Duodenum

The first part of the SI, the duodenum, comprises approximately 10% of its total length. It passes from the pylorus dorsally and to the right, at the level of the ninth intercostal space, and is immobilized by the hepatoduodenal ligament. It then turns caudally into the descending duodenum in contact with the right flank, turning again at the caudal flexure near the pelvic brim. It is in close association with the common bile duct and the head and right limb of the pancreas, which lie in its mesentery.

The common bile duct and one pancreatic duct enter the duodenum via the major papilla. In dogs an accessory pancreatic duct often enters at a minor papilla more distally and slightly more ventrally (Figure 57-2, A), but there is a range of variations in the actual number of ducts and their drainage pattern from the pancreas (see Chapter 60). The papillae are notable endoscopic landmarks in dogs, but may not be obvious in cats.

Figure 57-2 Videoendoscopic appearance of the normal upper small intestine.

A, The major duodenal papilla (M) in the duodenum of the dog is the site of entry of the common bile duct and major pancreatic duct. The minor duodenal papilla (m) is seen in some but not all dogs distal to the major papilla and approximately 100 degrees clockwise from it. B, Normal descending duodenum in a dog; the distal flexure is visible in the distance. C, Peyer patches (lymphoid aggregates) in the duodenum appear as pale oval depressions along the antimesenteric border of the descending duodenum.

(Reprinted with permission from Lhermette P, Sobel D: BSAVA Manual of Canine and Feline Endoscopy and Endosurgery. Gloucester, UK, 2008, BSAVA Publications.)

The distal duodenal flexure, where the duodenum courses to the left side of the abdomen (see Figure 57-2, B) is often at the limit of the reach of a standard 1-meter gastroscope, except in cats and small dogs. In dogs the antimesenteric side of the duodenum is marked by a line of whitish, mucosal depressions signifying the presence of specialized lymphoid areas, the Peyer patches (see Figure 57-2, C). Secretory Brunner glands and annular mucosal folds are features of the human proximal duodenum, but are not present in dogs and cats. After the distal duodenal flexure, the ascending limb of the duodenum crosses the midline and ends at the level of L6 close to the root of the mesentery near the left kidney, with a mesenteric attachment to the colon, the duodenocolic ligament.

Jejunum

The middle part of the SI, the jejunum, arises as an indistinct structural and functional transition from the duodenum and forms the majority of the SI. The jejunum is loosely suspended in the middle of the peritoneal cavity in a dorsal mesentery, forming mobile loops, and is potentially palpable throughout its length in cooperative and nonobese patients. The mesentery is normally a continuous sheet that is folded to allow the SI to loop within the peritoneal cavity, unlike in humans where segments of the duodenum (and colon) are retroperitoneal. The mesentery carries the vascular, lymphatic, and nervous connections between the SI and the rest of the body.

Defects in the mesentery, most often traumatic in origin, can allow internal hernia formation and small intestinal incarceration. An outpouching of the dorsal mesentery of the stomach forms the greater omentum. This structure functions as a protective, immunologic organ, having the ability to migrate to sites of intraperitoneal inflammation and potentially prevent leakage from an intestinal perforation and seal off pockets of infection.

Ileum

Approximately the last 30 cm of the SI comprises the ileum. The transition from jejunum to ileum in humans is based on changes in diameter, color, and the presence of Peyer patches; in dogs and cats the distinction has been arbitrarily based on the extent of attachment of the ileocolic ligament. In fact the basic structure of the ileum is no different from the rest of the SI and it is not clearly demarcated microscopically from the jejunum. However, it does have some unique functional characteristics, such as the absorption of bile salts and cobalamin. It is also a site of dense lymphoid follicle expression. Meckel diverticulum, a remnant of the embryonic omphalomesenteric duct, found in the ileum of approximately 2% of people and a potential source of bleeding, obstruction, intussusception, and volvulus, is not reported in dogs and cats. The ileum ends at the ileocolic valve in close association with the cecocolic junction.

