Chapter 381. Normal Structure and Function of the Gastrointestinal Tract

The gastrointestinal (GI) tract is a continuous tube beginning at the mouth and ending at the anus (Fig. 381-1). Its main function is to digest food and absorb nutrients and fluid. It is subdivided into 4 regions: (1) esophagus, (2) stomach, (3) small intestine, and (4) large intestine. The liver and pancreas directly communicate with the GI tract via ducts that join with the duodenum, the most anterior segment of small intestine. At the cellular level, the tissue architecture of the gut tube is similar throughout, consisting of 4 concentric layers.1 From inner to outer they are (1) mucosa, (2) submucosa, (3) muscularis propria (externa), and (4) adventitia or serosa. The mucosa is composed of epithelium, lamina propria, and muscularis mucosae (Fig. 381-2).

The epithelium throughout the GI tract is a highly proliferative tissue because it continuously undergoes renewal. The source of new epithelial cells is a stem cell compartment located in the most basal zone.2 The stem cells give rise to rapidly proliferating (transit amplifying) cells that migrate toward the lumen and differentiate into the epithelial subtypes that subserve tissue function. Conditions that result in epithelial damage often result in regenerative changes, reflecting increased cell turnover due to accelerated loss of epithelial cells. For example, esophagitis is often accompanied by basal zone hyperplasia, celiac disease by crypt hyperplasia, and colitis by branched and elongated crypts.2

The boundary between the epithelium and the lamina propria is formed by the basement membrane. It is made of extracellular matrix proteins such as collagen, laminin, and fibronectin elaborated by both the epithelium and the lamina propria cells. It serves an important function in the maintenance of a differentiated, functional epithelium.

The lamina propria contains fibroblasts and myofibroblasts that regulate epithelial proliferation and differentiation. Also in the lamina propria are immune cells, nerves, lymphatics, and blood vessels, all of which support the epithelium and guard against invasion by pathogens. Embedded within the lamina propria are epithelial glands that are contiguous with the surface epithelium and that open into the lumen. The muscularis mucosae is a thin band of smooth muscle that separates the mucosa layer from the underlying submucosa and provides additional structure and motility to the mucosa.

The submucosa consists of supporting collagenous fibers, larger blood vessels, lymphatics, nerve fibers and ganglia, and occasional lymphoid follicles. In the duodenum, the submucosa also contains Brunner glands that secrete bicarbonate to neutralize gastric acidity.

The muscularis propria consists of 2 bands of smooth muscle with an intervening layer of nerves and ganglia, the myenteric plexus. Coordinated contraction and relaxation of the circular (inner) and longitudinal (outer) muscle layers is required for gut peristalsis.

The outermost layer, the adventitia, consists of connective tissue and adipose. In many areas, the GI tract is surrounded completely by a sheath of mesentery or serosa, which tethers the gut tube to the body wall and serves as a conduit for major blood vessels and lymphatics.

Despite the overall similar architecture, specialization of the tissue layers, particularly the mucosa, confers specific functions to the different anatomic regions of the GI tract.

Esophagus

The esophagus extends from the posterior pharynx to the stomach, serving as a conduit for the passage of food. Esophageal epithelium is nonkeratinized, stratified, and squamous, designed to withstand abrasion as ingested food passes through it. Submucosal glands secrete mucins for lubrication and acid protection. The esophageal epithelium is not well suited to resist chemical insults, making it vulnerable to damage from caustic ingestions or chronic exposure to gastric secretions.

The muscularis propria of the esophagus is composed of a mixture of skeletal and smooth muscle fibers in the upper third, mixed fibers in the middle third, and smooth muscle in the distal third. Both the upper and lower openings of the esophagus remain closed by the tonic contraction of the muscularis propria. These sphincters relax in a coordinated fashion during swallowing. The lower esophageal sphincter prevents regurgitation of acidic stomach contents and ingested food back into the esophagus.

The blood supply for the esophagus comes from small branches of the aorta, the intercostal arteries, and esophageal branches of the left gastric artery. The veins accompany the arteries and create a connection between the portal and systemic venous circulations. This connection becomes relevant in patients with portal hypertension, because dilated varices can rupture and cause life-threatening hemorrhage.

Stomach

The stomach serves as a reservoir for ingested food and, through a combination of physical movement and chemical digestion, breaks down food into smaller particles. The largest region of the stomach is the gastric body, which is characterized grossly by thick mucosal folds or rugae (eFig. 381.1). The gastric body or corpus is the acid-secreting portion of the stomach. It is characterized at endoscopy by thick mucosal folds or rugae; it extends distally to the incisura on the lesser curvature. The fundus is the dome-shaped area immediately above the gastric body and, like the corpus, is lined with oxyntic mucosa. The body is lined by mucosa containing deep glands that contain acid-secreting parietal cells and pepsinogen-secreting chief (oxyntic) cells. Secreted acid serves as a barrier to bacterial colonization of the small intestine and enables the enzyme pepsin to initiate the digestion of proteins. Parietal cells also secrete intrinsic factor, which is necessary for the absorption of vitamin B12 in the ileum.

The gastric antrum extends from the incisura to the pylorus with a smooth (ie, nonrugose) mucosal surface. Glands in the antrum differ from those in the body in that they produce less acid, more mucus, and contain specialized cells that secrete hormones known as enterochromaffin cells. The stomach is also distinguished by having 3 layers in the muscularis externa—oblique, circular, and longitudinal—which enable vigorous mixing of ingested food. An important hormone secreted by the antrum is gastrin, which stimulates parietal cells to secrete acid. The muscularis propria of the stomach uniquely contains 3 layers—an outer longitudinal, inner circular, and innermost oblique layer—that allow dramatic variation in stomach size and contractile patterns. The blood supply of the stomach comes from 5 arteries, all of which arise from the celiac axis and anastomose freely on the external surface. Venous return is through the portal venous system.

