Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large Intestine

Mucosa

The mucosa consists of the glandular epithelium, lamina propria, and muscularis mucosae ( Fig. 98.3 A and B ). The mucosa is thick and highly vascularized, although less so in distal portions. It has concentric folds ( plicae circulares ) that are also referred to as the valves of Kerckring. The surfaces of the mucosal folds are studded with villus projections, and these features combine to produce a 400- to 500-fold increase in mucosal surface area. An intestinal villus will typically project 0.5 to 1.5 mm into the lumen, and the height of the villus decreases from proximal to distal small intestine. Villi are wider and more leaf-shaped in the duodenal bulb and proximal duodenum, becoming more finger-like in the distal duodenum, proximal jejunum, and remainder of intestine. The villi are covered with mature absorbing enterocytes interspersed with mucus-secreting goblet cells. Each villus contains an artery, vein, and central lacteal. A capillary bed forms along the epithelium, allowing for rapid clearance of absorbed nutrients, fluids, and electrolytes into the systemic circulation. To facilitate the absorptive process, capillary walls are fenestrated with diaphragmatic covers. The core of the villus also contains nerve fibers, plasma cells, macrophages, eosinophils, and fibroblasts. The villi are surrounded by cylindrical structures called the crypts of Lieberkühn, which extend through the lamina propria down to the muscularis mucosae. The crypts are lined with more immature epithelium that primarily functions as a secretory rather than an absorptive epithelium.

The epithelium of the small intestine is composed of various cell types: absorptive cells (columnar cells), secretory cells (goblet cells), undifferentiated cells, tuft cells, M cells, cup-like cells, and enteroendocrine cells. Crypts contain a similar cell population as the villi, with the addition of Paneth cells and stem cells.

The lamina propria is a layer of reticular connective tissue that provides the structural support for the mucosa, but it also contains many cellular elements important for absorption and immunity. The lamina propria is rich in arterioles, venules lacteals, nerve fibrils, and fibroblasts, lymphocytes, macrophages, neutrophils, eosinophils, and mast cells. The muscularis mucosae consists of a thin layer of smooth muscle only 3 to 10 cells thick at the boundary of the mucosa and submucosa.

Stem cells are pluripotential cells located at the bases of the intestinal crypts. With intense mitotic activity, stem cells give rise to all types of mature intestinal epithelial cells and at the same time replenish themselves through self-renewal. Mucosal epithelial cells turn over every 5 to 7 days. Intestinal epithelial cells are mature by the time they reach the upper third of the villus. Paneth cells are the only cells that do not migrate. Undifferentiated cells have fewer intracellular organelles and microvilli than absorptive cells. The absorptive cells (see Fig. 98.3 A ) are high columnar cells with oval basal nuclei, eosinophilic cytoplasm, and a periodic acid–Schiff (PAS)-positive free surface, the brush border (see Fig. 98.3 B ). On electron microscopic examination, the brush border is seen to be composed of microvilli (see Fig. 98.3 C ), which are more numerous in the small intestinal than in the colonic epithelium. Enterocyte microvilli are estimated to increase the luminal surface area of the cell 14- to 40-fold.

Goblet cells are mucin-producing cells that are scattered among intestinal villi but are more common in the distal ileum and large intestine. Goblet cells are oval or round with flattened basal nuclei ( Fig. 98.4 A ); their cytoplasm is basophilic, metachromatic (see Fig. 98.4 B ), and PAS-positive (see Fig. 98.4 C ) and consists mostly of mucin-secreting granules. Mucin is secreted by 2 pathways: in a neutrally mediated continuous manner, and by the active exocytosis of granules in response to extracellular stimuli.

Paneth cells are flask shaped with an eosinophilic granular cytoplasm and a broad base that is positioned against the basement membrane ( Fig. 98.5 ). In the small intestine, Paneth cells are located exclusively in the crypts of Lieberkühn and secrete α-defensins, antimicrobial proteins, lysozyme, and phospholipase A, thought to be important in protection from infectious pathogens and function to maintain enteric homeostasis.

