mesentery. The teniae coli converge and blend with the outer muscular layer about 5 to 6 cm proximal to the rectosigmoid junction. The outer rectal wall becomes progressively thickened, forming prominent anterior and posterior muscular bands as it descends toward the anus. The luminal surface of the rectum has two longitudinal and transverse folds; the longitudinal folds are more apparent in the empty state, being easily effaced by rectal distension. The transverse folds or shelves are permanent and more prominent; commonly three folds are present, but this number may vary.
Anal Canal
The junction of the rectum and anal canal occurs approximately 4 to 5 cm from the anal verge (2 cm in the infant). Just distal are the anal columns, a grouping of 6 to 10 folds that surrounds the anorectal canal and projects from a cephalad to caudad direction. These columns are more prominent in children than in adults. They converge distally to form small crescentic folds of tissue termed the anal valves at the pectinate line, which is thought to represent the junction between the endodermal and ectodermal portions of the anal canal. Beyond the pectinate line, the epithelial cell layer of the anal canal transitions abruptly from columnar to stratified squamous epithelium, which in turn continues and terminates in an irregular line or “white” zone at the anal opening, termed the zona alba. Differing from the external skin, the zona alba is composed of nonkeratinized stratified squamous epithelium, whereas beyond the zona alba, the epithelial layer changes to the typical keratinized squamous epithelium of the skin, with the full complement of sweat glands, sebaceous glands, and hair follicles.
The anal canal occupies the ischiorectal fossa, where it is supported by a number of ligaments and muscular attachments as it pierces the pelvic diaphragm, made up of the levator ani and coccygeus muscles. The segment of the levator ani sling that encircles the anorectal junction is termed the puborectalis muscle. The contraction of this muscle pulls the rectum forward to retain stool, and the relaxation straightens the anal canal, allowing defecation. The walls of the anal canal are surrounded by a complex of muscular fibers, arranged as the internal and external anal sphincters. Commencing at the anorectal junction, the circular muscle layer of the large intestine thickens to become the internal anal sphincter. This sphincter, composed of smooth muscle fibers, surrounds the upper three fourths of the anal canal. The external sphincter is made up of striated muscle. Surrounding the entire length of the anal canal, the external anal sphincter consists of three parts, namely the subcutaneous, superficial, and deep parts.
Intestinal Histology and Cellular Morphology
The intestinal wall is made up of four layers. From outside inwardly, these consist of the serosa or adventitia, the muscularis propria, the submucosa, and the mucosa. The mucosa is further subdivided into distinct layers, again starting from the outside inwardly: the muscularis mucosa, lamina propria, and epithelial cell layer ( Figure 30-1 ).
Serosa
The serosa, or the outermost layer, is a simple extension of the visceral peritoneum and mesentery as it envelops the tubular intestines. It consists of a single layer of flattened mesothelial cells supported by a small amount of connective tissue, the adventitia. All segments of the small intestine are fully invested in the serosal coat, with the exception of the retroperitoneal portions (the duodenum and the very terminal portion of the ileum), which have serosal covering only on their anterior or anterolateral surfaces. The large intestine is surrounded by a loose layer of connective tissue termed the adventitia. It is referred to as the serosa when covered by the peritoneal reflection containing squamous mesothelial cells. Scattered macrophages, eosinophils, mast cells, and fibroblasts are occasionally encountered within the serosa.
Muscularis Propria
The muscularis propria is made up of two distinct layers of smooth muscle: the thinner outer longitudinal layer and the thicker inner circular layer. In the large intestine, the outer longitudinal muscle layer is thickened to form three prominent muscular bands, the teniae coli, which run in parallel to the long axis of colon throughout its entire length. The width of the teniae ranges from 6 to 12 mm in different individuals, and their thickness increases caudally from the cecum to the sigmoid colon. The inner circular muscle layer is thin over the cecum and colon, running circumferentially, but maintaining a slightly oblique orientation to the long axis of the large intestine. Its fibers are especially thickened in the rectum, and in the anal canal they become numerous, forming the internal anal sphincter.