Small Intestine

The small intestine is the largest section of the gastrointestinal tract and is responsible for the bulk of its digestive and absorptive functions. The first portion, the duodenum, extends from the pylorus to the ligament of Treitz, forming a C-loop around the head of the pancreas. The common bile duct and pancreatic ducts enter the duodenum at the ampulla of Vater. The remainder of the small bowel is approximately 200 to 250 cm in length in the term newborn infant, and it reaches 350 to 600 cm in the adult. The proximal 40% is conventionally called the jejunum, and the remainder the ileum. There is no clear line dividing the two, but crescentic mucosal folds (ie, the valvulae conniventes) are more prominent and closely spaced in the jejunum, resulting in a feathery appearance on radiographic contrast examination compared with the ileum. In addition, the vascular arcades through the mesentery differ in the proximal jejunum and distal ileum.

The luminal surface of the small intestine is covered by a lawn of fingerlike projections called villi, which increase the surface area for digestion and absorption (eFig. 381.2). Invaginations at the bases of the villi are the crypts of Lieberkühn where epithelial stem cells are located. Every 5 to 7 days, the epithelium is continuously replenished by new cells derived from the crypts. There are 4 epithelial subtypes: enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Enterocytes account for over 90% of the epithelial cells. At the subcellular level, enterocytes have a specialized apical region called the brush border that contains numerous digestive enzymes and transport proteins. Goblet cells secrete mucus and enteroendocrine cells secrete a wide spectrum of hormones. Each enteroendocrine cell type is specialized for secretion of only one hormone. In addition to blood vessels, fibroblasts, immune cells, and smooth muscle fibers, the lamina propria contains lymphatic vessels called lacteals for transporting ingested fat to the circulation. Lymphoid aggregates are present throughout the submucosa and occasionally extend into the mucosa. Their size and number increase in the ileum, where they are known as Peyer patches. M cells are specialized epithelial cells typically associated with lymphoid follicles.

The duodenum is supplied with blood from the celiac and superior mesenteric arteries, and the remainder of the small bowel is supplied only by the superior mesenteric artery. Venous drainage is via the portal venous system.

Large Intestine

The large intestine recovers fluids and electrolytes from the gastrointestinal tract lumen before their loss in feces with undigestible materials. The large intestine begins at the cecum, from which extends a narrow terminal extension called the vermiform appendix. It includes the ascending, transverse, and descending colons, the sigmoid, and the rectum, ending at the anus (Fig. 381-1). The mucosa consists of a smooth surface without villi but containing crescentic submucosal folds (plicae semilunares) that project into the lumen. The epithelial lining contains absorptive cells with microvilli, which increase absorptive area. Mucosal glands have an abundance of mucus-producing goblet cells and rare endocrine cells. As in the small intestine, the epithelium is renewed every several days by stem cells that reside at the bases of crypts. The lamina propria of the colon contains numerous immune cells, including macrophages and large lymphoid nodules that extend into the submucosa. The muscularis propria contains circular and longitudinal muscle layers throughout, the latter of which are condensed into 3 thick bundles termed teniae coli. These bundles of muscle may shorten the colon during large bulk movements of luminal contents. The circular muscle is thickened adjacent to the anus, where it forms the internal anal sphincter. The pectinate line delineates the endoderm-derived mucosa from the ectoderm-derived skin.

The cecum and the ascending and proximal half of the transverse colon are supplied with blood from the superior mesenteric artery, and the remainder of the colon is supplied by the inferior mesenteric artery.

The gastrointestinal (GI) tract is a composite structure with components derived from all 3 germ layers. The inner epithelial lining is derived from the endoderm, but the surrounding layers come from mesoderm and ectoderm. Development of the GI tract can be divided into distinct phases: formation of the endoderm, morphogenesis and patterning of the gut tube, and organ morphogenesis and terminal differentiation.3-5 Each phase has been studied using molecular genetic techniques and a variety of animal models, including mouse, frog, zebrafish, fruit fly and roundworm.6 Thus, many of the morphological events described previously have been annotated with molecular details. In some cases, human mutations have been implicated in specific developmental defects. For example, a case of human congenital pancreatic agenesis was shown to result from a single nucleotide deletion in the pancreas/duodenum homeobox protein 1 gene (PDX1), which is required for pancreatic development in mice and zebrafish. The caveat remains, however, that there are likely aspects of human development that cannot be extrapolated directly from simpler organisms.

Early Development

During the third week of gestation, the endoderm forms during gastrulation, resulting in a trilaminar disk.7 A number of factors that promote endoderm formation are conserved across phyla, including Nodal signaling factors that direct a subset of blastomeres into the endoderm lineage. Nodals are members of the transforming growth factor (TGF)-β family of signaling molecules; they direct the expression of homeobox transcription factors in the MIX family. Other transcription factors acting downstream of Nodals include GATA4, GATA5, and GATA6, the homeobox factor SOX17, and the forkhead transcription factors FOXA1, FOXA2, and FOXA3.6 The gut tube forms by folding during the fourth week of gestation (eFig. 381.3).8 The ectoderm and endoderm of the trilaminar germ disk grow at different rates, which results in its folding inward to form a tube lined by endoderm, with ectoderm on the embryonic external surface. The endoderm-lined tube closes completely to form the foregut and hindgut, which terminate at the buccopharyngeal membrane and cloacal membranes respectively. The midgut portion of the tube remains open to the yolk sac until the sixth week of gestation, when the neck of the yolk sac is reduced to a slim stalk, the omphaloenteric (vitelline) duct. Persistence of the omphaloenteric duct can result in a spectrum of anomalies, ranging in severity from omphalocele to the more common Meckel diverticulum.