Cup cells and tuft cells are 2 intestinal epithelial cell types with unidentified functions. Cup cells are present in villi and crypts largely limited to the ileum. Tuft cells are marked by a tuft of long microvilli projecting from the apical surface of the cell.

The mucosa also contains specialized cells called enteroendocrine or neuroendocrine cells ( Fig. 98.6 A ) with specific endocrine functions. Intestinal endocrine cells are sparsely distributed and consist of 11 different cell types ( Table 98.1 ). These are tall columnar cells present in both the crypts and villi and contain prominent secretory granules. The neuroendocrine cells have been divided histologically into argentaffin (i.e., their granules are able to reduce silver nitrate) or enterochromaffin cells and argyrophilic cells (i.e., granules reduce silver nitrate only in the presence of a chemical reducer). These chemical properties subdivide the cell types, but a unifying concept derived from their common origin and functional capacity has led to the term APUD cells. The a mine p recursor, u ptake, and d ecarboxylation concept characterizes the cells as having a common embryonic origin from the neural crest and displaying similar cytochemical and electron microscopic features.

Ultrastructurally, enteroendocrine cells contain membrane-bound granules with variably sized electrodense cores (see Fig. 98.6 B ) that consist of large dense-core vesicles and smaller synaptic-type microvesicles. Neurosecretory granules can be demonstrated as dark granules with nonspecific agents (e.g., Grimelius stain [see Fig. 98.6 C ]), or more specific immunohistochemical stains can be used (e.g., neuron-specific enolase, chromogranin, synaptophysin). Chromogranin enables identification of the large dense-core vesicles, and synaptophysin targets the small synaptic-like microvesicles (see Fig. 98.6 D ). With specific immunohistochemical staining agents, it is possible to identify the individual chemical and protein components of neuroendocrine cells. The differential expression of certain proteins also makes it possible to subdivide neuroendocrine cell populations. For example, vesicular monoamine transporter (VMAT) has 2 isoforms: VMAT1 is restricted to serotonin-producing enterochromaffin cells, and VMAT2 is expressed by histamine-producing cells, enterochromaffin-like cells, and pancreatic islet cells.

The hormone products of these cells are discharged into the extracellular space on the basal and basolateral surfaces and have paracrine effects on absorption, secretion, motility, mucosal cell proliferation, possibly immunobarrier control, and even some endocrine effects upon systemic absorption.

The preferred designation of neuroendocrine cells is by their stored peptide. Serotonin-producing enterochromaffin cells, vasoactive intestinal polypeptide cells, and somatostatin D cells are distributed throughout the small and large intestine. Cells that produce gastrin, ghrelin, gastric inhibitory peptide, secretin, and CCK are found predominantly in the stomach and proximal small intestine. Cells that secrete peptide YY, glucagon-like peptide-1, glucagon-like peptide-2, and neurotensin are found in the ileum.

M cells are specialized epithelial cells overlying lymphoid follicles and Peyer patches in the small intestine and colon. M cells are an important site of luminal antigen sampling for immune processing by the mucosal lymphoid system. This process of sampling plays an important role in the development and maintenance of immune tolerance, host defense against pathogens, and intestinal homeostasis.

The interstitial cells of Cajal (ICC) are found in both the small intestine and colon and are located in the myenteric plexuses within the muscularis propria and the submucosa ( Fig. 98.7 [see Chapters 99 and 100 Chapter 100Chapter 99]). The ICC are important in the regulation of intestinal peristalsis and function as the pacemaker cells of the intestine. They influence the frequency of smooth muscle contraction, amplify neuronal signals, mediate neurotransmission from enteric motor neurons to smooth muscle cells, and set the smooth muscle membrane potential gradient. The ICC are spindle-shaped or stellate cells with long, ramified processes and express c-kit (CD117), a tyrosine kinase receptor critical for their survival.

Submucosa

The submucosa is a fibrous connective tissue layer that lies between the muscularis mucosae and the muscularis propria. It contains lymphocytes, fibroblasts, mast cells, blood and lymphatic vessels, and a nerve fiber plexus—Meissner plexus—composed of non-myelinated postganglionic sympathetic fibers and parasympathetic ganglion cells. The submucosa supports the mucosa in specialized functions of nutrient, fluid, and electrolyte absorption by conveying a rich network of blood vessels, lymphatics, and nerves that ensure efficient handling of absorbates.