There are two major ganglionated enteric nervous system plexuses embedded within the wall of the intestines, the submucosal (Meissner’s) plexus and the myenteric (Auerbach’s) plexus. Meissner’s plexus is found within the submucosa, and the myenteric plexus is located in the plane between the longitudinal and circular layers of the muscularis. The numerous ganglia and localized collection of nerve cell bodies that make up the submucosal and myenteric plexuses are extensively interconnected by nerve bundles, giving the appearance of a flat meshwork. Some of the nerve bundles do not connect to ganglia; they ramify over the smooth muscles within the plane of the myenteric plexus to contact individual smooth muscle cells.
Interstitial cells of Cajal, present within the myenteric plexus at the interface between the circular muscle and the submucosa, are now recognized as pacemakers of intestinal contractile activity and regulating intestinal tone. Abnormalities of the interstitial cells of Cajal have been demonstrated in several intestinal motility disorders.
Submucosa
The submucosa consists of a band of loose connective tissue with a scattering of cellular elements, which include lymphocytes, macrophages, mast cells, plasma cells, eosinophils, and fibroblasts. It is bounded below by the muscularis and above by the outermost layer of the mucosa, the muscularis mucosa. The submucosa, lying next to the mucosa, supports it in its specialized function of nutrient, fluid, and electrolyte absorption by carrying a rich network of blood vessels, lymphatics, and nerves. The rich vascular supply and lymphatic drainage ensure efficient handling of absorbed nutrients and fluids following a meal. The extensive nerve network, working via the enteric nervous system, ensures adequate agitation and propulsion of the ingesta, and hormonal secretion and control necessary for efficient digestion and absorption.
Brunner’s glands are located almost exclusively in the submucosa of the duodenum; they begin at the pylorus, where they are most numerous, and extend for a variable length within the walls of the proximal jejunum ( Figure 30-2 ). They form an array of extensively branched epithelial tubules that contain mainly mucous and serous secretions. Brunner’s glands secrete a layer of mucus, forming a slippery viscoelastic gel that lubricates the mucosal lining of the proximal intestinal tract. The mucous layer also possesses the capacity to protect the delicate epithelia surface from peptic digestion. This unique property is due primarily to the gel-forming properties of the glycoprotein molecules (Pb1), class III mucin glycoproteins, and is thought to be the product of mucin gene MUC6 , assigned to chromosome 11.
Brunner’s glands interconnect and drain into the base of the duodenal crypts, where they secrete mucin and bicarbonate, to a limited extent, along with a host of additional factors including epidermal growth factor, trefoil peptides, bactericidal factors, proteinase inhibitor, and surface-active lipids. These factors are said to guard against the degradation of the mucin-protective barrier coat and the underlying mucosa by digestive enzymes and other surface-active agents produced in this region. Some of these factors also play important roles in passive and active immunologic defense mechanisms. Brunner’s gland secretion also contributes to the increased luminal pH of the region by promoting pancreatic secretion and gallbladder contraction.
Mucosa
The muscularis mucosae is the deepest layer of mucosa, lying next to the submucosa. It consists of an outer longitudinal and inner circular layer of smooth muscle cells. It is a fairly thin layer, being only 3 to 10 cells thick, extending into the circular folds (plicae circularis). The colonic muscularis mucosae is thicker, and the thickness increases progressively from the cecum to the anal canal.
Lying above the muscularis mucosae, the lamina propria provides structural support for the basement membrane of the epithelium. It is composed of a thin layer of connective tissue that embraces the crypts and extends into the villous protrusions. The lamina propria is rich in arterioles, veins, lacteals, nerve fibrils, and fibroblasts, as well as various cell types, including lymphocytes, macrophages, eosinophils, mast cells, and neutrophils.