Gut Patterning and Morphogenesis

The primitive gut tube can be divided into 3 anatomic segments, the foregut, midgut, and hindgut, based on its blood supply. The foregut gives rise to the pharynx, respiratory tract, esophagus, stomach, and proximal duodenum (eFig. 381.4). At approximately 3 weeks of gestation, the respiratory diverticulum or lung bud develops as a ventral outpouching of the foregut. A septum forms in the foregut to separate the trachea from the prospective esophagus, and defects at this stage can lead to esophageal atresia or tracheoesophageal fistula.8

During the fifth week of embryonic development, the dorsal wall of the stomach grows faster than the ventral wall, thus forming the greater and lesser curvatures of the stomach. The stomach and liver rotate around a craniocaudal axis so that by the eighth week of gestation the greater curvature of the stomach lies to the left and the liver to the right side of the abdominal cavity. The liver, gallbladder, and ventral pancreatic bud develop from a ventral bud immediately caudal to the prospective stomach (Fig. 381-3). A separate dorsal pancreatic bud gives rise eventually to the body of the pancreas. Rotation of the duodenum results in the fusion of the pancreatic buds to form a single pancreas, followed by the unification of the pancreatic and bile ducts by the sixth week. Failure of these processes can result in annular pancreas or pancreas divisum, respectively.9

The jejunum, ileum, cecum, appendix, proximal colon, and distal half of the duodenum are derived from the midgut, supplied by the superior mesenteric artery. As the midgut elongates, there is insufficient space inside the peritoneal cavity, so it herniates into the extraembryonic coelom through the umbilical cord.8 During this period, the gut rotates counterclockwise about the axis of the superior mesenteric artery, a total of 270 degrees. After it returns into the abdominal cavity, it attaches to the posterior abdominal wall via its mesentery in a diagonal pattern extending from the left upper quadrant to the right lower quadrant (eFig. 381.5). Failure of midgut rotation or fixation of the mesentery results in malrotation, which can predispose to midgut volvulus around the superior mesenteric artery.

While the midgut lengthens, at the cellular level the prospective small intestinal epithelium begins to form its absorptive surface. Between 10 and 12 weeks of gestation, the stratified, squamous epithelium adopts a simple, columnar morphology as rudimentary villi emerge. This process occurs in a cranial-to-caudal direction3 (eFig. 381.6).

The hindgut gives rise to the left one third of the transverse colon, descending colon, and rectum. The cloaca is a transient structure derived from the end of the primitive hindgut. Between the fourth and sixth weeks, the cloacal lumen divides into the rectum posteriorly and the urogenital sinus anteriorly. The urogenital sinus gives rise to the bladder, urethra, and vestibule of the vagina. The rectum is contiguous with a depression in the ectoderm called the anal pit; this pit breaks down to permit continuity between the endodermal lining of the rectum and the ectodermal lining of the anus.7 Genetic inactivation of the Hoxd12 and Hoxd13 genes in mice resulted in disruption of anal sphincter morphogenesis. Further study of the Hoxd complex, in which 10 of the 12 Hoxd genes were inactivated, revealed their critical role in sphincter formation throughout the digestive tract. A number of human genetic syndromes exhibit anorectal defects, and the role of HOX genes in their pathogenesis remains to be tested.3

Molecular Genetics of Intestinal Development

Numerous molecular pathways have been associated with the patterning, cytodifferentiation, and proliferation of intestinal enterocytes. These include the Wnt, TGF-β, and hedgehog signaling pathways. In addition, transcription factors known to be involved include the gata, forkhead, caudal-related (CDX), and HOX families as discussed in more detail in additional text on DVD.10

Multiple members of the Wnt signaling pathway (including β-catenin, adenomatosis polyposis coli [APC], axin, TCF/LEF, c-Myc) have been implicated in regulating proliferation in epithelial cells.11 A key issue that remains poorly defined is the source of the Wnt signal and how it is regulated in vertebrate intestinal development.12 In Drosophila, a network of signals that regulates the spatial expression of wingless (a Wnt ortholog) is responsible for the anterior-posterior regionalization of the midgut. In Caenorhabditis elegans, a Wnt signal is required for specification of the E cell, which gives rise to all intestinal cells. Zebrafish mutants with defective enterocyte proliferation may be useful tools for in vivo analysis of Wnt signaling in the vertebrate intestine.6

The TGF-β signaling pathway has been implicated in juvenile polyposis via mutations in the signal transducer SMAD4. The polyps are hamartomatous, exhibiting overproliferation of mesenchymal elements, suggesting that loss of responsiveness to TGF-β signaling results in unrestrained mesenchymal proliferation. This indicates that members of the TGF-β superfamily are involved, along with sonic hedgehog, in signaling from the endoderm to the mesenchyme. In Drosophila, decapentaplegic, a TGF-β ortholog, is required for transduction of positional information from visceral mesoderm to endoderm.

Sonic hedgehog (Shh) signaling has been implicated in epithelial-mesenchymal interactions as a mediator of anterior-posterior regionalizing information in the hindgut. Endodermal overexpression of Shh was shown to elicit Hox gene expression and induce overproliferation of mesenchymal tissue. From these and other studies, a model for regional patterning of the gut epithelium was proposed in which Shh expression in the endoderm elicits a prepatterned response from the mesenchyme that in turn induces region-specific epithelial phenotypes.13

Transcriptional regulation of intestinal differentiation has been well studied from the standpoint of both cis-regulatory elements (ie, promoter elements) and transacting factors (ie, transcription factors). A key concept to emerge is that of a complex regulatory network consisting of nodes and branches. A regulatory network guiding endoderm differentiation has been inferred by combining expression patterns with known binding sites within cis-regulatory elements of known downstream genes. Some of the DNA binding proteins that have been implicated in endoderm differentiation include the caudal-related CDX factors; HNF3/forkhead-related factors; the GATA4, GATA5, and GATA6 factors; and HOX proteins.14

The interactions of enterocytes with various basement membrane components have been studied, and several conclusions have emerged. For example, epithelial-mesenchymal interactions are required for basement membrane formation in addition to epithelial cell differentiation. The observation that basement membrane components are elaborated by both mesenchyme and epithelium emphasizes the reciprocal nature of epithelial-mesenchymal interactions.15

Gastrointestinal Muscle Development

The muscle coat of the gastrointestinal tract consists of the muscularis mucosa, an inner circular layer, and an outer longitudinal layer. Layers of smooth muscle develop in the mesenchymal layer surrounding the bowel lumen in a craniocaudal pattern early during gestation, with the circular muscle layers being recognizable in the esophagus and stomach during week 5 of human gestation and in the ileum by 8 weeks. Longitudinal muscle layers are not present until 8 weeks and appear in the ileum by 10 weeks. The thickness of each muscle layer increases through gestation and after birth. The inner layer of circular muscle consists of a 3-cell to 8-cell-thick specialized layer of fibroblasts and muscle cells containing numerous junctions between cells. Termed the interstitial cells of Cajal, this layer generates the basic electrical rhythm, or slow waves, of the gastrointestinal tract.