Brunner glands are submucosal glands (see Fig. 98.9 B ) found primarily in the first portion of the duodenum and in decreased numbers in the distal duodenum; in children, these glands may also be present in the proximal jejunum.

The function of Brunner glands is to secrete a bicarbonate-rich alkaline secretion that helps neutralize gastric chyme; a mucinous secretion that helps lubricate the mucosa; EGF; a variety of trefoil peptides, bactericidal factors, proteinase inhibitors, and surface-active lipids. The secretions that drain into the base of the duodenal crypts contribute to increased luminal pH by promoting pancreatic secretion and gallbladder contraction. The mucous layer protects the epithelial surface from peptic digestion; this protection is thought to be due to glycoprotein class III mucin glycoproteins.

Muscularis Propria

The muscularis propria is mainly responsible for contractility and peristaltic movement of luminal contents through the GI tract. It consists of 2 layers of smooth muscle: an inner circular coat and an outer longitudinal coat arranged in a helicoidal pattern. A prominent nerve fiber plexus called the myenteric or Auerbach plexus is located in the plane between these 2 muscle layers ( Fig. 98.8 ). The ganglia in the myenteric plexus are more prominent than their submucosal counterpart. Parasympathetic and postganglionic sympathetic fibers terminate in parasympathetic ganglion cells, and postganglionic parasympathetic fibers terminate in smooth muscle.

Serosa

The serosa is the outermost layer of the intestinal wall and is composed of a thin layer of mesothelial cells, representing an extension of the visceral peritoneum and mesentery as it envelops the intestine.

Small Intestine

The mucosa of the small intestine is characterized by folds ( plicae circulares , or valves of Kerckring) and villi. The mucosal folds actually comprise mucosa and submucosa. Villi are mucosal folds that decrease in size from the proximal to distal small intestine and are of different shapes in the various segments of the small intestine. They may be broad, short, or leaf-like in the duodenum, tongue-like in the jejunum, and finger-like more distally ( Fig. 98.9A ). The villous pattern may vary in different ethnic groups; biopsy specimens from Africans, Indians, South Vietnamese, and Haitians have shorter and thicker villi, an increased number of leaf-shaped villi, and more mononuclear cells in comparison with specimens from North Americans. The implications of these changes with regard to symptoms and subclinical GI infection are discussed in Chapter 108 .

The height of the normal villus is 0.5 to 1.5 mm; villus height should be more than half the total thickness of the mucosa and 3 to 5 times the length of the crypts. Villi are lined by enterocytes, goblet cells, and enteroendocrine cells.

Enterocytes are tall columnar cells, each with a basally located, clear, oval-shaped nucleus and several nucleoli. The cells are tightly cemented to the basal lamina and adjoined to adjacent enterocytes at the apical pole by intracellular tight junctions. The luminal surface has microvilli that contain necessary enzymes for nutrient absorption; a central core cytoskeleton is made of actin, villin, fimbrin, brush border myosin, and spectrin. The apical surface of the epithelium carries brush border transporters, Na ⁺ /H ⁺ exchangers, and anion exchangers (see Chapter 101 ). The junction complexes are made up of 3 components: the proximal tight junction ( zonula occludens ), the intermediate junction ( zonula adherens ), and the deep junction, which includes the spot desmosome and the macular adherens zone (see Chapter 101 ). Movement through junctions is by paracellular transport and is the dominant pathway for passive ion and fluid flow. Tight junctions consist of claudins, occludens, and junctional adhesion molecules that bind and prevent passage of molecules between them in a regulated manner. They are leakier and have a lower resistance in the proximal small intestine, and tighter in the distal intestine. The zonula adherens is less adherent and involved in cell signaling. Spot desmosomes are thought to augment transmembrane linkages spanning the intercellular gap and are involved in cell wall communications. The basolateral membrane is responsible for carriers to facilitate diffusion of organic solutes not coupled to ion movements. Gap junctions allow for communication and intercellular passage of ions and low molecular weight nutrients and intracellular messengers such as cyclic adenosine monophosphate.

