Digestion and absorption are the ultimate functions of the gastrointestinal tract.
Digestion is the chemical breakdown of ingested foods into absorbable molecules. The digestive enzymes are secreted in salivary, gastric, and pancreatic juices and also are present on the apical membrane of intestinal epithelial cells. The sources of the various digestive enzymes are summarized in Table 8-5, and the digestive and absorptive functions are summarized in Table 8-6.
Table 8–6 Summary of Mechanisms of Digestion and Absorption of Nutrients
Absorption is the movement of nutrients, water, and electrolytes from the lumen of the intestine into the blood. There are two paths for absorption: a cellular path and a paracellular path. In the cellular path, the substance must cross the apical (luminal) membrane, enter the intestinal epithelial cell, and then be extruded from the cell across the basolateral membrane into blood. Transporters in the apical and basolateral membranes are responsible for the absorptive processes. In the paracellular path, substances move across the tight junctions between intestinal epithelial cells, through the lateral intercellular spaces, and into the blood.
The structure of the intestinal mucosa is ideally suited for absorption of large quantities of nutrients. Structural features called villi and microvilli increase the surface area of the small intestine, maximizing the exposure of nutrients to digestive enzymes and creating a large absorptive surface. The surface of the small intestine is arranged in longitudinal folds, called folds of Kerckring. Fingerlike villi project from these folds. The villi are longest in the duodenum, where most digestion and absorption occurs, and shortest in the terminal ileum. The surfaces of the villi are covered with epithelial cells (enterocytes) interspersed with mucus-secreting cells (goblet cells). The apical surface of the epithelial cells is further expanded by tiny enfoldings called microvilli. This microvillar surface is called the brush borderbecause of its “brushlike” appearance under light microscopy. Together, the folds of Kerckring, the villi, and the microvilli increase total surface area by 600-fold!
The epithelial cells of the small intestine have some of the highest turnover rates of any cells in the body—they are replaced every 3 to 6 days. The high turnover rate of the intestinal mucosal cells makes them particularly susceptible to the effects of irradiation and chemotherapy.
Carbohydrates constitute about 50% of the typical American diet. Ingested carbohydrates are polysaccharides, disaccharides (sucrose, lactose, maltose, and trehalose), and small amounts of monosaccharides (glucose and fructose).
Digestion of Carbohydrates
Only monosaccharides are absorbed by the intestinal epithelial cells. Therefore, to be absorbed, all ingested carbohydrates must be digested to monosaccharides: glucose, galactose, or fructose. The pathways for carbohydrate digestion are shown in Figure 8-26. Starch is first digested to disaccharides, and then disaccharides are digested to monosaccharides.
Figure 8–26 Carbohydrate digestion in the small intestine.
Digestion of starch begins with α-amylase. Salivary amylase starts the process of starch digestion in the mouth; it plays little role overall, however, because it is inactivated by the low pH of the gastric contents. Pancreatic amylase digests interior 1,4-glycosidic bonds in starch, yielding three disaccharides, α-limit dextrins, maltose, and maltotriose. These disaccharides are further digested to monosaccharides by the intestinal brush-border enzymes, α-dextrinase, maltase, and sucrase. The product of each of these final digestive steps is glucose. Glucose, a monosaccharide, can be absorbed by the epithelial cells.
The three disaccharides in food are trehalose, lactose, and sucrose. They do not require the amylase digestive step because they already are in the disaccharide form. Each molecule of disaccharide is digested to two molecules of monosaccharide by the enzymes trehalase, lactase, and sucrase. Thus, trehalose is digested by trehalase to two molecules of glucose; lactose is digested by lactase to glucose and galactose; and sucrose is digested by sucrase to glucose and fructose.
To summarize, there are three end products of carbohydrate digestion: glucose, galactose, and fructose; each is absorbable by intestinal epithelial cells.
Absorption of Carbohydrates
The mechanism of monosaccharide absorption by intestinal epithelial cells is shown in Figure 8-27. Glucose and galactose are absorbed by mechanisms involving Na+-dependent cotransport. Fructose is absorbed by facilitated diffusion.
Figure 8–27 Mechanism of absorption of monosaccharides by epithelial cells of the small intestine. ATP, Adenosine triphosphate.