Enteric Nervous System Development

The enteric nervous system is derived from the neural crest.16 Enteric neurocyte precursors migrate from the neural crest through the fetal gut in a craniocaudal direction, being observed first in the stomach and duodenum at 7 weeks and reaching the rectum by 12 weeks. The congenital disorder of Hirschsprung disease results from a failure of migration by these neurocytes. The migration and maturation of enteric neural elements is controlled by interactions between the neural crest cells and the intercellular matrix. A molecular signaling pathway important for this interaction includes the glial-derived neurotrophic factor (GDNF) and its receptor RET, a tyrosine kinase. Mutations in these genes have been associated with aganglionosis in humans and animal models.

Once the neurocytes enter the bowel, they undergo phenotypic development, with the complexity of the axonal and dendritic networks increasing through gestation and after birth. Neuronal intestinal dysplasias or congenital neuropathic pseudoobstruction syndromes may represent abnormalities of neurodifferentiation.

Digestion is the chemical breakdown of food into fundamental building blocks.17 The process occurs in 3 phases with sequential action of a variety of enzymes with specific roles (eTable 381.1). The intraluminal phase involves a process of digestion whereby dietary carbohydrates, proteins, and fats are hydrolyzed and solubilized. Hydrolysis is largely dependent on enzymes from the pancreas and brush border membrane of the intestinal villi, while solubilization requires biliary secretions. The mucosal phase involves the uptake of peptides, simple carbohydrates, and lipids by the enterocytes with subsequent processing and packaging in preparation for transport. The removal phase involves the movement of the absorbed nutrients into the vascular or lymphatic circulation. Digestion begins in the mouth where mastication breaks the food down mechanically and mixes it with saliva. The stomach then grinds the food further and mixes it with acidic gastric secretions to render it into chyme. Chyme is released into the duodenum where it meets with bicarbonate to neutralize the acid. Bile secreted by the liver emulsifies ingested fat, and enzymes secreted by the pancreas digest carbohydrates, proteins, and lipids into smaller molecules. Peptidases and disaccharidases located on the brush border surface of the intestinal enterocytes perform the final step, converting peptides and disaccharides into monomers. The transport of nutrients across the intestinal epithelium is highly selective, occurring by 3 mechanisms: active transport, facilitated diffusion, and passive diffusion. Electrolytes are absorbed via specific transporters. In this chapter, we describe the digestion and absorption of 3 main classes of nutrients: carbohydrates, amino acids, and fats, as well as mechanisms of water and electrolyte transport. Disorders of digestion and absorption are discussed in Chapter 408.

Digestion and Absorption of Carbohydrates

Lactose is the primary carbohydrate for breast-fed and most formula-fed infants. It consists of glucose and galactose linked by an α-1,4 glycosidic bond. Lactase-mediated hydrolysis is the rate-limiting step in lactose assimilation. Lactase is localized to the microvilli of enterocytes at the villous tips, and its expression is developmentally regulated. A low level of lactase activity is present by 11 weeks of gestation and increases to 25% of term levels by 34 weeks. It peaks at birth in term infants and then declines to approximately 25% of term levels by 1 year of age. Despite the high levels of lactase activity in early infancy, the large quantities of lactose that are ingested daily (approximately 10–14 g/kg) overwhelm the absorptive capacity of the small intestine, and a large amount of ingested lactose reaches the colon. Intestinal bacteria further digest the lactose to organic acids that are absorbed, salvaging nutrient calories for the infant. Further decline in lactase activity during mid to late childhood leads to lactose intolerance in much of the world’s population. It is a benign condition, but diarrhea and bloating can cause substantial discomfort and inconvenience.

After weaning, most carbohydrate is ingested in the form of starch, sucrose, glucose and fructose. Starch or amylopectin, is a glucose polymer linked by both α-1,4 and α-1,6 linkages. Starch is initially hydrolyzed by salivary and pancreatic amylases to generate substrates recognized by the brush border hydrolases glucoamylase and maltase. Both amylases have nearly identical structures, and both are potent endoglycosidases. They act at the internal α-1,4 bonds of amylose and amylopectin to produce some glucose but mainly trioses, disaccharides, and limit dextrins, which are then sequentially hydrolyzed by the brush border α-glucosidases: (1) glucoamylase, (2) isomaltase, and (3) sucrase. In the neonate, the quantitative contribution of salivary and pancreatic amylase to starch digestion is poorly defined. Salivary amylase secretion is present in the preterm infant by 34 weeks of gestation, but no pancreatic amylase secretion can be demonstrated until 4 to 6 months after birth, when starches normally are introduced into the infant diet. Salivary amylase is thought to be of minimal quantitative importance for carbohydrate digestion in the adult, but a more significant role has been postulated in the preterm infant. The brush border enzyme glucoamylase hydrolyzes the products of amylase digestion. It has maximum activity for oligomers containing between 5 and 9 glucose residues, and higher-molecular-weight compounds or complex carbohydrates with multiple branch points are less efficiently hydrolyzed. Glucoamylase is detectable by 20 weeks of gestation, and levels increase throughout gestation so that by 34 weeks activity is similar to that of older children. Developmental regulation and the role of diet on pancreatic amylase and intestinal hydrolase expression are now being investigated at a molecular level. Clinically significant starch intolerance is relatively rare in infancy beyond the neonatal period. Sucrose is digested by sucrase-isomaltase, a major intestinal brush border enzyme that is first synthesized as a single-chained precursor containing active sites for sucrose and isomaltose hydrolysis. It undergoes extensive intracellular modification before being incorporated into the brush border membrane, where it is rapidly cleaved by pancreatic proteases into the two subunits sucrase and isomaltase. Despite proteolytic cleavage, the subunits remain associated and fully active, being responsible for the hydrolysis of sucrose, isomaltose, and maltose. In the human infant, sucrase-specific activity is high by 20 weeks of gestation, being nearly equal to one half to three quarters the full-term infant and adult values. The jejunal-specific activity of sucrase-isomaltase in full-term infants and adults is nearly twice that of lactase, making monosaccharide absorption, rather than hydrolysis, the rate-limiting step in the assimilation of sucrose. Nondigestible carbohydrates that comprise the structural component of plants constitute dietary fiber. Fiber cannot be hydrolyzed by mammalian intestinal enzymes but is hydrolyzed in the colon by bacterial enzymes.