Blood Supply, Lymphatic Drainage, and Innervation

The blood supply to the proximal duodenum is from the celiac artery. Its cranio-pancreatico-duodenal branch anastomoses with the caudo-pancreatico-duodenal branch of the cranial mesenteric artery. The latter is the major blood supply to the remainder of the SI and proximal colon, anastomosing distally with the caudal mesenteric artery. It forms an arcade along the mesenteric border of the jejunum and ileum, with a short antimesenteric ileal branch. Its branching nature is an important consideration when assessing the viability of lengths of SI during surgical resection and end-to-end anastomosis.

The venous drainage of the whole SI is ultimately to the liver via the hepatic portal vein. Multiple embryonic vessels linking portal venous drainage and the systemic venous system (i.e., via ovarian veins, caudal vena cava, and esophageal veins) exist but only become functional shunting vessels if there is chronic portal hypertension as a consequence of liver disease.

Lacteals in the villi drain via intestinal lymphatics in the mesentery to the mesenteric lymph nodes and then the cisterna chyli and on to the thoracic duct. Vagal and sympathetic innervation coordinate with the intrinsic enteric nervous system and enteric hormones to regulate SI motility and function.

Microflora

The microflora of the SI is an integral part of its structure and function. There is a gradual increase in bacterial numbers and a shift from aerobic to anaerobic organisms progressing distally down the SI. Chapter 2 provides a more detailed description of the composition of the microflora and its interaction with the mucosa.

Mucosa

The SI mucosa performs the intestinal barrier and absorptive functions, and is comprised of an intestinal epithelium covering the lamina propria that hosts the local mucosal immune system, and is surrounded by the submucosa and the outer muscle layers.

One of the most important structural modifications of the mucosa is a vast increase in its surface area relative to the size of the animal, with an almost 600-fold increase compared with the basic tubular structure of the intestine. The surface area of the human intestine has been estimated at 175 m², and although the adult human intestine is longer than in even the largest dog, the villi in cats and dogs are almost twice as long (approximately 1 mm) compared with those of humans. The increase in surface area is created by folds in the mucosal wall (tripling the surface area), villus projections into the intestinal lumen (providing an approximate 10-fold increase), and microvilli on the surface of each epithelial cell (providing a further 20-fold increase in area) (see Figure 57-1, C). Diseases causing villus atrophy or even just microvillus damage are likely to produce profound malabsorption and diarrhea.

Gut-Associated Lymphoid Tissue

The GI tract is the largest immunologic organ in the body, and the SI comprises a large component of the mucosal immune system. Within the SI, the Peyer patches (see Figure 57-2, C) act as inductive sites and are covered with a specialized epithelium containing microfold (M) cells, which sample luminal antigens. Activated lymphocytes migrate via mesenteric lymph nodes to the circulation, from where they home to their effector sites, the lamina propria and epithelium. Chapter 3 details the structure and role of the gut-associated lymphoid tissue.

Carbohydrate

Starch and glycogen are the major carbohydrates in the diet and must be hydrolyzed completely to glucose for absorption (Figure 57-5, A). There is no salivary amylase activity in dogs and cats, and these complex carbohydrates are hydrolyzed by pancreatic α-amylase. Straight-chain starch molecules (amylose) are split to maltose, maltotriose, and some glucose. Branched-chain starch molecules (amylopectin) and glycogen are also hydrolyzed to the same products, except that the branched parts of their molecules remain as α-limit dextrins as their 1,6-glycosidic bond cannot be hydrolyzed by α-amylase. The digestion products of α-amylase are subsequently hydrolyzed, particularly by brush-border maltase (glucoamylase) and isomaltase (α-dextrinase). The brush-border enzyme trehalase hydrolyzes the 1,1 link in the fungal sugar trehalose, but is not expressed in cats.