The mucosa is thick and highly vascularized in the proximal portion of the small intestine, but thinner and less vascular in the distal small intestine. The mucosa is thrown into crescentic folds, the plicae circulares (also termed the valves of Kerckring). The small intestinal surface is studded with finger-like or leaflike protrusions, the intestinal villi. These two striking morphologic and physiologic features, along with the formation of microvilli on the epithelial cell surface, combine to produce a 400- to 500-fold increase in the surface area of the mucosa. The mucosa of the colon is devoid of villi that characterize the small intestine, but contains crypts of Lieberkühn (which are larger than those found in the ileum) and crescentic folds (plicae circulares) that correspond to the external sacculations termed haustra.
The luminal surface of small intestine is covered by millions of tiny hairlike, highly vascularized structures called villi ( Figure 30-3 ). The villi project for about 0.5 to 1.5 mm into the lumen, giving it a velvety appearance and feel. The height of the villi decreases progressively from the duodenum to the ileum. Villi are larger and denser in the duodenum and jejunum, and smaller and fewer in the ileum. They are wider and ridge-shaped in the proximal duodenum, whereas in the distal duodenum and proximal jejunum they are predominantly leaf-shaped and only occasionally finger-shaped. Finger-shaped villi predominate in the distal jejunum and ileum. Villi are covered primarily with mature absorptive enterocytes, interspersed with few mucus-secreting goblet cells and rare enteroendocrine cells. Each villus contains a central arteriole, a venule, and a central lacteal. A cascading capillary bed is formed at the tips of the villi in proximity to the basal surfaces of the epithelium, allowing for rapid clearance of absorbed nutrients, fluids, and electrolytes into portal flow then systemic circulation. The capillary walls are fenestrated with diaphragmatic covers, greatly facilitating the absorptive process. The core of the villus also contains some small nerve fibers, plasma cells, macrophages, mast cells, lymphocytes, eosinophils, and fibroblasts. The bases of the villi are surrounded by several pitlike crypts, the crypts of Lieberkühn, extending down through the lamina propria to the muscularis mucosa.
The epithelial cell lining of the small intestine is continuous, but the cell population differs between the villi, the crypts, and the epithelium overlying the Peyer’s patches. The crypts, the bases of which contain the intestinal stem cell (ISC) niche, are populated primarily by undifferentiated columnar epithelial cells, with a minor scattering of goblet cells, Paneth cells, tuft cells, cuplike cells, and enteroendocrine cells. The villous epithelium contains the same array of cells, with the exception of Paneth cells. The undifferentiated cells are replaced with mature enterocytes. The epithelial cells overlying the Peyer’s patches contain all of the aforementioned cells plus functionally and structurally distinct membranous cells (M cells), which are thought to be key sites of antigen and luminal bacteria sampling for the mucosa-associated lymphoid system. M cells are responsible for transepithelial transport, delivering foreign antigens and microorganisms to the mucosal lymphoid tissue for recognition and handling, an attribute currently being exploited in vaccine production. Structurally distinct, the M cells usually assume an oval or globular configuration, but with a widened base and narrowed apex. Some enteroinvasive pathogens are known to exploit these features of M cells to bridge the intestinal epithelial barrier. The M cells are also found in other parts of the body, especially where there is an interface between the mucosa and the external environment; these sites include, but are not limited to, the tonsils, adenoids, airways, and ocular mucosa. The apical microvilli overlying Peyer’s patches are randomly shortened and occasionally fused into folds or ridges.
The mucosal epithelial cells are turned over every 5 to 7 days; therefore, intense mitotic activity occurs within the intestinal crypts. All intestinal epithelial cells are thought to derive from long-lived, resident progenitors or “stem cells.” These intestinal stem cells are located near the base of the crypts, where they divide to produce additional stem cells (to maintain their numbers) as well as rapidly dividing progenitors, termed “transit amplifying” cells, that will differentiate into the various epithelial cell types. The transit amplifying cells undergo several additional cell divisions as they migrate upward along the intestinal crypt wall. Cell cycle arrests and differentiation occur as distinct cell types (terminal differentiation) form near the top of the crypt. In the small intestine, most terminally differentiated cells migrate out of the crypt and onto the villi and are fully mature by the time they reach the upper third of the villus; Paneth cells migrate to the base of the crypt where they reside in proximity to the stem cells. In the large intestine, terminal differentiation occurs in the upper one-third of the crypt, and most cells migrate onto the mucosal surface; in some regions of the large intestine, terminally differentiated cells also migrate to the crypt base, displacing the proliferating cells upward. Old and spent cells are extruded into the intestinal lumen in a process termed anoikis, usually at the tip of the villi or the surface of the colon, to face the same fate of digestion and absorption along with the ingesta. Overlying the Peyer’s patches, epithelial cell differentiation includes the production of M cells from nearby stem cells.