Two types of glands are present in the small intestine: Brunner glands (see previously) and crypts of Lieberkühn (intestinal crypts). The crypts of Lieberkühn are tubular glands that extend to the muscularis mucosae (see Fig. 98.5 ); they are occupied mainly by undifferentiated cells and Paneth cells. Cells are generated at the crypt base and migrate up the villus. During this migration, these cells mature and differentiate into a secretory lineage (goblet cells, enteroendocrine cells) and enterocytes. The commitment of the stem cells to differentiate is acquired in the upper third of the crypt where cells lose their ability to divide. The constant renewal of enterocytes is regulated by human acyl-coenzyme A synthetase.

Paneth and columnar cells predominate in the base of the crypt. Above the base are absorptive cells and oligomucin cells; the latter originate from undifferentiated cells and differentiate into goblet cells. Goblet cells predominate in the upper half of the crypt. Enteroendocrine cells are admixed with goblet cells. A certain number of CD3 ⁺ intraepithelial T lymphocytes (up to 30 per 100 epithelial cells) are normally present in the villi. Smooth muscle is found in the lamina propria of the small intestinal villus, extending vertically up from the muscularis mucosae. Plasma cells containing primarily immunoglobulin A, and mast cells are also present. Lymphoid tissue is prominent in the lamina propria as both solitary nodules and confluent masses—Peyer patches—and is seen in the submucosa. Peyer patches are distributed along the anti-mesenteric border and are most numerous in the terminal ileum; their numbers decrease with age.

Most types of enteroendocrine cells are present in the duodenum. Cells that produce ghrelin, gastrin, CCK, motilin, neurotensin, gastric inhibitory peptide, and secretin are restricted to the small intestine.

The proportions of cells differ in the villi and crypts as well as in different segments of the intestine. Ninety percent of the villus epithelial cells are absorptive cells intermingled with goblet and enteroendocrine cells. The proportion of goblet to absorptive cells is increased in the ileum. The ICC are more abundant in the myenteric plexus of the small intestine than in the colon.

Colon

The colonic walls are similar to those of the small intestine. The outer layer forms the taeniae coli , which run in parallel to the long axis of the colon throughout its entire length. The width of the taeniae extends from 6 to 12 mm, and thickness gradually increases from the cecum to the sigmoid colon. The epithelial layer is smooth with crescentic folds corresponding to external sacculations. The surface epithelium is simple columnar type and is interspersed with vascular cells and goblet cells. The epithelial surface and upper third of the crypts are mostly lined with tall, slender absorptive columnar cells called principal cells. Goblet cells are the second most abundant cells on the surface of the colonic epithelium; they produce mucin, which aids in the passage of feces. Colonic epithelial cells are generated from stem cells at the base of the crypts and migrate toward the intestinal lumen 3 to 5 days after initiation of apoptosis. Most epithelial cells undergo apoptosis when they lose contact with the extracellular matrix and are shed into the lumen through caspase (cysteine-aspartic protease) activation. Caspase activation is responsible for the cleavage of essential intracellular proteins that leads to apoptosis and, therefore, loss of anchorage.

The mucosa of the large intestine is characterized by the crypts of Lieberkühn, which dip to the muscularis mucosae and contain goblet cells, absorptive and enteroendocrine cells, and undifferentiated cells that are restricted to the lower third of the crypts. Glucagon-like immunoreactant pancreatic polypeptide-like peptide (PYY) with N -terminal tyrosine amide–producing L-cells predominate in the large intestine. Paneth cells are scarce and normally are noted only in the proximal colon. The lamina propria of the large intestine contains solitary lymphoid follicles that extend into the submucosa. Lymphoid follicles are more developed in the rectum and decrease in number with age. Confluent lymphoid tissue is present in the appendix. Macrophages (muciphages) predominate in the subepithelial portion of the lamina propria, are weakly PAS positive, and are associated with stainable lipids.