Figure 57-5 Diagram of the digestion and absorption of (A) carbohydrate, (B) protein, and (C) fat.

BS, bile salts; DG, diglyceride; FA, fatty acids; MG, monoglyceride; PL, phospholipids; TG, triglyceride.

(Adapted from Batt RM: The molecular basis of malabsorption. J Small Anim Pract 21:555, 1980.)

Sucrose is an unusual constituent of canine and feline diets unless semimoist pet foods or human foods are fed. It is hydrolyzed directly at the brush-border to glucose by sucrase, part of the sucrase–isomaltase brush-border enzyme complex. Congenital sucrase–isomaltase deficiency is a rare genetic defect of man, but has not been recorded in small animals. Sucrase activity in cats is lower than dogs (Table 57-1), probably reflecting the average composition of their diets.

Table 57-1 Jejunal Brush-Border Disaccharidase Activities (U/mg Protein) Reported in Dogs and Cats

Lactose is found almost exclusively in dairy products and its hydrolysis to glucose and galactose by brush-border lactase is nutritionally most important in the nursing animal. At weaning, activities of lactase begin to decline, especially in cats, and adult animals may exhibit lactose intolerance if fed excess milk. This mirrors the age-related downregulation of lactase expression seen in certain human races. If animals have underlying SI disease, dairy products should be avoided as marginal lactase activities will be reduced even further. Absolute congenital lactase deficiency, as seen rarely in humans, has not been demonstrated in cats or dogs.

Protein

Digestion of proteins follows a similar overall pattern to carbohydrate digestion (see Figure 57-5, B), and the amounts of pancreatic enzyme secreted and mucosal peptidases expressed are influenced by the protein content of the diet. Digestion is initiated by acidic denaturation and the proteolytic activity of pepsin in the stomach. Luminal digestion under a more neutral pH is continued in the SI by pancreatic proteases (trypsin, chymotrypsin, elastase, and carboxypeptidase), which are initially secreted as inactive proforms, and are subsequently activated by enterokinase and trypsin. Luminal proteolysis results in a mixture of oligo-, tri-, and dipeptides as well as free amino acids. Oligopeptides are subsequently hydrolyzed by brush-border peptidases, which have some selectivity for particular amino acid residues. However, there is considerable overlap in specificity, and a selective deficiency of aminopeptidase N reported in dogs is of no clinical consequence. Furthermore, any tri- and dipeptides can still be absorbed on a brush-border carrier. Theoretically a deficiency of enterokinase could cause protein malabsorption through failure of trypsin activation, but this has never been documented in dogs and cats, and trypsin autoactivation would probably still occur.

Lipid

Fat digestion is completed entirely within the GI lumen by secreted enzymes and bile salts. Partial digestion is begun in the stomach by the action of gastric lipase secreted by gastric epithelial mucus cells. Subsequent mixing of the fat emulsifies it into small droplets. Further mixing with bile and pancreatic juice results in the formation of mixed micelles, which are approximately the size of the smallest fat droplet and solubilize approximately 1000 times more fatty acids. At the surface of mixed micelles, triglyceride is hydrolyzed by pancreatic lipase to di- and monoglycerides and free fatty acids (Figure 57-6). Maximal lipase activity in the gut lumen is dependent on a protein cofactor, colipase, which is secreted by the pancreas as inactive procolipase. There is some reserve capacity for fat digestion if pancreatic function is normal, and a fat-rich diet, especially one rich in unsaturated fatty acids, also stimulates increased pancreatic lipase secretion. However, neuroendocrine mechanisms initiated by the presence of fat in the duodenum and ileum, control the rate of gastric emptying and hence the rate of fat delivery. Thus a fat-rich diet or intestinal fat malabsorption delays gastric emptying.

Figure 57-6 Mechanisms of diffusion.