The final step in the assimilation of carbohydrates after luminal or brush border hydrolysis is absorption of monosaccharides. Glucose, galactose, and fructose are transported across the enterocyte into the portal circulation by passive and active transport mechanisms. Glucose and galactose transport occurs by two mechanisms: simple, non saturable diffusion (if luminal concentration exceeds 3 mmol/L) and active transport. The active transport mechanism is mediated at the brush border by a Na+-coupled glucose transporter, SGLT-1, which provides the basis for including glucose and sodium chloride in oral rehydration solution. The facultative glucose transporter, GLUT-2, is located on the basolateral membrane. The glucose transporter is stereospecific for d-glucose and d-galactose. Active glucose transport can be demonstrated in vitro at 10 weeks of gestation, and the transporter is present throughout the entire intestine by 17 to 20 weeks of gestation, with activity increasing throughout gestation. Mutations of the SGLT-1 gene have been shown to cause glucose-galactose malabsorption, which can result in fatal diarrhea in newborn infants. Fructose is transported either by facilitated diffusion or by a high-affinity glucose-dependent facultative transporter, GLUT-5, located on the enterocyte brush border. When large amounts of fructose are ingested without glucose, as in fruit juices, transport mechanisms may be overwhelmed, causing diarrhea.

Digestion and Absorption of Protein

Dietary proteins exhibit an enormous structural and biological diversity, requiring a surfeit of proteolytic enzymes and transport systems to ensure efficient digestion and absorption. As with carbohydrates, protein digestion is achieved through a series of coordinated hydrolytic steps, beginning with pepsin in the stomach and reaching completion in the intestine through the action of pancreatic proteases and peptidases (eTable 381.1). The final hydrolysis and absorption of the newly produced oligopeptides are then mediated by integral membrane hydrolases and amino acid transporters that are located within the enterocyte brush border.

Digestion of proteins is initiated in the stomach by the enzyme pepsin that is secreted by chief cells in concert with gastric acid production. The products of gastric digestion are large polypeptides and oligopeptides. Intraluminal proteolysis continues in the intestine and is mediated by endopeptidases and ectopeptidases that are secreted by the pancreas in precursor form. Enzyme activation requires the initial digestion of trypsinogen to trypsin by an enterokinase, a brush border enzyme. Trypsin then activates the other pancreatic enzymes. The endopeptidases act at the interior of the protein molecule to produce oligopeptides, usually of 2 to 6 amino acid residues in length, and the ectopeptidases act at the carboxyl-terminal end of the protein to remove a single amino acid. It is estimated that luminal protein digestion yields 70% oligopeptides and 30% amino acids. Peptides resulting from luminal hydrolysis are further hydrolyzed by brush border surface oligopeptidases.

Specific sodium-dependent carrier proteins of overlapping specificity actively transport amino acids into the cell. These carriers interact with all 3 classes of amino acids: (1) neutral, (2) acidic, and (3) basic. Other sodium-independent facilitated amino acid transport systems are present in the enterocyte on both the apical and basolateral membranes. In addition, proteins transport dipeptides and tripeptides, which are further hydrolyzed by cytosolic enzymes before transport of the amino acids into the portal circulation.

The process of protein digestion and absorption is remarkably efficient, with over 95% of luminal protein being absorbed. Most luminal protein is absorbed in the duodenum and proximal jejunum; only relatively minor amounts ever reach the colon. Protein digestion and absorption are efficient even in preterm infants. Enterokinase appears relatively late in gestation (ie, 28 weeks) and reaches only 10% of adult levels by birth. In the pancreas, chymotryptic and tryptic activity have been demonstrated in vitro by 26 weeks of gestation, and a pancreatic response to secretagogues is functional at 30 weeks of gestation. The ontogeny of the brush border amino-oligopeptidases as well as the dipeptide and amino acid transport systems parallel carbohydrate enzymes, although regulatory mechanisms differ. Amino-oligopeptidases are first detected immunohistochemically by 10 to 16 weeks of gestation. By 28 to 30 weeks, enzyme values are approximately one half the values found in term infants, so all aspects of intestinal proteolysis and transport are relatively intact even in the preterm infant.

Digestion and Absorption of Fats

Fats or lipids supply nearly 50% of the energy in human milk and about 30% of caloric intake in the typical Western diet. The process of digestion and absorption of lipid can be divided into 5 phases: (1) intraluminal hydrolysis, (2) micellar solubilization, (3) permeation from the lumen into the cell, (4) reesterification in the cell, and (5) packaging into chylomicrons for transport out of the enterocyte. Intraluminal digestion begins with the mechanical emulsification of the food in the mouth and the stomach. The emulsified fat is then hydrolyzed by lipase enzymes, forming fine droplets of monoglycerides and fatty acids.

