Digestion is the chemical breakdown of food into its component nutrients. It occurs primarily in the stomach and small intestine and is due to the actions of gastric acid (on proteins only) and digestive enzymes.
Absorption is the movement of molecules from the lumen of the gastrointestinal (GI) tract into enterocytes (intestinal cells) and then into the bloodstream or lymph. The absorption of nutrients and water occurs primarily in the small intestine; the absorption of most of the remaining water occurs primarily in the colon.
22.1 Carbohydrate Digestion and Absorption
Carbohydrate Digestion
Salivary and pancreatic α-amylase hydrolyzes the α-1–4 glycosidic bonds in starch, forming maltose, maltotriose, and α-limit dextrins. The effects of salivary α-amylase are limited because it is inactivated by gastric acid. Isomatose breaks down the α-1–6 glycosidic bonds in α-limit dextrins to form maltose (Fig. 22.1).
Fig. 22.1 
Carbohydrate digestion and absorption.
Salivary and pancreatic amylase break down ingested polysaccharides into their component disaccharides. Lactase, maltase, and sucrase break down their respective disaccharides into monosaccharides in the lumen. Monosaccharides are then able to be absorbed into the bloodstream.
Lactase, maltase, and sucrase in the brush border of the small intestine break down the disaccharides lactose, maltose, and sucrose, respectively, into monosaccharides:
– Lactose is broken down into galactose and glucose.
– Maltose is broken down into two glucose molecules.
– Sucrose is broken down into glucose and fructose.
Humans are unable to digest fiber, for example, cellulose (found in the cell walls of plants), because we lack the enzymes necessary to break down the β-acetyl linkages. However, dietary fiber has many effects on the GI tract (Fig. 22.2).
Lactose intolerance
Lactose intolerance is an inability to digest lactose in dairy products caused by a deficiency (partial or total) of lactase. Lactase is a brush border enzyme that converts lactose to the monosaccharides glucose and galactose, which are then absorbed into the bloodstream. Without lactase, lactose remains in the intestinal lumen, where it presents as osmotic load, resulting in diarrhea. Excess gas is also produced by fermentation of the luminal lactose to methane and hydrogen gas. Lactose intolerance can be diagnosed by the hydrogen breath test, which measures the amount of hydrogen produced after ingestion of a known amount of pure lactose (following an initial period of fasting). If the amount of hydrogen rises by 20 ppm, then a diagnosis of lactose intolerance can be made. The symptoms of lactose intolerance can be minimized in lactose-intolerant individuals by limiting their intake of dairy products or by oral ingestion of lactase-containing foods or drugs (e.g., Lactaid) with a meal that is high in dairy. By introducing the exogenous enzyme and the substrate at the same time, the digestion of the substrate can proceed almost normally within the GI tract.
Fig. 22.2 Fiber: Effects.
In the stomach, fiber binds water, which enlarges the particle size so that fiber particles pass the pyloric sphincter later and therefore undergo delayed gastric emptying. In the ileum and colon the water-binding (swelling) capacity lowers transit time. Fiber may bind mineral and trace elements as well as fat-soluble vitamins, which may not allow them to be absorbed. The binding of steroids leads to an increased excretion of bile acids and cholesterol, which may be helpful in people with fat metabolism disorders. Glucose absorption is also delayed by high-fiber intake, improving glucose control in diabetics. Stool volume is increased, and the consistency of stool is softer with fiber intake. However, intestinal bacteria ferment the polysaccharides in fiber, producing methane and CO2. During fermentation, short-chain fatty acids (FA) are produced that positively affect the composition of the intestinal flora and the intestinal pH. Finally, the binding of ammonia increases fecal nitrogen excretion, thereby unburdening the liver and kidneys.
Carbohydrate Absorption
Only the monosaccharides galactose, glucose, and fructose are absorbed into the bloodstream (Fig. 22.1).
Active transport of monosaccharides from the lumen into the bloodstream occurs throughout the length of the small intestine. The rate of absorption is greatest in the proximal intestine and decreases distally. Under normal conditions, all carbohydrates have been absorbed by the time the chyme reaches the mid-jejunum.