Pancreatic phospholipase A₂ is secreted in an inactive form, and once activated in the intestinal lumen hydrolyzes phospholipid to lysophospholipids. Finally, pancreatic cholesterol esterase deesterifies cholesterol. After fat absorption, the bile salts may form further mixed micelles, but ultimately are reabsorbed by a specific sodium-linked cotransporter in the ileum and recycled from the portal blood back into bile.

Nucleotides

Little is known of the digestion of dietary nucleotides and hydrolysis of nucleic acids released from exfoliated enterocytes. Ribonuclease and deoxyribonuclease are present in pancreatic secretions, and there is a common sodium-dependent brush-border carrier for the uptake of purines and pyrimidines.

Digested Nutrients

Simple sugars, amino acids and oligopeptides, and fatty acids and other lipids are delivered to the body across the mucosal barrier and then via the lymphatics or bloodstream.^23,24 Uptake occurs by passive diffusion or by active or facilitated carrier-mediated transport mechanisms (see Figure 57-6). Endocytosis of small, antigenic peptides is of no nutritional significance, but is involved in the neonatal absorption of colostral antibodies, and is crucial to the mucosal immune response.

The products of fat digestion are absorbed by passive diffusion from mixed micelles across the MVM and ultimately lipoproteins are passed into lacteals. The limiting factors, assuming normal pancreatic function, are the intestinal surface area and lymphatic functionality, and so villus atrophy and lymphangiectasia are likely to cause malabsorption of fat.

Passive Diffusion

Lipid-soluble products of digestion do not need a specific carrier mechanism to be absorbed across the mucosal barrier, and can bypass passive diffusion by “dissolving” in the brush-border membrane. This absorptive process obeys the Graham Law of Diffusion, being proportional to the concentration gradient across the membrane, nonsaturable, and limited only by the surface area of the membrane. Diffusion back across the brush-border is prevented by reesterification of free fatty acids within the enterocyte.

Carrier-Mediated Transport

Some small, nonpolar, water-soluble molecules (and perhaps water molecules) also appear to be absorbed by passive diffusion through “pores” in the mucosal membrane. The structure of these hypothetical pores is likened to that of ion channels in other membranes (i.e., small fixed channels through the membrane that function without a conformational change). Molecules with a molecular radius greater than 0.4 nm appear to be excluded, but larger, although numerically fewer pores may traverse tight junctions. Debate remains as to whether the predominant route is via an intracellular or paracellular route through tight junctions.

Water-soluble nutrient molecules that are too large to diffuse via the “pore route” and are insoluble in the lipid MVM must cross the brush-border on specific carrier proteins that bridge the membrane. Conformational changes in the carriers are thought to shuttle the substrate molecule across. The products of carbohydrate and protein digestion enter by this process. Transport proteins are usually highly specific and may only carry the L or D isomer of a molecule, but competitive inhibition with related solutes may occur. The number of carrier molecules in the mucosa is finite, so that the process is saturable, and although the expression of the carriers may be inducible, dietary overload is likely to cause transient intolerance and diarrhea.

Active transport of substrates across the MVM into the enterocyte is usually against a concentration gradient and energy must be expended to drive the process (see Figure 57-6). Usually the uptake of the nutrient is linked to the entry of sodium down its electrochemical gradient, with energy expenditure by a N⁺-K⁺-ATPase on the basolateral membrane of the enterocyte pumping sodium back out of the cell.

Facilitated transport is the carriage of substrates by a transport protein across the MVM, down a concentration gradient without energy expenditure (see Figure 57-6). Some sugars, oligopeptides, and folate are absorbed by this process. The number of carriers is finite, and the process saturable and subject to competitive inhibition.

Endocytosis

Small antigenic peptides may be engulfed nonspecifically within endocytotic vesicles of epithelial cells. The amounts absorbed by this route are negligible from a nutritional standpoint, but this sampling of luminal contents is crucial to the mucosal immune response (see Chapter 3). Receptor-mediated endocytosis enables the uptake of small amounts of a specific intact nutrient and is the mechanism of cobalamin absorption.