Anal Canal

Microscopically, the anal canal is divided into 3 zones: proximal, intermediate or pectinate, and distal or anal skin. The proximal zone is lined by stratified cuboidal epithelium, and the transition with the rectal mucosa, which is lined by high columnar mucus-producing cells, is called the anorectal histologic junction ( Fig. 98.10 A ). The intermediate or pectinate zone is lined by stratified squamous epithelium but without adnexae (e.g., hair, sebaceous glands) and is also referred to as anoderm. Its proximal margin, in contact with the proximal zone, is called the dentate line; its distal margin, in contact with the anal skin, constitutes the pectinate line, also referred to as the mucocutaneous junction (see Fig. 98.10 B ). Some authors use the terms pectinate line and dentate line interchangeably. The anal skin is lined by squamous stratified epithelium and contains hair and sebaceous glands.

Vasculature

Large arterial branches enter the muscularis propria through the serosa and pass to the submucosa, where they branch to form large plexuses. In the small intestine, 2 types of branches arise from the submucosal plexuses: some arteries branch on the inner surface of the muscularis mucosae and break into a capillary network that surrounds the crypts of Lieberkühn; other arteries are destined for villi, each villus receiving 1 or 2 arteries, to set up the anatomic arrangement that allows a countercurrent mechanism, thus aiding absorption. One or several veins originate at the tip of each villus from the superficial capillary plexus, anastomose with the glandular venous plexus, and then enter the submucosa to join the submucosal venous plexus.

In the colon, branches from the submucosal arterial plexus extend to the surface, giving rise to capillaries that supply the submucosa, and there branch to form a capillary meshwork around the crypts of Lieberkühn. From the periglandular capillary meshwork, veins form a venous plexus between the base of the crypts and the muscularis mucosae. From this plexus, branches extend into the submucosa and form another venous plexus from which large veins follow the distribution of the arteries and pass through the muscularis propria into the serosa.

Lymph Vessels

The lymphatics of the small intestine are called lacteals and become filled with milky-white lymph called chyle after eating. Each villus contains 1 central lacteal, except in the duodenum, where 2 or more lacteals per villus may be present. The wall of the lacteal consists of endothelial cells, reticulum fibers, and smooth muscle cells. At the base of the villus, the central lacteals anastomose with the lymphatic capillaries between the crypts of Lieberkühn. They also form a plexus on the inner surface of the muscularis mucosae. Branches of this plexus extend through the muscularis mucosae to form a submucosal plexus. Branches from the submucosal plexus penetrate the muscularis propria, where they receive branches from plexuses between the inner and outer layers. Lymphatic vessels are absent in the colonic mucosa, but the distribution of lymphatics in the remaining colonic layers is similar to that in the small intestine.

Nerves

The intrinsic nervous system (enteric nervous system [ENS]) consists of subserosal, muscular, and submucosal plexuses. The subserosal plexus contains a network of thin nerve fibers without ganglia that connects the extrinsic nerves with the intrinsic plexus. The myenteric plexus, or Auerbach plexus, is situated between the outer and inner layers of the muscularis propria (see Fig. 98.8 ); it consists of ganglia and bundles of unmyelinated axons that connect with the ganglia to form a meshwork. These axons originate from processes of the ganglion cells and extrinsic vagus and sympathetic ganglia. The deep muscular plexus, or Schabadasch plexus, is situated on the mucosal aspect of the circular muscular layer of the muscularis propria. It does not contain ganglia; it innervates the muscularis propria and connects with the myenteric plexus. The submucosal plexus, or Meissner plexus, consists of ganglia and nerve bundles. The nerve fibers of this plexus innervate the muscularis mucosae and smooth muscle in the core of the villi. Fibers from this plexus also form a mucosal plexus that is situated in the lamina propria and provides branches to the intestinal crypts and villi. The ganglion cells of the submucosal plexus are distributed in 2 layers; one is adjacent to the circular muscular layer of the muscularis propria, and the other is contiguous to the muscularis mucosae. Ganglion cells are large cells, isolated or grouped in small clusters called ganglia ( Fig. 98.11 ). Ganglion cells have an abundant basophilic cytoplasm, a large vesicular round nucleus, and a prominent nucleolus. Ganglion cells are scarce in the physiologically hypoganglionic segment 1 cm above the anal verge.