Glucose and galactose are absorbed across the apical membrane by secondary active transport mechanisms similar to those found in the early proximal convoluted tubule. Both glucose and galactose move from the intestinal lumen into the cell on the Na+-glucose cotransporter (SGLT 1), against an electrochemical gradient. The energy for this step does not come directly from adenosine triphosphate (ATP) but from the Na+ gradient across the apical membrane; the Na+ gradient is, of course, created and maintained by the Na+-K+ ATPase on the basolateral membrane. Glucose and galactose are extruded from the cell into the blood, across the basolateral membrane, by facilitated diffusion (GLUT 2).
Fructose is handled differently from glucose and galactose. Its absorption does not involve an energy-requiring step or a cotransporter in the apical membrane. Rather, fructose is transported across both the apical and basolateral membranes by facilitated diffusion; in the apical membrane, the fructose-specific transporter is called GLUT 5, and in the basolateral membrane, fructose is transported by GLUT 2. Because only facilitated diffusion is involved, fructose cannot be absorbed against an electrochemical gradient (in contrast to glucose and galactose).
Disorders of Carbohydrate Digestion and Absorption
Most disorders of carbohydrate absorption are the result of a failure to break down ingested carbohydrates to an absorbable form (i.e., to monosaccharides). If nonabsorbable carbohydrates (e.g., disaccharides) remain in the gastrointestinal lumen, they “hold” an equivalent amount of water to keep the intestinal contents isosmotic. Retention of this solute and water in the intestine causes osmotic diarrhea.
Lactose intolerance, which is caused by lactase deficiency, is a common example of failure to digest a carbohydrate to an absorbable form. In this disorder, the brush-border lactase is deficient or lacking and lactose is not digested to glucose and galactose. If lactose is ingested in milk or milk products, the lactose remains undigested in the lumen of the intestine. Lactose, a disaccharide, is nonabsorbable, holds water in the lumen, and causes osmotic diarrhea. Persons with lactose intolerance either may avoid ingesting milk products or may ingest milk products supplemented with lactase (Box 8-2).
BOX 8–2 Clinical Physiology: Lactose Intolerance
DESCRIPTION OF CASE. An 18-year-old college student reports to her physician complaining of diarrhea, bloating, and gas when she drinks milk. She thinks that she has always had difficulty digesting milk. The physician suspects that the woman has lactose intolerance. He requests that she consume no milk products for a 2-week period and note the presence of diarrhea or excessive gas. Neither symptom is noted during this period.
EXPLANATION OF CASE. The woman has lactase deficiency, a partial or total absence of the intestinal brush-border enzyme lactase. Lactase is essential for the digestion of dietary lactose (a disaccharide present in milk) to glucose and galactose. When lactase is deficient, lactose cannot be digested to the absorbable monosaccharide forms and intact lactose remains in the intestinal lumen. There, it behaves as an osmotically active solute: It retains water isosmotically, and it produces osmotic diarrhea. Excess gas is caused by fermentation of the undigested, unabsorbed lactose to methane and hydrogen gas.
TREATMENT. Apparently, this defect is specific only for lactase; the other brush-border enzymes (e.g., α-dextrinase, maltase, sucrase, trehalase) are normal in this woman. Therefore, only lactose must be eliminated from her diet by having her avoid milk products. Alternatively, lactase tablets can be ingested along with milk to ensure adequate digestion of lactose to monosaccharides. No further testing or treatment is necessary.
Dietary proteins are digested to absorbable forms (i.e., amino acids, dipeptides, and tripeptides) by proteases in the stomach and small intestine and then absorbed into the blood. The proteins contained in gastrointestinal secretions (e.g., pancreatic enzymes) are similarly digested and absorbed.
Digestion of Proteins
The digestion of protein begins in the stomach with the action of pepsin and is completed in the small intestine with pancreatic and brush-border proteases (Figs. 8-28 and 8-29). The two classes of proteases are endopeptidases and exopeptidases. Endopeptidases hydrolyze the interior peptide bonds of proteins. The endopeptidases of the gastrointestinal tract are pepsin, trypsin, chymotrypsin, and elastase.Exopeptidases hydrolyze one amino acid at a time from the C-terminal ends of proteins and peptides. The exopeptidases of the gastrointestinal tract are carboxypeptidases A and B.
Figure 8–28 Activation of proteases in the stomach (A) and small intestine (B). Trypsin autocatalyzes its own activation and the activation of the other proenzymes.
Figure 8–29 Digestion of proteins in the stomach (A) and small intestine (B).