Carbohydrate

The main product of carbohydrate digestion, glucose, is absorbed by active transport on a stereo-specific carrier that recognizes a D-pyranose structure with a C-2 hydroxyl group. Glucose is cotransported with sodium; the energy required for the coupling is provided through the entry of sodium down a concentration gradient but with the basolateral N⁺-K⁺-ATPase reexporting sodium against the concentration gradient. The carrier molecule in the brush-border has been identified in many species, including dogs and cats, as the sodium-glucose cotransporter protein (SGLT1; Figure 57-7). This molecule has the highest affinity for glucose, but it is also the carrier for galactose. Indirect evidence for this is shown by the inability to absorb either sugar in people with glucose–galactose malabsorption in whom a single amino acid mutation (Asp₂₈ → Asn₂₈) in the SGLT1 protein has been identified. Glucose and galactose thus may exhibit competitive inhibition, but glucose is the major substrate. There is circumstantial evidence for another aldohexose carrier in cats.

Figure 57-7 Diagram of the absorption of monosaccharides by enterocytes. GLUT, Glucose transporter; SGLT, sodium-glucose co-transporter protein.

Facilitated transport of glucose across mammalian cell membranes is performed by a family of facilitated glucose transporters (GLUTs) with different isoforms found in different tissues. One member of this family, GLUT2, is found on the basolateral membrane of enterocytes, where it shuttles glucose, galactose, and fructose out of the enterocyte by facilitated diffusion (see Figure 57-7). GLUT2 is absent from the brush-border, and so a mechanism exists for active transport of glucose across the MVM into the enterocyte by SGLT1 and facilitated transport into the body by GLUT2. Most of the glucose is not used within the enterocyte, because of expression of a phosphofructokinase isomer that directs metabolism away from glycolysis.

Another member of the facilitated glucose transporter family, GLUT5, is found on the brush-border. It shares homology with other family members but actually allows facilitated diffusion of fructose; it is not even competitively inhibited by glucose. In humans, GLUT5 is also probably the site of D-xylose absorption, as both fructose and xylose absorption are unaffected in glucose–galactose malabsorption. However, the mechanism of D-xylose uptake is species dependent, and evidence for facilitated diffusion in dogs and cats has largely been extrapolated from humans. Nevertheless, fructose uptake in cats is low, and D-xylose absorption is equally low. This may be one reason why the xylose absorption test is unhelpful in cats. However, potential fructose malabsorption has little clinical relevance in cats as the feline diet likely contains little fructose.

Although dietary carbohydrates must be hydrolyzed to monosaccharides to be absorbed and be nutritionally useful, a small but measurable amount of disaccharide can cross the brush-border, probably through leaky tight junctions. This is of no nutritional significance, but increased uptake and subsequent urinary excretion of disaccharides can be a marker of increased intestinal permeability when damaged.

Protein

The products of protein digestion are absorbed on carriers that are stereo-specific for L-amino acids (Figure 57-8; also see Figure 57-5, B).²⁵ Sodium-linked active transport is responsible for free amino acid uptake via one of four different carriers that have a variable degree of selectivity for neutral (Gly, Ala), acidic (Asp, Glu), basic (Arg, Lys), and imino (Pro, HO-Pro) amino acids. The cat has the highest rate of uptake of basic amino acids perhaps because it has an essential requirement for arginine.

Figure 57-8 Diagram of the absorption of di- and tripeptides by enterocytes. Pept 1, a peptide carrier.

