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Digestion and Absorption
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The intestinal epithelium is the interface through which absorption and secretion occur. It has features characteristic of absorptive epithelia in general including epithelial cells with cellular membranes possessing distinct apical (luminal) and basolateral (serosal) domains demarcated by intercellular tight junctions and an asymmetric distribution of transmembrane transporter mechanisms that promotes vectorial transport of solutes across the epithelium.
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Solutes can traverse the epithelium by active or passive transport. Passive transport of solutes occurs through diffusion or convection and is driven by existing electrochemical gradients. Active transport is the energy-dependent net transferof solutes in the absence of or against an electrochemical gradient.
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Active transport occurs through transcellular pathways (through the cell), whereas passive transport can occur through either transcellular or paracellular pathways (between cells through the tight junctions). Transcellular transport requires solutes to traverse the cell membranes through specialized membrane proteins, such as channels, carriers, and pumps. The molecular characterization of transporter proteins is evolving rapidly, with different transporter families, each containing many individual genes encoding specific transporters, now identified. Similarly, understanding of the paracellular pathway is evolving. In contrast to what was once believed, it is becoming apparent that paracellular permeability is substrate-specific, dynamic, and subject to regulation by specific tight junction proteins.
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Water and Electrolyte Absorption and Secretion
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Eight to nine L of fluid enters the small intestine daily. Most of this volume consists of salivary, gastric, biliary, pancreatic, and intestinal secretions. Under normal conditions, the small intestine absorbs over 80% of this fluid, leaving approximately 1.5 L that enters the colon (Fig. 28-4). Small-intestinal absorption and secretion are tightly regulated; derangements in water and electrolyte homeostasis characteristic of many of the disorders discussed in this chapter play an important role in contributing to their associated clinical features.
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Gut epithelia have two pathways for water transport: (a) the paracellular route, which involves transport through the spaces between cells, and (b) the transcellular route, through apical and basolateral cell membranes. Although most water absorption was thought to occur through the paracellular pathway, it is now well documented that most intestinal water transport occurs through the transcellular pathway.4 The specific transport mechanisms mediating this transcellular transport are not completely characterized and may involve passive diffusion through the phospholipid bilayer, cotransport with other ions and nutrients, or diffusion through water channels called aquaporins. Many different types of aquaporins have been identified; however, their contribution to overall intestinal water absorption appears to be relatively minor.5
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The prevailing model for intestinal epithelial Na+ absorption is shown in Fig. 28-5. Activity of the Na+/K+ ATPase enzyme, which is located in the basolateral membrane and exchanges three intracellular Na+ for every two extracellular K+ in an energy-dependent process, generates the electrochemical gradient that drives the transport of Na+ from the intestinal lumen into the cytoplasm of enterocytes. Na+ ions traverse the apical membrane through several distinct transporter mechanisms including nutrient-coupled sodium transport (e.g., sodium glucose cotransporter-1 [SGLT1]), sodium channels, and sodium-hydrogen exchangers (NHEs). Absorbed Na+ ions are then extruded from enterocytes through the Na+/K+ ATPase located in the basolateral membrane. Similar mechanistic models that account for the transport of other common ions such as K+ and HCO3– also exist.
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Substantial heterogeneity, with respect to both crypt-villus and craniocaudal axes, exists for intestinal epithelial transport mechanisms. This spatial distribution pattern is consistent with a model in which absorptive function resides primarily in the villus and secretory function in the crypt.
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Intestinal absorption and secretion are subject to modulation under physiologic and pathophysiologic conditions by a wide array of hormonal, neural, and immune regulatory mediators (Table 28-1).
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Carbohydrate Digestion and Absorption
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Approximately 45% of energy consumption in the average Western diet consists of carbohydrates, approximately one half of which is in the form of starch (linear or branched polymers of glucose) derived from cereals and plants. Other major sources of dietary carbohydrates include sugars derived from milk (lactose), fruits and vegetables (fructose, glucose, and sucrose), or purified from sugar cane or beets (sucrose). Processed foods contain a variety of sugars including fructose, oligosaccharides, and polysaccharides. Glycogen derived from meat contributes only a small fraction of dietary carbohydrate.