As noted, protein digestion begins with the action of pepsin in the stomach. The gastric chief cells secrete the inactive precursor of pepsin, pepsinogen. At low gastric pH, pepsinogen is activated to pepsin. There are three isozymes of pepsin, each of which has a pH optimum ranging between pH 1 and 3; above pH 5, pepsin is denatured and inactivated. Therefore, pepsin is active at the low pH of the stomach, and its actions are terminated in the duodenum, where pancreatic HCO3− secretions neutralize gastric H+ and increase the pH. Interestingly, pepsin is not essential for normal protein digestion. In persons whose stomach has been removed or persons who do not secrete gastric H+ (and cannot activate pepsinogen to pepsin), protein digestion and absorption are normal. These examples demonstrate that pancreatic and brush-border proteases alone can adequately digest ingested protein.
Protein digestion continues in the small intestine with the combined actions of pancreatic and brush-border proteases. Five major pancreatic proteases are secreted as inactive precursors: trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase A, and procarboxypeptidase B (see Fig. 8-28).
The first step in intestinal protein digestion is the activation of trypsinogen to its active form, trypsin, by the brush-border enzyme enterokinase. Initially, a small amount of trypsin is produced, which then catalyzes the conversion of all of the other inactive precursors to their active enzymes. Even the remaining trypsinogen is autocatalyzed by trypsin to form more trypsin. The activation steps yield five active enzymes for protein digestion: trypsin, chymotrypsin, elastase, carboxypeptidase A, and carboxypeptidase B. These pancreatic proteases then hydrolyze dietary protein to amino acids, dipeptides, tripeptides, and larger peptides called oligopeptides. Only the amino acids, dipeptides, and tripeptides are absorbable. The oligopeptides are further hydrolyzed by brush-border proteases, yielding the smaller absorbable molecules (see Fig. 8-29). Finally, the pancreatic proteases digest themselves and each other!
Absorption of Proteins
As previously described, the products of protein digestion are amino acids, dipeptides, and tripeptides. Each form can be absorbed by intestinal epithelial cells. Especially note the contrast between proteins and carbohydrates: Carbohydrates are absorbable in the monosaccharide form only, whereas proteins are absorbable in larger units.
The L-amino acids are absorbed by mechanisms analogous to those for monosaccharide absorption (Fig. 8-30). The amino acids are transported from the lumen into the cell by Na+-amino acid cotransporters in the apical membrane, energized by the Na+ gradient. There are four separate cotransporters: one each for neutral, acidic, basic, and imino amino acids. The amino acids then are transported across the basolateral membrane into the blood by facilitated diffusion, again by separate mechanisms for neutral, acidic, basic, and imino amino acids.
Figure 8–30 The mechanism of absorption of amino acids, dipeptides, and tripeptides in the small intestine. ATP, Adenosine triphosphate.
Most ingested protein is absorbed by intestinal epithelial cells in the dipeptide and tripeptide forms rather than as free amino acids. Separate H+-dependent cotransporters in the apical membrane transport dipeptides and tripeptides from the intestinal lumen into the cell, utilizing an H+ ion gradient created by an Na+-H+ exchanger in the apical membrane (not shown in Fig. 8-30). Once inside the cell, most of the dipeptides and tripeptides are hydrolyzed to amino acids by cytosolic peptidases, producing amino acids that exit the cell by facilitated diffusion; the remaining dipeptides and tripeptides are absorbed unchanged.
Disorders of Protein Digestion and Absorption
Disorders of protein digestion or absorption occur when there is a deficiency of pancreatic enzymes or when there is a defect in the transporters of the intestinal epithelial cells.
In disorders of the exocrine pancreas such as chronic pancreatitis and cystic fibrosis, there is a deficiency of all pancreatic enzymes including the proteases. Dietary protein cannot be absorbed if it is not digested by proteases to amino acids, dipeptides, and tripeptides. The absence of trypsin alone makes it appear as if all of the pancreatic enzymes are missing because trypsin is necessary for the activation of all precursor enzymes (including trypsin itself) to their active forms (see Fig. 8-28).