Traditionally, peptide uptake has been considered to be facilitated diffusion, with the concentration gradient being maintained by intracellular peptide hydrolysis, and only free amino acids being exported from enterocytes into the portal blood (see Figure 57-8). A single carrier for di- and tripeptides with no selectivity for their amino acid content has been demonstrated. However, in people this peptide carrier, Pept-1, is involved in the active influx of peptides, being linked to the influx of H⁺ down an electrochemical gradient. The protons are exchanged across the MVM with sodium, which is pumped out by the basolateral N⁺, K⁺ ATPase. A mixture of peptides and free amino acids is exported to the blood, but it appears that peptides are absorbed more readily than free amino acids. This has clinical significance as the inclusion of dipeptides in elemental diets has a theoretical advantage over simple amino acid solutions. This transport protein is also the carrier for peptidomimetic drugs such as β-lactams and angiotensin-converting enzyme inhibitors.

Lipid

The products of fat digestion are absorbed by passive diffusion from mixed micelles into lacteals (see Figure 57-5, C). The limiting factors, assuming normal pancreatic function, are the intestinal surface area and lymphatic functionality, and so villus atrophy and lymphangiectasia are likely to cause malabsorption of fat.

Generally, the products of fat digestion are reassembled within enterocytes to prevent rediffusion back out of the enterocyte. They are combined with synthesized lipoproteins for passage into the lymphatics as chylomicrons. However, medium-chain triglycerides (length = 8-12 carbon atoms) can be absorbed directly into the portal blood, and provide an alternative route for fat uptake when lymphatic flow is impaired, as in lymphangiectasia. However, evidence exists that a proportion of medium-chain triglycerides are absorbed into the lacteals as they can be found within the thoracic duct.

Fat-Soluble Vitamins

Dietary fat-soluble vitamins A, D, E, and K are solubilized in mixed micelles before passive diffusion across the brush-border. Fat malabsorption associated with inadequate amounts of bile salts (e.g., bile duct obstruction), lymphangiectasia, or severe villus atrophy is also likely to result in vitamin deficiency. This is clinically most relevant for vitamin K as its body stores are not large and, particularly in cats, can lead to vitamin K–dependent coagulation factor deficiencies.

Vitamin A (retinol) is ingested either as a dimer (beta-carotene) or as an ester that must be hydrolyzed by pancreatic esterases. Beta-carotene is absorbed directly from micelles, but retinol is insoluble and must be anchored by a binding protein before absorption. Subnormal serum vitamin A concentrations have been observed in dogs with EPI but no associated signs of deficiency have been reported. However, vitamin A supplementation has been recommended following surgery in animals subsequently treated with corticosteroids to aid wound healing, and would be particularly relevant in animals that have had surgical intestinal biopsies.

Vitamin D is absorbed from mixed micelles. It is important for calcium homeostasis, controlling calcium absorption from the gut, as well as renal excretion. Vitamin D malabsorption may be (partly) responsible for the reductions in serum ionized calcium and magnesium that are reported in protein-losing enteropathies, which cannot be due to reduced protein binding because of hypoalbuminemia.

Vitamin E (α-tocopherol) is absorbed from mixed micelles by passive diffusion, and passes into the lymphatics unchanged. Vitamin E deficiency has been reported in Beagles with severe malabsorption, and is associated with EPI and bacterial overgrowth in German Shepherd dogs.

Vitamin K is derived from dietary sources (K₁) and synthesis by the enteric flora (K₂). Vitamin K₂ is probably absorbed in the ileum and colon. As well as bile salt deficiency, prolonged antibiotic usage may result in vitamin K deficiency.

Water-Soluble Vitamins

Water-soluble vitamins B and C are absorbed by a mixture of passive diffusion (e.g., pyridoxine [B₆] and C), saturable facilitated transport (e.g., riboflavin [B₂]), or active and facilitated transport (e.g., thiamine [B₁]) in other species, but the mechanisms in cats and dogs are uncertain. The absorptive mechanisms for folic acid and vitamin B₁₂ are more complex and important clinically as they may be helpful in determining the site and nature of intestinal disease.