Differentiation and homeostasis of the intestinal epithelium are regulated by several key developmental pathways including the WNT (wingless), NOTCH, BMP (bone morphogenetic protein), and HEDGEHOG pathways. These pathways involve signaling between epithelial cells as well as between the epithelium and the underlying lamina propria, particularly the myofibroblasts. In addition, the growth and integrity of the intestinal mucosa are maintained under the influence of the ingesta and several luminal factors as well as autocrine, endocrine, and paracrine secretion from the surrounding cells. Thus, enteral, humoral, and tissue factors are all essential for the well-being of the intestinal mucosa.
It is now clear that therapeutic drugs can be developed to target these developmental pathways. Keratinocyte growth factor (KGF, also termed fibroblast growth factor 7, or palifermin) has been approved for the treatment of radiation- or chemotherapy-induced alimentary canal mucositis. Other peptides secreted from enteroendocrine cells play a major cytoprotective and reparative role in the survival and proliferation of the intestinal mucosa, such as the glucagon-like peptides. Glucagon-like peptide (GLP) 1 and GLP2 are released from enteroendocrine cells in response to nutrient ingestion. GLP1 enhances glucose-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying, and feeding. It also has proliferative and antiapoptotic effects on pancreatic β cells. GLP2 is a 33-amino-acid peptide, encoded carboxy-terminal to the sequence of GLP1 in the proglucagon gene. It is an intestinal trophic peptide that stimulates cell proliferation and inhibits apoptosis in the intestinal crypts. Recent clinical trials using GLP2 suggest that it may have utility in treating patients with short bowel syndrome and Crohn’s disease.
Absorptive Cells
Lining both the villi and crypts is a layer of cells referred to as the enterocytes, or absorptive cells. These are tall columnar cells, each possessing a basally located, clear, oval nucleus and several nucleoli. The cells are tightly cemented to the basal lamina and are joined to the adjacent enterocytes at the apical pole by intercellular tight junctions. The luminal surface is studded with densely packed (1000 to 2000 per cell) finger-like, cylindrical projections termed microvilli. Each microvillus is about 1 µm long and 0.1 µm wide. The microvilli are constantly bathed by luminal contents and contain the membrane-bound digestive proteins, transport proteins, and other cellular elements necessary for nutrient absorption.
The intestinal microvillus is supported by a central core of cytoskeleton, which consists of highly concentrated microfilaments made up of five major proteins: actin, villin, fimbrin, brush border myosin I, and spectrin. Villin and fimbrin are bundling proteins that crosslink to support a central core of about 20 to 30 actin filaments ( Figure 30-4 ). The microfilaments are continuous and linked at the apical bases of the microvillus, forming a plexiform band called the terminal web, which consists mainly of spectrin. The terminal webs are also interconnected with the junctional complexes or tight junctions. The microvillus is rich in glycoprotein, cholesterol, and glycolipids.
The apical surfaces of the intestinal epithelial cells carry multiple brush-border transporters that couple ion influxes to organic solute influxes, or exchange one ion for another. Three Na/H exchangers (NHEs) have been localized to intestinal brush-border membranes. NHE2 and NHE3 are found in both small intestine and colon. NHE1 is present only in the basolateral membrane of enterocytes and is thought to be involved with HCO 3 secretion. Two anion exchangers have also been localized to small-intestinal and colonic brush-border membranes and cloned. They are named “downregulated in adenoma” (DRA) and putative anion transporter 1 (PAT1).