Several diseases are caused by a defect in or absence of an Na+-amino acid cotransporter. Cystinuria is a genetic disorder in which the transporter for the dibasic amino acids cystine, lysine, arginine, and ornithine is absent in both the small intestine and the kidney. As a result of this deficiency, none of these amino acids is absorbed by the intestine or reabsorbed by the kidney. The intestinal defect results in failure to absorb the amino acids, which are excreted in feces. The renal defect results in increased excretion of these specific amino acids and gives the disease its name, cystinuria or excess cystine excretion.
The dietary lipids include triglycerides, cholesterol, and phospholipids. A factor that greatly complicates lipid digestion and absorption is their insolubility in water (their hydrophobicity). Because the gastrointestinal tract is filled with an aqueous fluid, the lipids must somehow be solubilized to be digested and absorbed. Thus, the mechanisms for processing lipids are more complicated than those for carbohydrates and proteins, which are water soluble.
Digestion of Lipids
The digestion of dietary lipids begins in the stomach with the action of lingual and gastric lipases and is completed in the small intestine with the actions of the pancreatic enzymes pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2 (Fig. 8-31).
Figure 8–31 Digestion of lipids in the small intestine.
The function of the stomach in lipid digestion is to churn and mix dietary lipids and to initiate enzymatic digestion. The churning action breaks the lipids into small droplets, increasing the surface area for digestive enzymes. In the stomach, the lipid droplets are emulsified (kept apart) by dietary proteins. (Bile acids, the primary emulsifying agents in the small intestine, are not present in the gastric contents.)Lingual and gastric lipases initiate lipid digestion by hydrolyzing approximately 10% of ingested triglycerides to glycerol and free fatty acids. One of the most important contributions of the stomach to overall lipid digestion (and absorption) is that it empties chyme slowly into the small intestine, allowing adequate time for pancreatic enzymes to digest lipids. The rate of gastric emptying, which is so critical for subsequent intestinal digestive and absorptive steps, is slowed by CCK. CCK is secreted when dietary lipids first appear in the small intestine.
Most lipid digestion occurs in the small intestine, where conditions are more favorable than in the stomach. Bile salts are secreted into the lumen of small intestine. These bile salts, together with lysolecithin and products of lipid digestion, surround and emulsify dietary lipids. Emulsification produces small droplets of lipid dispersed in the aqueous solution of the intestinal lumen, creating a large surface area for the action of pancreatic enzymes. The pancreatic enzymes (pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2) and one special protein (colipase) are secreted into the small intestine to accomplish the digestive work (see Fig. 8-31).
Pancreatic lipase is secreted as the active enzyme. It hydrolyzes triglyceride molecules to one molecule of monoglyceride and two molecules of fatty acid. A potential problem in the action of pancreatic lipase is that it is inactivated by bile salts. Bile salts displace pancreatic lipase at the lipid-water interface of the emulsified lipid droplets. This “problem” is solved by colipase. Colipase is secreted in pancreatic juices in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Colipase then displaces bile salts at the lipid-water interface and binds to pancreatic lipase. With the inhibitory bile salts displaced, pancreatic lipase can proceed with its digestive functions.
Cholesterol ester hydrolase is secreted as an active enzyme and hydrolyzes cholesterol ester to free cholesterol and fatty acids. It also hydrolyzes ester linkages of triglycerides, yielding glycerol.
Phospholipase A2 is secreted as a proenzyme and, like many other pancreatic enzymes, is activated by trypsin. Phospholipase A2 hydrolyzes phospholipids to lysolecithin and fatty acids.
The final products of lipid digestion are monoglycerides, fatty acids, cholesterol, lysolecithin, and glycerol (from hydrolysis of ester bonds of triglycerides). With the exception of glycerol, each end product is hydrophobic and therefore is not soluble in water. Now the hydrophobic digestive products must be solubilized in micelles and transported to the apical membrane of the intestinal cells for absorption.
Absorption of Lipids
Absorption of lipids occurs in a series of steps illustrated in Figure 8-32 and is described as follows. The circled numbers on the figure correlate with the following steps:
Figure 8–32 Mechanism of absorption of lipids in the small intestine. The circled numbers correspond to the steps described in the text. Apo B, β-Lipoprotein; Chol, cholesterol; Chol E, cholesterol ester; FFA, free fatty acids; LysoPL, lysolecithin; MG, monoglycerides; PL, phospholipids; TG, triglycerides.