Three major lipases are important for fat digestion. Acid-stable lipases are secreted by the body of the stomach and begin the process of fat digestion in the acid milieu of the stomach, being responsible for 20 to 30% of the lipid digestion in infants. When nutrients enter the duodenum, mucosal hormones are released, which stimulates the pancreas to secrete pancreatic lipase and colipase. These enzymes are responsible for most fat hydrolysis in adults, being present in concentrations that are 1000-fold those required for adequate fat digestion. However, in the newborn infant (and particularly in premature infants), pancreatic secretion of lipase and bile salt secretion are relatively inadequate, causing formula-fed infants to mal absorb 10 to 15% of dietary lipids. Breast-fed infants absorb significantly more lipid because of the presence of a unique lipase in breast milk that traverses the stomach and is then activated by bile salts in the small intestine. Breast-milk lipase may be responsible for up to two thirds of lipid hydrolysis in breast-fed infants. The free fatty acids and monoglycerides released by lipolysis are readily solubilized into micelles by detergent like bile salts secreted from the liver. The micelle approaches the brush border surface of the enterocyte, and the fatty acids dissociate from the micelle and diffuse into the lipophilic cell membrane. A lack of adequate bile-salt secretion, as occurs in liver disease, results in malabsorption of fats because of inadequate solubilization. Intraluminal bile-salt concentrations are low in the newborn infant, but this does not appear to significantly limit lipid absorption.

Once the fatty acid enters the enterocyte, fatty acid–binding protein transports long-chain fats to the smooth endoplasmic reticulum where they are reesterified and, together with phospholipids and cholesterol, are joined by apolipoproteins to form very low-density lipoproteins, low-density lipoproteins, high-density lipoproteins, and chylomicrons. Chylomicrons are assembled in the endoplasmic reticulum of the enterocyte and transported to the Golgi apparatus. Chylomicron-containing Golgi vesicles are subsequently released to fuse with the basolateral membrane and are excreted by exocytosis into the intercellular space before entering the lymphatic system. The enterocyte repackages newly formed triglycerides, phospholipids, and various apolipoproteins into chylomicrons, which are transported through the basolateral membrane of the enterocyte and into the lymphatics. Lipoprotein synthesis and chylomicron formation are intact at birth and do not appear to limit nutrient lipid absorption postnatally in healthy infants. Medium-chain fatty acids are taken up directly into the portal system, offering an alternative source of energy if a step in the long-chain fatty acid pathway is blocked.

Absorption and Secretion of Electrolytes and Water

A key principle governing gastrointestinal (GI) fluid balance is that all water movement across the intestinal barrier is determined by osmotic gradients created by solute ingestion and transport. Dramatic fluid shifts accompany the ingestion of food. About 100 cc/kg/day of electrolyte-containing and enzyme-containing fluid is secreted into the GI lumen, most of which is reabsorbed via the uptake of nutrients and electrolytes. Figure 381-4 provides an overview of fluid secretion and absorption. The chyme that initially enters the small intestine from the stomach is typically not hyperosmotic, but as its macromolecular components are digested, the osmolarity increases dramatically, and water is pulled into the lumen. As the contents are absorbed, osmolarity decreases, and water can be absorbed. Active Na transport across the intestinal enterocyte is a two-step process that involves either channel-mediated or non-channel-mediated entry of Na into the enterocyte down an electrochemical gradient that is maintained by a basolaterally located sodium pump, the Na,K ATPase. In the small intestine, apical transporters include Na,Cl cotransporters (ie, Na,H and Cl,HCO3 exchange) and nutrient carriers such as the Na,glucose (or galactose) transporter and Na,amino acid cotransporter. In the colon, Na loss is prevented by a volatile fatty acid–stimulated cotransport system and an aldosterone-sensitive Na transport mechanism that actively transport Na against a concentration gradient. The basolateral Na,K ATPase is present early during gestation in all polar epithelial cells. Expression is regulated by glucocorticoids and aldosterone. Nutrient transporters have similar ontogenic patterns, although specific regulatory elements and determinants may vary.

Secretion by the stomach, pancreas, biliary tree, and intestinal crypt cells is modulated by the active transport of electrolytes into the bowel lumen. Secretion is mediated by the electrogenic transport of Cl or HCO3 into the lumen. In the stomach, secretion also results from H+ transport into the lumen. Na+ and K+ are passively transported into the small bowel lumen so that luminal concentrations in general resemble plasma concentrations. In contrast, Cl is exchanged for HCO3 so that concentrations of both are in the 60-mmol/L to 70-mmol/L range. In the colon, an amiloride-sensitive sodium channel actively removes Na+ and water, so the Na+ content of stool falls to 30 mmol/L. In contrast, K+ concentration increases to 75 mmol/L because of permeability characteristics of the colon and an active potassium secretory mechanism. The mucosa of the large intestine also can actively secrete Cl, producing net solute and water flow into the lumen. Various neurotransmitters, locally acting paracrine agents such as prostaglandins, and infectious agents such as bacterial enterotoxins alter the direction of net ion movement and water flow across the small and large intestines. In general, these agents act via intracellular second messengers, including cAMP, cGMP, Ca2+, and inositol phosphate-diacyl glycerol.

Movement of material through the gastrointestinal tract occurs largely by peristalsis, the coordinated contraction and relaxation of smooth muscle, and is controlled by both extrinsic and intrinsic innervation of the muscularis externa.16-18 Extrinsic innervation is provided by the parasympathetic and sympathetic components of the autonomic nervous system, whereas the intrinsic innervation is provided by the enteric nervous system (ENS).

The parasympathetic innervation is supplied by preganglionic neurons located in either the brainstem or sacral spinal cord. Axons extend through the vagus or pelvic splanchnic nerves, respectively, to synapse with enteric neurons within the target organs. Sensory fibers also run through these nerve bundles. Sympathetic innervation is provided by preganglionic fibers that run from the thoracolumbar spinal cord to prevertebral ganglia where they synapse with postganglionic fibers that enter the target organs and synapse with components of the enteric nervous system.