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Pancreatic amylase is the major enzyme of starch digestion, although salivary amylase initiates the process. The terminal products of amylase-mediated starch digestion are oligosaccharides, maltotriose, maltose, and α-limit dextrins (Fig. 28-6). These products, as well as the major disaccharides in the diet (sucrose and lactose), are unable to undergo absorption in this form. They must first undergo hydrolytic cleavage into their constituent monosaccharides; these hydrolytic reactions are catalyzed by specific brush border membrane hydrolases that are expressed most abundantly in the villi of the duodenum and jejunum. The three major monosaccharides that represent the terminal products of carbohydrate digestion are glucose, galactose, and fructose.
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Under physiologic conditions, most of these sugars are absorbed through the epithelium via the transcellular route. Glucose and galactose are transported through the enterocyte brush border membrane via intestinal Na+-glucose cotransporter, SGLT1 (Fig. 28-7). Fructose is transported through the brush border membrane by facilitated diffusion via GLUT5 (a member of the facilitative glucose transporter family). All three monosaccharides are extruded through the basolateral membrane by facilitated diffusion using GLUT2 and GLUT5 transporters. Extruded monosaccharides diffuse into venules and ultimately enter the portal venous system.
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There is evidence of overexpression of hexose transporters, specifically SGLT1, in disease states such as diabetes.6 Several approaches aimed at downregulation of intestinal glucose transporter are being investigated as a novel therapy for disease states such as diabetes and obesity.7
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Protein Digestion and Absorption
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Ten to fifteen percent of energy consumption in the average Western diet consists of proteins. In addition to dietary proteins, approximately one half of the protein load that enters the small intestine is derived from endogenous sources including salivary and gastrointestinal secretions and desquamated intestinal epithelial cells. Protein digestion begins in the stomach with action of pepsins. This is not, however, an essential step, since surgical patients who are acholorhydric or who have lost part or all their stomach are still able to successfully digest proteins. Digestion continues in the duodenum with the actions of a variety of pancreatic peptidases. These enzymes are secreted as inactive proenzymes. This is in contrast to pancreatic amylase and lipase, which are secreted in their active forms. In response to the presence of bile acids, enterokinase is liberated from the intestinal brush border membrane to catalyze the conversion of trypsinogen to active trypsin; trypsin in turn activates itself and other proteases. The final products of intraluminal protein digestion consist of neutral and basic amino acids and peptides two to six amino acids in length (Fig. 28-8). Additional digestion occurs through the actions of peptidases that exist in the enterocyte brush border and cytoplasm. Epithelial absorption occurs for both single amino acids and di- or tripeptides via specific membrane-bound transporters. Absorbed amino acids and peptides then enter the portal venous circulation.
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Of all amino acids, glutamine appears to be a unique, major source of energy for enterocytes. Active glutamine uptake into enterocytes occurs through both apical and basolateral transport mechanisms.
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Fat Digestion and Absorption
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Approximately 40% of the average Western diet consists of fat. Over 95% of dietary fat is in the form of long-chain triglycerides; the remainder includes phospholipids such as lecithin, fatty acids, cholesterol, and fat-soluble vitamins. Over 94% of the ingested fats are absorbed in the proximal jejunum.
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Since fats are normally water insoluble, key to successful digestion of ingested fats is solubalization of them into an emulsion by the mechanical actions of mastication and antral peristalsis. Although lipolysis of triglycerides to form fatty acids and monoglyciderides is initiated in the stomach by gastric lipase, its principal site is the proximal intestine, where pancreatic lipase is the catalyst (Fig. 28-9).
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Bile acids act as detergents that help in solubalization of the lipolysis by forming mixed micelles. These micelles are polymolecular aggregates with a hydrophobic core of fat and a hydrophilic surface that act as shuttles, delivering the products of lipolysis to the enterocyte brush border membrane, where they are absorbed. The bile salts, however, remain in the bowel lumen and travel to the terminal ileum, where they are actively resorbed. They enter the portal circulation and are resecreted into bile, thus completing the enterohepatic circulation.
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Dissociation of lipids from the micelles occurs in a thin layer of water (50–500 μm thick) with an acidic microenvironment immediately adjacent to the brush border called the unstirred water layer. Most lipids are absorbed in the proximal jejunum, whereas bile salts are absorbed in the distal ileum through an active process. Fatty acid binding proteins (FABPs) are a family of proteins located on the brush border membrane, facilitating diffusion of long-chain fatty acids across the brush border membrane. Cholesterol crosses the brush border membrane through an active process that is yet to be completely characterized. Within the enterocytes, triglycerides are resynthesized and incorporated into chylomicrons that are secreted into the intestinal lymphatics and ultimately enter the thoracic duct. In these chylomicrons, lipoproteins serve a detergent-like role similar to that served by bile salts in the mixed micelles.