1. The products of lipid digestion (cholesterol, monoglycerides, lysolecithin, and free fatty acids) are solubilized in the intestinal lumen in mixed micelles, except glycerol, which is water soluble. Mixed micelles are cylindrically shaped disks with an average diameter of 50 Å. As discussed earlier, the core of a micelle contains products of lipid digestion and the exterior is lined with bile salts, which areamphipathic. The hydrophilic portion of the bile salt molecules dissolves in the aqueous solution of the intestinal lumen, thus solubilizing the lipids in the micellar core.
2. The micelles diffuse to the apical (brush-border) membrane of the intestinal epithelial cells. At the apical membrane, the lipids are released from the micelle and diffuse down their concentration gradients into the cell. The micelles per se do not enter the cell, however, and the bile salts are left behind in the intestinal lumen to be absorbed downstream in the ileum. Because most ingested lipid is absorbed by the midjejunum, the “work” of the bile salts is completed long before they are returned to the liver via the enterohepatic circulation.
3. Inside the intestinal epithelial cells, the products of lipid digestion are reesterified with free fatty acids on the smooth endoplasmic reticulum to form the original ingested lipids, triglycerides, cholesterol ester, and phospholipids.
4. Inside the cells, the reesterified lipids are packaged with apoproteins in lipid-carrying particles called chylomicrons. The chylomicrons, with an average diameter of 1000 Å, are composed of triglycerides and cholesterol at the core and phospholipids and apoproteins on the outside. Phospholipids cover 80% of the outside of the chylomicron surface, and the remaining 20% of the surface is covered withapoproteins. Apoproteins, which are synthesized by the intestinal epithelial cells, are essential for the absorption of chylomicrons. Failure to synthesize Apo B (or β-lipoprotein) results inabetalipoproteinemia, a condition in which a person is unable to absorb chylomicrons and, therefore, is also unable to absorb dietary lipids.
5. The chylomicrons are packaged in secretory vesicles on the Golgi apparatus. The secretory vesicles migrate to the basolateral membranes, and there is exocytosis of the chylomicrons. The chylomicrons are too large to enter vascular capillaries, but they can enter the lymphatic capillaries (lacteals) by moving between the endothelial cells that line the lacteals. The lymphatic circulation carries the chylomicrons to the thoracic duct, which empties into the bloodstream.
Abnormalities of Lipid Digestion and Absorption
The mechanisms for lipid digestion and absorption are more complex and involve more steps than those for carbohydrate and protein. Thus, there are also more steps at which an abnormality of lipid digestion or absorption can occur. Each step in the normal process is essential: pancreatic enzyme secretion and function, bile acid secretion, emulsification, micelle formation, diffusion of lipids into intestinal epithelial cells, chylomicron formation, and transfer of chylomicrons into lymph. An abnormality at any one of the steps will interfere with lipid absorption and result in steatorrhea (fat excreted in feces).
Pancreatic insufficiency. Diseases of the exocrine pancreas (e.g., chronic pancreatitis and cystic fibrosis) result in failure to secrete adequate amounts of pancreatic enzymes including those involved in lipid digestion, pancreatic lipase and colipase, cholesterol ester hydrolase, and phospholipase A2. For example, in the absence of pancreatic lipase, triglycerides cannot be digested to monoglycerides and free fatty acids. Undigested triglycerides are not absorbable and are excreted in feces.
Acidity of duodenal contents. If the acidic chyme delivered to the duodenum is not adequately neutralized by the HCO3−-containing pancreatic secretions, then pancreatic enzymes are inactivated (i.e., the pH optimum for pancreatic lipase is 6). The gastric chyme, which is delivered to the duodenum, has a pH ranging from 2 at the pylorus to 4 at the duodenal bulb. Sufficient HCO3− must be secreted in pancreatic juice to neutralize the H+ and increase the pH to the range where pancreatic enzymes function optimally.
There are two reasons that all of the H+ delivered from the stomach might not be neutralized: (1) Gastric parietal cells may be secreting excessive quantities of H+, causing an overload to the duodenum; or (2) the pancreas may fail to secrete sufficient quantities of HCO3− in pancreatic juice. The first reason is illustrated by Zollinger-Ellison syndrome, in which a tumor secretes large quantities of gastrin (Box 8-3). The elevated levels of gastrin stimulate excessive secretion of H+ by the gastric parietal cells, and this H+ is delivered to the duodenum, overwhelming the ability of pancreatic juices to neutralize it. The second reason is illustrated by disorders of the exocrine pancreas (e.g., pancreatitis) in which there is impaired HCO3− secretion (in addition to impaired enzyme secretion).