Contiguous enterocytes are tightly apposed at their apicolateral poles by the formation of junctional complexes. These consist of adherence membranes in three areas:
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The most proximal tight junction, or zonula occludens
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An intermediate junction, or zonula adherens
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A deeper junction, the spot desmosome or macular adherence zone
Movements of fluid and ions through this intercellular space from the apical to the basolateral compartment are termed paracellular transport and are the dominant pathway for passive fluid and ion flow across the intestinal epithelial barrier into the endothelial compartment. Permeability depends on the regulation of the tight junctions.
The tight junction, or zonula occludens, measures approximately 100 to 600 nm in depth, serving as a regulatable, semipermeable diffusion barrier and permitting the passage of ions while restricting the movement of large molecules. The tight junction is leakier and has a lower resistance in the proximal intestine, where absorption is most efficient, and tighter with a higher resistance in the ileum and large intestine. There is also strong evidence suggesting variations in the functional states of the junctional complexes, maintaining a relatively high resistance in the fasting state and a low resistance in the fed state.
Tight junctions contain of a family of transmembrane proteins—claudins, occludens, and junctional adhesion molecules—which are anchored to the membranes of two adjacent cells and interact with one another to bind the cells together and prevent the passage of molecules between them. These membrane proteins are connected with the various signal transduction and transcriptional pathways involved in the regulation of tight junction function via interaction with scaffold proteins.
Knowledge about the tight junction has evolved from a relatively simplistic view of it being a physical and permeability barrier in the paracellular space to one of a multicomponent, multifunctional complex that is involved in regulating numerous and diverse cell functions. The tight junction membrane proteins interact with an increasingly complex array of tight junction plaque proteins to regulate paracellular solute and water flux and to integrate diverse processes such as gene transcription, tumor suppression, cell proliferation, and cell polarity.
The zonula adherens, also called the adherens or intermediate junction, is located just below the zonula occludens on the lateral aspect of contiguous cells and is less adherent, with cells being separated by a 15- to 20-nm gap. Forming a beltlike region of cell-to-cell adhesion, the zonula adherens represents the intercellular linkage of transmembrane cadherins to the actin cytoskeleton via the catenins. The zonula adherens component β-catenin plays a dual role as a structural component of those junctions and as a key molecule in the WNT signaling pathway, where it functions as a transcriptional activator.
The most distal portion of the junctional complex is a small circular junction located just below the zonula adherens, often referred to as the macula adherens or spot desmosome. The adjacent lateral membranes here are separated by a gap of about 30 to 50 nm. Unlike the zonula occludens, spot desmosomes are not continuous around the circumference of the cell, but are rather scattered around the cell perimeter in an uneven row. Three calcium-dependent adhesion molecules belonging to the cadherin family—desmoglein I and desmocollins I and II—mediate intercellular attachment. These proteins bind to keratin intermediate filaments via desmoplakins. The overall function of desmosomes appears to be primarily to support cell–cell adhesion and to provide mechanical stability to the epithelium.
The remainder of the lateral wall of the enterocyte below the macula adherens is termed the basolateral membrane. This membrane has unique structural and biologic characteristics that differentiate it from the apical membrane. The basolateral membrane is often plicated and interdigitates with the adjacent lateral cellular membranes. Lacking the brush-border transporters, NHEs, and digestive enzymes present on the apical membrane, it is embedded with basolateral membrane carriers that facilitate diffusion of organic solutes and are not coupled to ion movements. The basolateral membrane K + channels are responsible for K + extrusion from the cell and NaK 2 Cl cotransporter, which determines the maximal rate of chloride entry into the cell. Na,K-ATPase in the basolateral membrane uses energy from ATP hydrolysis to drive Na + extrusion and K + uptake.
Gap junctions are communication junctions, consisting of small, circular structures between contiguous cell membranes with a narrow gap in between. The gaps are connected by tiny tubular channels called connexons, composed of connexin proteins, which allow the intercellular passage of ions and low-molecular-weight nutrients and intracellular messengers such as cyclic adenosine monophosphate (cAMP).