Galactose and Glucose Absorption
Galactose and glucose are absorbed into enterocytes by Na+-dependent cotransport (SGLT1). Galactose and glucose are transported “uphill,” and Na+ is transported “downhill.” The Na+ gradient is maintained by the Na+−K+ ATPase pump on the basolateral membrane of enterocytes. Galactose and glucose are then transported from enterocytes into the portal circulation by facilitated diffusion (via GLUT2 transporter).
Fructose Absorption
Fructose is absorbed by facilitated diffusion into enterocytes via GLUT5 on the luminal membrane and into blood via GLUT2 on the basolateral membrane. Enterocytes possess the appropriate biochemical pathways for the conversion of fructose to other substrates (e.g., glucose); this keeps the intracellular concentration low enough to support its continued facilitated diffusion into the cell.
22.2 Protein Digestion and Absorption
Protein Digestion
Gastric acid (HCl) denatures proteins, unfolding them to expose their bonds to pepsin, which breaks those bonds by hydrolysis (Fig. 22.3).
Fig. 22.3 Protein digestion and absorption of peptides and amino acids.
Ingested proteins are denatured by HCl. HCl also activates pepsin from pepsinogen (1). Pepsin becomes inactive in the small intestine (pH 7−8). Pancreatic juice also contains proenzymes of other peptidases that are activated in the duodenum (2). The endopeptidases trypsin, chymotrypsin, and elastase hydrolyze the protein molecules into short-chain peptides. Carboxypeptidase A and B (from the pancreas), as well as dipeptidases and aminopeptidase (brush border enzymes), also break proteins down into tripeptides, dipeptides, and amino acids. Tripeptides and dipeptides are absorbed by H+-dependent active transport. Amino acids are transported into the portal blood by a number of specific carriers by Na+-dependent active transport. (AA, amino acids)
Pancreatic proteolytic enzyme precursors trypsinogen, procarboxypeptidase, chymotrypsinogen, and proelastase are secreted into the small intestine, where they are activated.
– Trypsinogen is activated to trypsin by enteropeptidase, an enzyme in the brush border.
– Trypsin activates procarboxypeptidase, chymotrypsinogen, and proelastase to their active forms (carboxypeptidase, chymotrypsin, and elastase, respectively) and stimulates production of more trypsin from trypsinogen.
Trypsin, carboxypeptidase, chymotrypsin, and elastase break down polypeptides into tri- and dipeptides.
Protein Absorption
Most amino acids and peptides are absorbed in the jejunum, but some amino acids may be absorbed in the ileum.
Free Amino Acids
Amino acids are absorbed from the lumen into enterocytes by a variety of Na+-dependent and -independent cotransport systems in the luminal membrane. They are then transported into the portal circulation by facilitated diffusion.
Dipeptides and Tripeptides
Dipeptides and tripeptides are readily absorbed by enterocytes via H+-dependent cotransport systems (PepT1) in the luminal membrane. Once inside enterocytes, peptides are hydrolyzed into free amino acids and pass into the portal circulation by facilitated diffusion.
22.3 Lipid Digestion and Absorption
Some digestion of lipids occurs in the stomach (10%); the remaining digestion and the entire absorption process occurs in the small intestine.
Lipid Digestion
Lipid Digestion in the Stomach
Contractions in the stomach stir and emulsify lipid droplets so lingual lipase can break them down (short-chain partially water-soluble lipids only) into monoglycerides and free fatty acids (Fig. 22.4).
Note: The effects of lingual lipase are functionally minor compared with pancreatic lipase.
Lipid Digestion in the Small Intestine
Emulsified lipids combine with bile salts in the duodenum to form simple micelles. Simple micelles are much smaller than emulsified lipid droplets and thus greatly increase their surface area. Bile salts prevent lipids from coalescing, but they also inhibit pancreatic lipase from binding to the droplets, limiting its effect. This is overcome by colipase, a polypeptide secreted by the pancreas. In the presence of colipase, pancreatic lipase is able to hydrolyze triglycerides into monoglycerides and free fatty acids. Similarly, cholesterol esterase hydrolyzes cholesterol; and phospholipase A2 hydrolyzes phospholipids. These lipid digestion products and bile salts then combine to form mixed micelles, which have their hydrophilic polar heads on the outside and hydrophobic nonpolar tails on the inside. Mixed micelles are then able to penetrate through the unstirred water layer adjacent to the luminal surface of the brush border membrane, thereby facilitating lipid absorption.