BOX 8–3 Clinical Physiology: Zollinger-Ellison Syndrome
DESCRIPTION OF CASE. A 52-year-old man visits his physician complaining of abdominal pain, nausea, loss of appetite, frequent belching, and diarrhea. The man reports that his pain is worse at night and is sometimes relieved by eating food or taking antacids containing HCO3−. Gastrointestinal endoscopy reveals an ulcer in the duodenal bulb. Stool samples are positive for blood and fat. Because Zollinger-Ellison syndrome is suspected in this patient, his serum gastrin level is measured and found to be markedly elevated. A computerized tomographic (CT) scan reveals a 1.5-cm mass in the head of the pancreas. The man is referred to a surgeon. While awaiting surgery, the man is treated with the drug omeprazole, which inhibits H+ secretion by gastric parietal cells. During a laparotomy, a pancreatic tumor is located and excised. After surgery the man’s symptoms diminish, and subsequent endoscopy shows that the duodenal ulcer has healed.
EXPLANATION OF CASE. All of the man’s symptoms and clinical manifestations are caused, directly or indirectly, by a gastrin-secreting tumor of the pancreas. In Zollinger-Ellison syndrome, the tumor secretes large amounts of gastrin into the circulation. The target cell for gastrin is the gastric parietal cell, where it stimulates H+ secretion.
The gastric G cells, the physiologic source of gastrin, are under negative feedback control. Thus, normally, gastrin secretion and H+ secretion are inhibited when the gastric contents are acidified (i.e., when no more H+ is needed). In Zollinger-Ellison syndrome, however, this negative feedback control mechanism does not operate: Gastrin secretion by the tumor is not inhibited when the gastric contents are acidified. Therefore, gastrin secretion continues unabated, as does H+ secretion by the parietal cells.
The man’s diarrhea is caused by the large volume of fluid delivered from the stomach (stimulated by gastrin) to the small intestine; the volume is so great that it overwhelms the capacity of the intestine to absorb it.
The presence of fat in the stool (steatorrhea) is abnormal because mechanisms in the small intestine normally ensure that dietary fat is completely absorbed. Steatorrhea is present in Zollinger-Ellison syndrome for two reasons: (1) The first reason is that excess H+ is delivered from the stomach to the small intestine and overwhelms the buffering ability of HCO3−-containing pancreatic juices. The duodenal contents remain at acidic pH rather than being neutralized, and the acidic pH inactivates pancreatic lipase. When pancreatic lipase is inactivated, it cannot digest dietary triglycerides to monoglycerides and fatty acids. Undigested triglycerides are not absorbed by intestinal epithelial cells, and thus they are excreted in the stool. (2) The second reason for steatorrhea is that the acidity of the duodenal contents damages the intestinal mucosa (evidenced by the duodenal ulcer) and reduces the microvillar surface area for absorption of lipids.
TREATMENT. While the man is awaiting surgery to remove the gastrin-secreting tumor, he is treated with omeprazole, which directly blocks the H+-K+ ATPase in the apical membrane of gastric parietal cells. This ATPase is responsible for gastric H+ secretion. The drug is expected to reduce H+ secretion and decrease the H+ load to the duodenum. Later, the gastrin-secreting tumor is surgically removed.
Deficiency of bile salts. Deficiency of bile salts interferes with the ability to form micelles, which are necessary for solubilization of the products of lipid digestion. Ileal resection (removal of the ileum) interrupts the enterohepatic circulation of bile salts, which then are excreted in feces rather than being returned to the liver. Because the synthesis of new bile salts cannot keep pace with the fecal loss, the total bile salt pool is reduced.
Bacterial overgrowth. Bacterial overgrowth reduces the effectiveness of bile salts by deconjugating them. In other words, bacterial actions remove glycine and taurine from bile salts, converting them to bile acids. Recall that at intestinal pH, bile acids are primarily in the nonionized form (because their pKs are higher than intestinal pH); the nonionized form is lipid soluble and readily absorbed by diffusion across the intestinal epithelial cells. For this reason, the bile acids are absorbed “too early” (before reaching the ileum), before micelle formation and lipid absorption is completed. Similarly, decreased pH in the intestinal lumen promotes “early” absorption of bile acids by converting them to their nonionized form.