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The steps described above are required for the digestion and absorption of triglycerides containing long-chain fatty acids. However, triglycerides containing short- and medium-chain fatty acids are more hydrophilic and are absorbed without undergoing intraluminal hydrolysis, micellular solubilization, mucosal re-esterification, and chylomicron formation. Instead, they are directly absorbed and enter the portal venous circulation rather than the lymphatics. This information provides the rationale for administering nutritional supplements containing medium-chain triglycerides to patients with gastrointestinal diseases associated with impaired digestion and/or malabsorption of long-chain triglycerides.
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Vitamin and Mineral Absorption
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Vitamin B12 (cobalamin) malabsorption can result from a variety of surgical manipulations. The vitamin is initially bound by saliva-derived R protein. In the duodenum, R protein is hydrolyzed by pancreatic enzymes, allowing free cobalamin to bind to gastric parietal cell–derived intrinsic factor. The cobalamin-intrinsic factor complex is able to escape hydrolysis by pancreatic enzymes, allowing it to reach the terminal ileum, which expresses specific receptors for intrinsic factor. Subsequent events in cobalamin absorption are poorly characterized, but the intact complex probably enters enterocytes through translocation. Because each of these steps is necessary for cobalamin assimilation, gastric resection, gastric bypass, and ileal resection can each result in vitamin B12 insufficiency.
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Other water-soluble vitamins for which specific carrier-mediated transport processes have been characterized include ascorbic acid, folate, thiamine, riboflavin, pantothenic acid, and biotin. Fat-soluble vitamins A, D, and E appear to be absorbed through passive diffusion. Vitamin K appears to be absorbed through both passive diffusion and carrier-mediated uptake.
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Calcium is absorbed through both transcellular transport and paracellular diffusion. The duodenum is the major site for transcellular transport; paracellular transport occurs throughout the small intestine. A key step in transcellular calcium transport is mediated by calbindin, a calcium-binding protein located in the cytoplasm of enterocytes. Regulation of calbindin synthesis is the principle mechanism by which vitamin D regulates intestinal calcium absorption. Abnormal calcium levels are increasingly seen in surgical patients who have undergone a gastric bypass. Although usual calcium supplementation is often in the form of calcium carbonate, which is cheap, in such patients with low acid exposure, calcium citrate is a better formulation for supplemental therapy.
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Iron and magnesium are each absorbed through both transcellular and paracellular routes. A divalent metal transporter capable of transporting Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+, and Pb2+ that has recently been localized to the intestinal brush border may account for at least a portion of the transcellular absorption of these ions.8
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Barrier and Immune Function
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Although the intestinal epithelium allows for the efficient absorption of dietary nutrients, it must discriminate between pathogens and harmless antigens such as food proteins and commensal bacteria, and it must resist invasion by pathogens. Factors contributing to epithelial defense include immunoglobulin A (IgA), mucins, and the relative impermeability of the brush border membrane and tight junctions to macromolecules and bacteria. Recently described factors likely to play important roles in intestinal mucosal defense include antimicrobial peptides such as the defensins.9 The intestinal component of the immune system, known as the gut-associated lymphoid tissue (GALT), contains over 70% of the body’s immune cells.
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The GALT is conceptually divided into inductive and effector sites.10 Inductive sites include Peyer’s patches, mesenteric lymph nodes, and smaller isolated lymphoid follicles scattered throughout the small intestine (Fig. 28-10). Peyer’s patches are macroscopic aggregates of B-cell follicles and intervening T-cell areas found in the lamina propria of the small intestine, primarily the distal ileum. Overlying Peyer’s patches are a specialized epithelium containing microfold (M) cells. These cells possess an apical membrane with microfolds rather than microvilli, which is characteristic of most intestinal epithelial cells. Using transepithelial vesicular transport, M cells transfer microbes to underlying professional antigen-presenting cells (APCs), such as dendritic cells. Dendritic cells, in addition, may sample luminal antigens directly through their dendrite-like processes that extend through epithelial tight junctions. APCs interact with and prime naïve lymphocytes, which then exit through the draining lymphatics to enter the mesenteric lymph nodes where they undergo differentiation. These lymphocytes then migrate into the systemic circulation via the thoracic duct and ultimately accumulate in the intestinal mucosa at effector sites. Alternative induction mechanisms, such as antigen presentation within mesenteric lymph nodes, are also likely to exist.