Fig. 22.4 Lipid digestion.
After ingestion, first lingual lipase and then gastric lipase are secreted and mixed with the food particles. Both enzymes are active at low pH values. Gastric motility ensures thorough mixing with the enzymes and the breakdown of fat into smaller particles. The emulsified lipids are then released into the duodenum. Bile acids attach to the fat particles (termed simple micelles), causing their surface to become negatively charged, which allows colipase to attach to the triglycerides. Pancreatic lipase, which is inhibited by bile acids, now binds to colipase and hydrolyzes the triglycerides. Similarly, cholesterol esterase hydrolyzes cholesterol, and phospholipase A2 hydrolyzes phospholipids. Together with bile acids, the resulting products of fat digestion assemble spontaneously into mixed micelles, with polar heads facing out and nonpolar tails inside the micelle. Mixed micelles are able to traverse the unstirred water layer above the microvilli, and in the slightly acidic environment found here, they spontaneously break apart, allowing their lipid content to be released and absorbed by enterocytes, largely by passive diffusion. The bile salt component of the mixed micelle is then recycled via the enterohepatic circulation.
Lipid Absorption
Short-chain fatty acids diffuse passively across the enterocyte membrane, but carrier-mediated absorption is now the proposed mechanism for the uptake of long-chain fatty acids (aliphatic chain > 12 carbons) and sterically large lipids (Fig. 22.5). The lipid transporters identified in the small intestine are the plasma membrane fatty acid–binding protein (FABPpm), the fatty acid transport protein 4 (FATP4), and the fatty acid translocase (FAT/CD36).
Intestinal cholesterol absorption is also reported to be facilitated by the scavenger receptor SR-BI and by Niemann–Pick C-1-like 1 (NPC1L1). This is the reason that the absorption of cholesterol can now be inhibited by drugs. Lipid transport may be bidirectional, and some lipids may be secreted by intestinal cells.
Once monoglycerides and free fatty acids are absorbed into enterocytes, they are reesterified into triglycerides and form droplets. A lipoprotein layer coats the droplet, forming a chylomicron. These leave the cell by exocytosis and enter the bloodstream via the lymphatic circulation because they are too large to enter the bloodstream directly.
Note: All ingested fat is digested and absorbed. The 2 to 4% of stool that is fat usually comes from exfoliated cells and colonic bacteria.
Steatorrhea
Steatorrhea is the production of feces that have a high content of fat. They are often oily and foul-smelling, and they tend to float. Steatorrhea occurs when fat digestion or absorption is impaired. This can occur due to pancreatic disease (e.g., cystic fibrosis, and chronic pancreatitis), in which there is a deficiency of pancreatic lipase that would normally digest fats. It may also occur in conditions that cause hypersecretion of gastrin (e.g., Zollinger–Ellison syndrome), in which gastrin increases H+ secretion, which lowers duodenal pH, inactivating pancreatic lipase. It may also occur due to liver disease, which causes a deficiency of bile acids. Ileal resection will impair fat absorption due to impairment of bile recirculation to the liver. Treatment for steatorrhea due to pancreatic disease is pancreatic enzyme replacement (e.g., pancrelipase).
Fig. 22.5 Lipid absorption.