Decreased intestinal cells for absorption. In conditions such as tropical sprue, the number of intestinal epithelial cells is reduced, which reduces the microvillar surface area. Because lipid absorption across the apical membrane occurs by diffusion, which depends on surface area, lipid absorption is impaired because the surface area for absorption is decreased.
Failure to synthesize apoproteins. Failure to synthesize Apo B (β-lipoprotein) causes abetalipoproteinemia. In this disease, chylomicrons either do not form or are unable to be transported out of intestinal cells into lymph. In either case, there is decreased absorption of lipids into blood and a buildup of lipid within the intestinal cells.
Vitamins are required in small amounts to act as coenzymes or cofactors for various metabolic reactions. Because vitamins are not synthesized in the body, they must be acquired from the diet and absorbed by the gastrointestinal tract. The vitamins are categorized as either fat soluble or water soluble.
The fat-soluble vitamins are vitamins A, D, E, and K. The mechanism of absorption of fat-soluble vitamins is easily understood: They are processed in the same manner as dietary lipids. In the intestinal lumen, fat-soluble vitamins are incorporated into micelles and transported to the apical membrane of the intestinal cells. They diffuse across the apical membrane into the cells, are incorporated inchylomicrons, and then are extruded into lymph, which delivers them to the general circulation.
The water-soluble vitamins include vitamins B1, B2, B6, B12, C, biotin, folic acid, nicotinic acid, and pantothenic acid. In most cases, absorption of the water-soluble vitamins occurs via an Na+-dependent cotransport mechanism in the small intestine.
The exception is the absorption of vitamin B12 (cobalamin), which is more complicated than the absorption of the other water-soluble vitamins. Absorption of vitamin B12 requires intrinsic factor and occurs in the following steps: (1) Dietary vitamin B12 is released from foods by the digestive action of pepsin in the stomach. (2) Free vitamin B12 binds to R proteins, which are secreted in salivary juices. (3) In the duodenum, pancreatic proteases degrade the R proteins, causing vitamin B12 to be transferred to intrinsic factor, a glycoprotein secreted by the gastric parietal cells. (4) The vitamin B12-intrinsic factor complex is resistant to the degradative actions of pancreatic proteases and travels to the ileum, where there is a specific transport mechanism for its absorption.
A consequence of gastrectomy is loss of the source of intrinsic factor, the parietal cells. Therefore, after a gastrectomy, patients fail to absorb vitamin B12 from the ileum, eventually become vitamin B12deficient, and may develop pernicious anemia. To prevent pernicious anemia, vitamin B12 must be administered by injection; orally supplemented vitamin B12 cannot be absorbed in the absence of intrinsic factor.
Ca2+ is absorbed in the small intestine and depends on the presence of the active form of vitamin D, 1,25-dihydroxycholecalciferol, which is produced as follows: Dietary vitamin D3 (cholecalciferol) is inactive. In the liver, cholecalciferol is converted to 25-hydroxycholecalciferol, which also is inactive but is the principal circulating form of vitamin D3. In the proximal tubules of the kidney, 25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol, catalyzed by 1α-hydroxylase. 1,25-Dihydroxycholecalciferol, the biologically metabolite of vitamin D, has actions on intestine, kidney, and bone. The role of 1,25-dihydroxycholecalciferol in calcium homeostasis is discussed in Chapter 9. Briefly, its most important action is to promote Ca2+ absorption from the small intestine by inducing the synthesis of vitamin D–dependent Ca2+-binding protein (calbindin D-28 K) in intestinal epithelial cells.
In vitamin D deficiency or when there is failure to convert vitamin D to 1,25-dihydroxycholecalciferol (as occurs in chronic renal failure), there is inadequate Ca2+ absorption from the gastrointestinal tract. In children, inadequate Ca2+ absorption causes rickets, and in adults, it causes osteomalacia.
Iron is absorbed across the apical membrane of intestinal epithelial cells as free iron (Fe2+) or as heme iron (i.e., iron bound to hemoglobin or myoglobin). Inside the intestinal cells, heme iron is digested by lysosomal enzymes, releasing free iron. Free iron then binds to apoferritin and is transported across the basolateral membrane into the blood. In the circulation, iron is bound to a β-globulin calledtransferrin, which transports it from the small intestine to storage sites in the liver. From the liver, iron is transported to the bone marrow, where it is released and utilized in the synthesis of hemoglobin.