In addition to the basally located nuclei, other cellular organelles are present within the enterocyte in anticipated polarity. The Golgi apparatus, responsible for terminal glycosylation of synthesized proteins, lies in a supranuclear position, and just below the terminal web at the apical portion are numerous membrane-bound lysosomes. Also scattered throughout the cytoplasm are free ribosomes, mitochondria, lysosomes, microtubules, and smooth and rough endoplasmic reticulum. The cellular structure and organelles are efficiently arranged and coordinated to work in concert for the absorption, packaging, and subsequent extrusion of absorbed lipids, carbohydrate, and peptides.
Surface Epithelial Cell
Corresponding to the absorptive cells of the small intestine, surface epithelial cells (also termed principal cells) line the large intestinal epithelial surface and the upper one-third of the crypt. The luminal surfaces of these columnar cells are capped by apical membranes containing numerous microvilli supported by well-developed terminal webs. The lateral borders of the luminal surfaces are bound by junctional complexes similar to those found in the small intestine. Their cytoplasm contains the usual cytoplasmic organelles. The nucleus is centrally located with a scattering of endoplasmic reticulum located both above and below. The apical cytoplasm is particularly rich in secretory granules along with scant amounts of Golgi apparatus.
Goblet Cells
Goblet cells are mucin-producing cells found scattered among other cells of the intestinal villi and crypts in lesser numbers than the absorptive cells. Overall, they are found in greater numbers in the large intestine and distal ileum than in the rest of the intestine. The term goblet cell derives from the characteristic wineglass shape of these cells in conventionally fixed tissue: a narrow base and an oval apical portion (expanded with mucin-secreting granules) that sometimes extends into the intestinal lumen. If special precautions are taken during tissue fixation, goblet cells can be seen as cylindrically shaped.
Goblet cells usually assume a distinctly polarized morphology, with the nucleus and Golgi apparatus basally situated. The remaining cellular organelles are aligned along the lateral margins of the cell, compressed to these regions by the abundant, membrane-bound mucus-secreting granules within the cell interior. Mucin secreted from the goblet cells is composed largely of highly glycosylated proteins suspended in an electrolyte solution. The mucin is secreted via two pathways: (1) a low-level, unregulated, and essentially continuous secretion dependent on cytoskeletal movement of secretory granules; and (2) stimulated secretion via regulated exocytosis of granules in response to irritating extracellular stimuli. This second pathway ensures that mucin production and secretion can be rapidly increased. The goblet cell mucin provides a protective lubricant barrier against shear stress and shields the intestinal mucosa from peptic digestion and chemical damage. It is also thought to bind surface antigens and inhibit their attachment to the epithelial surfaces. The copious amounts of mucin produced by goblet cells are crucial in providing lubrication for the passage of feces.
Gut Endocrine Cells
Enteroendocrine cells, or gut endocrine cells, are a highly specialized mucosal cell subpopulation, sparsely distributed throughout the entire length of the small intestine. The enteroendocrine lineage consists of at least 15 different cell types that are categorized based on their morphology, specific regional distribution, and peptide hormone expression. These cells are typically tall and columnar in appearance, and the apical surface is studded with microvilli. They are present in both crypts and villi. Their large nucleus is usually basally located, with the Golgi apparatus situated above the nucleus. The most distinct feature of gut endocrine cells is the prominent cytoplasmic secretory granules, distributed mainly in the basal region of the cell. The secretory granules of the individual gut endocrine cell appear relatively uniform in size, shape, and density, suggesting that the granules may be specific for a single active amine or peptide hormone.
The hormone products are discharged into the extracellular space on the basal and basolateral side of the cell. The hormone diffuses a short distance and passes into the capillary bed underneath, exerting paracrine effects locally within the gastrointestinal tract and endocrine effects regionally or at distal target-organ sites. Some of the specific products of the different cells are shown in Table 30-1 . Two pathways of secretion are recognized in gut endocrine cells: one regulating secretion of large, dense-core vesicles (LDCVs), and a second regulating secretion of synaptic-like microvesicles (SLMVs).
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