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Effector lymphocytes are distributed into distinct compartments. IgA-producing plasma cells are derived from B cells and are located in the lamina propria. CD4+ T cells are also located in the lamina propria. CD8+ T cells migrate preferentially to the epithelium, but are also found in the lamina propria. These T cells are central to immune regulation; in addition, the CD8+ T cells have potent cytotoxic (CTL) activity. IgA is transported through the intestinal epithelial cells into the lumen, where it exists in the form of a dimer complexed with a secretory component. This configuration renders IgA resistant to proteolysis by digestive enzymes. IgA is believed to both help prevent the entry of microbes through the epithelium and to promote excretion of antigens or microbes that have already penetrated into the lamina propria.
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It has been increasingly recognized that the gastrointestinal tract is colonized with many bacteria that are essential for health. Communication between the microbiota and the host defense allows for protective immune responses against pathogens while preventing adverse inflammatory responses to harmless commensal microbes, which could lead to chronic inflammatory disorders such as celiac disease and Crohn’s disease.11
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Myocytes of the intestinal muscle layers are electrically and mechanically coordinated in the form of syncytia. Contractions of the muscularis propria are responsible for small-intestinal peristalsis. Contraction of the outer longitudinal muscle layer results in bowel shortening; contraction of the inner circular layer results in luminal narrowing. Contractions of the muscularis mucosa contribute to mucosal or villus motility, but not to peristalsis.
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Several distinctive patterns of muscularis propria activity have been observed to occur in the small intestine. These patterns include ascending excitation and descending inhibition in which muscular contraction occurs proximal to a stimulus, such as the presence of a bolus of ingested food, and muscular relaxation occurs distal to the stimulus (Fig. 28-11). These two reflexes are present even in the absence of any extrinsic innervation to the small intestine and contribute to peristalsis when they are propagated in a coordinated fashion along the length of the intestine. The fed or postprandial pattern begins within 10 to 20 minutes of meal ingestion and abates 4 to 6 hours afterward. Rhythmic segmentations or pressure waves traveling only short distances also are observed. This segmenting pattern is hypothesized to assist in mixing intraluminal contents and in facilitating their contact with the absorptive mucosal surface. The fasting pattern or interdigestive motor cycle (IDMC) consists of three phases. Phase I is characterized by motor quiescence, phase II by seemingly disorganized pressure waves occurring at submaximal rates, and phase III by sustained pressure waves occurring at maximal rates. This pattern is hypothesized to expel residual debris and bacteria from the small intestine. The median duration of the IDMC ranges from 90 to 120 minutes. At any given time, different portions of the small intestine can be in different phases of the IDMC.
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The regulatory mechanisms driving small-intestinal motility consist of both pacemakers intrinsic to the small intestine and external neurohumoral modulatory signals. The interstitial cells of Cajal are pleomorphic mesenchymal cells located within the muscularis propria of the intestine that generate the electrical slow wave (basic electrical rhythm or pacesetter potential) that plays a pacemaker role in setting the fundamental rhythmicity of small-intestinal contractions. The frequency of the slow wave varies along the longitudinal axis of the intestine: it ranges from 12 waves per minute in the duodenum to 7 waves per minute in the distal ileum. Smooth muscle contraction occurs only when an electrical action potential (spike burst) is superimposed on the slow wave. Thus, the slow wave determines the maximum frequency of contractions; however, not every slow wave is associated with a contraction.
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This intrinsic contractile mechanism is subject to neural and hormonal regulation. The enteric nervous system (ENS) provides both inhibitory and excitatory stimuli. The predominant excitatory transmitters are acetylcholine and substance P, and the inhibitory transmitters include nitric oxide, vasoactive intestinal peptide, and adenosine triphosphate. In general, the sympathetic motor supply is inhibitory to the ENS; therefore, increased sympathetic input into the intestine leads to decreased intestinal smooth muscle activity. The parasympathetic motor supply is more complex, with projections to both inhibitory and excitatory ENS motor neurons. Correspondingly, the effects of parasympathetic inputs into intestinal motility are more difficult to predict.