The ENS has been called the “second brain” because it contains as many neurons as the spinal cord and can regulate motility and secretion independently of the central nervous system. The ENS is organized into the myenteric and submucosal plexuses (eFig. 381.7). The myenteric plexus controls the contractile activity of the circular and longitudinal layers, whereas the submucosal plexus also controls blood flow and mucosal secretion.

The directional movement of material from mouth to anus is accomplished by several mechanisms, the most important being the peristaltic reflex. In response to the distention of the gut lumen, enterochromaffin (EC) cells in the mucosa release serotonin (5-hydroxytryptophan, 5-hydroxytryptamine), which activates intrinsic primary afferent neurons in the gut wall. A series of interneural connections, acting through the interstitial cells of Cajal (ICC), activate smooth muscle contraction upstream and relaxation downstream of the stimulus (Fig. 381-5). These opposing responses create a directional pressure gradient to propel material forward. The ICC generate slow waves that are not, in themselves, sufficient to elicit contraction of smooth muscle. However, enteric neuronal input in concert with ICC depolarization generates depolarizing events; hence, the ICC are known as the intestine’s “pacemaker.”

Multiple neurotransmitters mediate intercellular communication within the enteric nervous system. The excitatory response in the proximal gut is mediated by acetylcholine, and the distal inhibitory response utilizes nitric oxide, vasoactive inhibitory peptide, neuropeptide Y, and adenosine triphosphate. Although small in number, dopaminergic neurons exert an important modulatory effect on cholinergic neurons by inhibiting release of acetylcholine. Dopamine receptor (D2) antagonists such as metoclopramide are believed to stimulate motility by promoting acetylcholine release. Serotonin release from distension can also activate neurons that transmit pain signals to the brain via extrinsic afferent fibers. This provides the rationale for the treatment of motility disorders, including irritable bowel syndrome, by selective serotonin receptor antagonists.

Different regions of the gastrointestinal tract display considerable variation in motility. In addition, the most proximal and distal ends of the gastrointestinal tract need to integrate voluntary with autonomic functions. For example, feeding involves coordinating a voluntary action (swallowing) followed by an autonomic wave of esophageal peristalsis. Likewise, defecation involves a voluntary Valsalva maneuver (to increase intra-abdominal pressure) working in concert with an autonomic reflex (relaxation of the internal anal sphincter). Given the complexity of these processes, it is not surprising that children with compromised neuromuscular functioning may have impairment in feeding or defecation.

Normal Esophageal Motility

The process of swallowing involves integrated activities of the mouth, pharynx, esophagus, and proximal stomach. After the oral and pharyngeal phases, the bolus of food is propelled into the esophagus via a coordinated involuntary reflex. The coordination of pharyngeal with esophageal contraction is accomplished by an area in the brainstem known as the swallowing center. Both somatic motor and visceral motor fibers originate from this area and travel via the vagus nerve to regulate esophageal motility.

Shortly before the posterior pharyngeal muscles contract, the upper esophageal sphincter relaxes to allow the food bolus to pass, after which it returns to its resting tone. A wave of peristalsis then propels the bolus distally through the body of the esophagus at a rate of 2 to 6 cm/second, taking about 10 seconds for it to reach the stomach. Anticipating the arrival of the bolus, the lower esophageal sphincter relaxes transiently and then reassumes baseline tone after its passage. The peristaltic wave following pharyngeal contractions is termed primary peristalsis (Fig. 393-1). If food or refluxed gastric contents distend the esophagus, a secondary wave of peristalsis is elicited to clear the material.

Gastric Motility

After a meal, food in the stomach is digested by the combined action of acid, pepsin, and the physical activity of the stomach musculature. Within the stomach, the different anatomic regions subserve specific functions. The most proximal region accommodates food and contributes little to mixing. In contrast, the more distal areas engage in peristaltic contractions that propel some food antegrade into the duodenum, but most of the food moves retrograde into the mid portion of the gastric body. This repetitive back-and-forth movement reduces the size of the gastric particles. The regulation of gastric emptying is complex, relying on a combination of factors: compliance of the proximal stomach, increases in the force of contraction in the distal body, and modulation of the diameter of the pylorus (see Chapter 407). As nutrients arrive in the intestine, a feedback signal (not well defined) downregulates emptying until this material has been propelled forward. During the interdigestive period, the migrating motor complex serves a housekeeping function by generating forceful contractions that propel residual gastric material into the duodenum.

Small Intestinal Motility

Various types of contractions are seen in the small intestine; they can be grouped into 3 general categories: segmenting, peristaltic, and migrating motor complex (MMC). Contractions are mostly local (except for the MMC), involving segments 1 to 4 cm in length and occurring with a frequency around 5 per second, though the range is quite large (1–45/second). Segmentation involves localized contractions that can propel luminal material in either direction, which promotes mixing and prolongs exposure of nutrients to the absorptive epithelial surface. Propulsive contractions are a localized response to distension, and are responsible for the net movement of material toward the anus. MMCs occur during fasting and sweep undigested material through the small intestine into the colon, thereby helping to keep the bacterial count low. Feeding abolishes the migrating motor complex contractions and stimulates a more continuous pattern of segmental contractions (see Chapter 407).

Colonic and Anorectal Function

Colonic contractions mix luminal contents to promote fluid absorption. Large, high-amplitude propagating contractions propel the stool bolus toward the rectum after feeding and awakening. The rectum normally contains only small amounts of material because of the frequent segmenting contractions of the more proximal regions. The rectum fills intermittently, which elicits the urge to defecate and concomitant relaxation of the internal anal sphincter (the rectosphincteric reflex).

Defecation involves a combination of voluntary and involuntary actions. When rectal distension leads to defecation, the muscles of the distal colon, sigmoid, and rectum contract while both the internal and external sphincters relax. Evacuation of the rectum is aided by increased intra-abdominal pressure generated by diaphragmatic contraction and closure of the upper airway (Valsalva maneuver), contraction of abdominal musculature, and lowering of the pelvic floor (see Chapters 386 and 407). In Hirschsprung disease, the absence of enteric neurons results in loss of the rectosphincteric reflex and increased tone in the intestine in the aganglionic segments. The “normal” bowel proximal to the diseased segment can become severely dilated, producing a megacolon.