Folic acid is present in adequate amounts in most commercial foods, but is also produced by the enteric flora. It is usually conjugated in a poorly absorbable polyglutamate form and must be hydrolyzed by folate deconjugase, a brush-border enzyme, before absorption. Folate (pteroyl monoglutamate) is absorbed by a carrier-mediated process at low luminal concentrations and by passive diffusion at high concentrations (Figure 57-9). After absorption folate is methylated in the cell to form methyltetrahydrofolate.

Figure 57-9 Diagram of the absorption of folate and cobalamin.

Folate is absorbed in the proximal SI by means of carrier-mediated diffusion. Dietary cobalamin is initially protected from digestion by R proteins, and is then absorbed in the ileum through receptor-mediated endocytosis bound to intrinsic factor (IF).

(From Ettinger SJ, Feldman EC, editors: Textbook of Veterinary Internal Medicine, ed 7, Philadelphia, 2010, Saunders, p 1528, Figure 270-1A.)

Vitamin B₁₂ (cobalamin) is absorbed by receptor-mediated endocytosis in the ileum (see Figure 57-9), but the process is complex so that intact cobalamin is absorbed and potentially harmful analogues are excluded. Following ingestion, cobalamin is released from food in the stomach and then bound by R proteins (haptocorrins), which are nonspecific binding proteins of salivary and gastric origin. At acidic pH, cobalamin has high affinity for R proteins, but on entering the more alkaline environment of the SI, R proteins bind cobalamin less avidly and undergo proteolysis. Thus cobalamin is transferred to another binding protein, intrinsic factor, which promotes cobalamin absorption in the ileum. The source of intrinsic factor is the stomach and pancreas in dogs and solely the pancreas in cats. Intrinsic factor–bound cobalamin complexes pass to the ileum until they bind specific receptors and are endocytosed. Cobalamin is passed into the portal blood where it is bound to a protein, transcobalamin 2, enabling it to enter tissues and to be reexcreted in bile. Inherited abnormalities of the cobalamin–intrinsic factor receptor in breeds such as the Giant Schnauzer and Border Collie cause selective cobalamin deficiency.

Minerals

Zinc and copper are absorbed via divalent cation transporters. There is competition for binding, while intracellular binding of copper by metallothionein is also part of the normal homeostatic mechanism, as the copper is trapped within effete enterocytes and shed.

Iron is absorbed by the duodenum and proximal jejunum both as heme and nonheme iron. Heme, found largely in meat, is better absorbed as it is unaffected by other dietary constituents or intraluminal factors. Gastric acid and chelation with mucopolysaccharide, ascorbate, and citrate help maintain iron in solution for absorption, and ferrous forms of nonheme iron are better absorbed than ferric forms. Ferrous iron is absorbed by an energy-dependent carrier mechanism, and is carried out of the enterocyte bound to transferrin. However, absorption is regulated, and if the body is iron-replete, crypt cells synthesize apoferritin, which traps iron in enterocytes as ferritin. When the enterocyte is exfoliated at the villus tip, the trapped iron is excreted back into the lumen.

Calcium absorption is complex and is modulated by systemic control mechanisms. In particular, vitamin D stimulates the activity of calcium-binding protein within enterocytes. However, uptake of calcium at the brush-border is an active process and is markedly influenced by the intraluminal pH and other substances such as organic and inorganic phosphates.

Control of Fluid Balance

Intestinal fluid balance is regulated by the neurocrine systems in the submucosal plexus as a largely autonomous process.^35,36 Acetylcholine and vasoactive intestinal polypeptide are major mediators of secretion, increasing intracellular calcium and cyclic adenosine monophosphate (cAMP), inhibiting neutral sodium and chloride absorption, and facilitating transcellular chloride efflux. Many bacterial agents exert their diarrheagenic effects by increasing cAMP in enterocytes. The principal regulators of absorption—noradrenaline, somatostatin, and opioids—lower intracellular cAMP and calcium concentrations and stimulate neutral NaCl absorption and thereby can have therapeutic antidiarrheal effects.