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Endocrinology as a discipline was born with the discovery of secretin, an intestinal regulatory peptide that was the first hormone to be identified. Our improving understanding of the physiology of the small intestine has lead to identification of many additional intestinal-derived hormones that make this the largest hormone-producing organ in the body. Over 30 peptide hormone genes have been identified as being expressed in the gastrointestinal tract. Because of differential posttranscriptional and posttranslational processing, over 100 distinct regulatory peptides are produced. In addition, monoamines, such as histamine and dopamine, and eicosanoids with hormone-like activities are produced in the intestine.
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“Gut hormones” were previously conceptualized as peptides produced by the enteroendocrine cells of the intestinal mucosa that are released into the systemic circulation to reach receptors in target sites in the gastrointestinal tract. Now it is clear that “gut hormone” genes are widely expressed throughout the body, not only in endocrine cells, but also in central and peripheral neurons. The products of these genes are general intercellular messengers that can act as endocrine, paracrine, autocrine, or neurocrine mediators. Thus, they may act as true blood-borne hormones as well as through local effects.
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There are notable homology patterns among individual regulatory peptides found in the gastrointestinal tract. Based on these homologies, approximately one half of the known regulatory peptides can be classified into families.12 For example, the secretin family includes secretin, glucagon, and glucagon-like peptides, glucose-dependent insulinotropic peptide, vasoactive intestinal polypeptide, peptide histidine isoleucine, growth hormone–releasing hormone, and pituitary adenylyl cyclase–activating peptide. Other peptide families include those named for insulin, epidermal growth factor, gastrin, pancreatic polypeptide, tachykinin, and somatostatin.
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Receptor subtype multiplicity and cell-specific expression patterns for these receptor subtypes that are characteristic of these regulatory mediators make definition of their actions complex. Detailed description of these actions is beyond the scope of this chapter; however, examples of regulatory peptides produced by enteroendocrine cells of the small-intestinal epithelium and their most commonly ascribed functions are summarized in Table 28-2. Some of these peptides, or their analogues, are used in routine clinical practice. For example, therapeutic applications of octreotide, a long-acting analogue of somatostatin, include the amelioration of symptoms associated with neuroendocrine tumors (e.g., carcinoid syndrome), postgastrectomy dumping syndrome, enterocutaneous fistulas, and the initial treatment of acute hemorrhage due to esophageal varices. The gastrin secretory response to secretin administration forms the basis for the standard test used to establish the diagnosis of Zollinger-Ellison syndrome. Cholecystokinin is used in evaluations of gallbladder ejection fraction, a parameter that may have utility in patients who have symptoms of biliary colic but are not found to have gallstones. Of the peptides listed in Table 28-2, glucagon-like peptide-2 (GLP-2) has been identified as a specific and potent intestinotrophic hormone and is currently under clinical evaluation as an intestinotrophic agent in patients suffering from the short bowel syndrome, as discussed in the later Short Bowel Syndrome section.
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Intestinal Adaptation
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The small intestine has the capacity to adapt in response to varying demands imposed by physiologic and pathologic conditions. Of particular relevance to many of the diseases discussed in this chapter is the adaptation that occurs in the remnant intestine following surgical resection of a large portion of the small intestine (massive small bowel resection). Postresection intestinal adaptation has been studied extensively using animal models. Within a few hours after bowel resection, the remnant small intestine displays evidence of epithelial cellular hyperplasia. With additional time, villi lengthen, intestinal absorptive surface area increases, and digestive and absorptive functions improve. Postresection intestinal adaptation in human patients is less well studied, but seems to follow similar steps as those seen in experimental models, and takes 1 to 2 years to complete.13
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The mechanisms responsible for inducing postresection intestinal adaptation are under active investigation. Several classes of effectors that stimulate intestinal growth include specific nutrients, peptide hormones and growth factors, pancreatic secretions, and some cytokines. Nutritional components with intestinal growth-stimulating effects include fiber, fatty acids, triglycerides, glutamine, polyamines, and lectins.
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Postresection adaptation serves to compensate for the function of intestine that has been resected. Jejunal resection is generally better tolerated, as ileum shows better capacity to compensate. However, the magnitude of this response is limited. If enough small intestine is resected, a devastating condition known as the short bowel syndrome results. This condition is discussed in the Short Bowel Syndrome section at the end of this chapter.