The gastrointestinal tract is in continuity with the external environment and therefore is exposed to a vast array of foreign antigens, including ingested food and its digestion products, infectious pathogens, and nonpathogenic microbes. When functioning normally, nonpathogenic organisms and food antigens are effectively ignored, whereas pathogens are neutralized via a self-limited immune response. Luminal contents are continuously sampled by the mucosa via 2 pathways: the enterocyte pathway and the microfold (M-cell) pathway (eFig. 381.8), both of which interact with the innate and adaptive immune systems to modulate the response to foreign antigens. The systems of defense can be categorized into functional classes: (1) the physical-chemical barrier, (2) the innate immune system, (3) the adaptive immune system, and (4) the commensal microbial ecosystem.

The Physical-Chemical Barrier

The acid milieu of the stomach, proteolysis of antigens by pancreatic secretions, and peristalsis either inactivate or evacuate antigens and microbes.19 In addition, mucus on the epithelial surface inhibits the adhesion of bacteria and the attachment of antigens. The intestinal epithelium forms a physical barrier between the body’s internal and external milieus. The cell’s apical plasma membrane forms most of this interface, and it is impermeable to hydrophilic solutes unless they are actively taken up or transported. The spaces between the cells are sealed by intercellular junctions, the most important of which are the tight junctions. Contrary to earlier assumptions, tight-junction structure is dynamic and can be altered by physiologic stimuli such as hypoxia or exposure to toxins elaborated by pathogenic bacteria.

The Innate Immune System

The innate immune system comprises the cells and mechanisms that defend the host from infection in a nonspecific manner. Two families of molecules are employed by epithelial cells to discriminate pathogenic from nonpathogenic bacteria. These are the pattern-recognition receptors toll-like receptors (TLRs) and the nucleotide-binding oligomerization domain (NOD) family. TLRs recognize molecular patterns typical of pathogenic bacteria, eliciting proinflammatory cytokine production from macrophages, such as tumor necrosis factor. The NOD proteins recognize intracellular bacterial components, which can lead to activation of the transcription factor NF-κB, also leading to the elaboration of proinflammatory mediators.

The microbial environment of the intestine is also modulated by antimicrobial peptides, known as defensins, secreted from the mucosa.20,21 These peptides are encoded in the genome and expressed in Paneth cells, a secretory epithelial subtype found at the base of the crypts of Lieberkühn throughout the small intestine. Defensins induce cell death in bacteria by disrupting their cell wall. They also function as chemoattractants for dendritic cells (see next section), thereby bridging the innate and adaptive immune systems. The exact role of defensins in mucosal immunity is still under investigation.

The Adaptive Immune System

The adaptive immune system consists of cells that recognize and remember specific pathogens and mount a response each time the pathogen is encountered. Lymphoid tissues are distributed diffusely through the lamina propria and also organized into epithelial-associated follicles located in Peyer patches.22 Overlying these follicles are specialized epithelia known as M (microfold) cells, which function in the uptake and sampling of luminal antigens. Antigens are taken up by M cells and transported intact to the mucosa-associated lymphoid tissue. Antigens are then taken up and processed by dendritic cells or macrophages, which then present epitopes to T cells. Stimulated T and B cells migrate into the lymph and then pass into the peripheral circulation, where they “home” to the lamina propria of the gut and other exocrine tissues. The selected B-cell clones mature into plasma cells and secrete IgA or IgM into the gastrointestinal tract lumen.

Oral tolerance is an immunologic state of unresponsiveness induced by the prior feeding of an antigen and is a unique aspect of the immune system of the gastrointestinal tract. Feeding of a soluble protein antigen can suppress the systemic IgM, IgG, and IgE antibodies and cell-mediated immune responses to future exposures to the antigen. This mechanism prevents hypersensitivity reactions to most soluble antigens that are contained in foods while maintaining active immunity to other antigens and invasive organisms. Failure to develop oral tolerance may be responsible for certain food allergies. The selections of antigens for tolerance and the complex mechanisms involved in the development of oral tolerance have not been completely defined. However, this mechanism prevents hypersensitivity reactions to most soluble antigens that are contained in foods while maintaining active immunity to other antigens and invasive organisms. Failure to develop oral tolerance may be responsible for certain food allergies.

In the newborn, there are no reactive B-cell follicles in the mucosa-associated lymphoid tissue, virtually no IgA-secreting cells in the lamina propria, and very few T cells in the gut epithelium. However, IgA contained in breast milk provides passive immunity. Within several weeks after birth, germinal centers appear, and by 3 months of age, IgA-secreting cells predominate in the lamina propria. The number of IgA-secreting cells and T cells increases with time, reaching adult numbers by 2 years of age. Despite these low cell numbers, it seems that the human mucosal immune system has all of the components to generate an immune response at birth.

About 1014 bacteria consisting of 500 to 1000 different species colonize the gastrointestinal tract. Most of the bacteria are located in the colon and distal small intestine. Studies on germ-free animals have shown that bacterial colonization is essential for normal intestinal development and continued health. Germ-free animals are highly susceptible to infections and grow poorly. They also require supplementation with vitamin K and some B vitamins, since these metabolites are derived from microbiota.23,24

Prebiotics are nutrients that promote the growth of specific bacteria in the colonic lumen and may thereby provide some health benefits. Probiotics are microorganisms with beneficial effects on the host; their increased usage as an adjunct for treating inflammatory bowel disease testifies to the importance of the gut microbiota in modulating the gut immune system. The organisms typically administered are Lactobacillus species, which have been shown to induce anti-inflammatory cytokines (TGF-β and interleukin-10). Probiotic bacteria may also protect the intestine by competingwith pathogens for attachment, by strengthening tight junctionsbetween enterocytes, or by enhancing the mucosal immune response to pathogens.