Dietary triglycerides (TG) are broken down into free fatty acids (FFA) and monoglycerides (MG) in the gastrointestinal (GI) tract. Short-chain FFA (e.g., acetic and butyric acid) do not need to be ferried across the unstirred water layer in mixed micelles because they are sufficiently water soluble to do this by themselves. In addition, they are also sufficiently lipid soluble to diffuse out of the enterocyte at the basolateral membrane and go directly to the bloodstream (portal venous blood), without the necessity of being incorporated into chylomicrons. Long-chain FFA and MG are not soluble in water. They are resynthesized to TG in the enterocytes. Because TG are not soluble in water, they are subsequently loaded into chylomicrons, which are exocytosed into the extracellular fluid, then passed on to the intestinal lymph (thereby bypassing the liver), from which they finally reach the greater circulation.
22.4 Absorption of Vitamins, Water, and Electrolytes
Absorption of Vitamins
Fat-soluble Vitamins
Fat-soluble vitamins (A, D, E, and K) require bile salts to facilitate micelle formation for efficient absorption. They are then incorporated into chylomicrons and enter the bloodstream via the lymphatic system.
Although diffuse intestinal absorption remains the only pathway described for vitamins D and K, the uptake of vitamins A and E may also be mediated by lipid transporters. SR-B1 is involved in the uptake of vitamin E, and NPC1L1 and ABCA1 may also play a role in the facilitated transport of vitamin A.
Vitamin K
Vitamin K is absorbed in the small intestine during lipid digestion and transported to the liver in chylomicrons. It is required for blood coagulation. Inactive precursors of the coagulation factors are synthesized in the liver and activated by γ-glutanyl carboxylase. Vitamin K is a cofactor for this reaction. Vitamin K results in the activation of factors II, VII, IX, and X, which are then released into the bloodstream.
Water-soluble Vitamins
Water-soluble vitamins are (mostly) absorbed by Na+-dependent cotransport systems (Fig. 22.6).
Fig. 22.6 Absorption of water-soluble vitamins.
Water-soluble vitamins (except vitamin B12) are absorbed by Na+-dependent cotransport in the small intestine. (ATP, adenosine triphosphate)
Vitamin B12 absorption, however, is more complicated and involves several steps (Fig. 22.7): B12 is released from dietary proteins by gastric acid. It then binds to R proteins, which are secreted in saliva. In the duodenum, trypsin digests the R protein, liberating B12, which then forms a complex with intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells. This B12−IF complex is resistant to the effects of trypsin and travels to the terminal ileum, where it binds to specific receptors and is absorbed.
Fig. 22.7 Vitamin B12 absorption.
Vitamin B12 is a relatively large and lipophobic molecule that requires transport proteins. During passage through the GI tract, plasma, and other compartments, vitamin B12 binds to intrinsic factor (IF), which is secreted by gastric parietal cells; transcobalamin II (TC II) in plasma; and R proteins in plasma (TC I), granulocytes (TC III), saliva, bile, milk, and other agents. Gastric acid releases vitamin B12 from dietary proteins. In most cases, the B12 then binds to R protein from saliva or (if the pH is high) IF (1). The R protein is digested by trypsin in the duodenum, which liberates B12, which is then bound by IF (trypsin resistant). The mucosa of the terminal ileum has highly specific receptors for the B12−IF complex. It binds to these receptors, and B12 is absorbed by receptor-mediated endocytosis, provided the pH is > 5.6 and Ca2+ ions are available (2). B12 then binds to TC I, II, and III in plasma (3). TC II mainly distributes B12 to all cells undergoing division. TC III (from granulocytes) transports excess B12 to the liver, where it is either stored or excreted as bile. TC I has a half-life of ~10 days and serves as a short-term reservoir of B12 in plasma.
Vitamin C (ascorbic acid)
The majority of vitamin C is absorbed in the proximal small intestine and is excreted by the kidneys. However, increasingly large amounts are excreted in feces following megadoses. Vitamin C is a reductant substance, and this property allows it to act as a H+ donor in hydroxylation reactions (e.g., during the biosynthesis of catecholamines when it is a cofactor for dopamine-β-hydroxylase). Other biological effects are based on different mechanisms, some of which are unknown (e.g., it is involved in collagen biosynthesis). It is also involved in the synthesis of bile acids from cholesterol, the synthesis of hormones (e.g., gastrin, gastrin- releasing peptide [GRP, bombesin], corticotropin-releasing hormone [CRH], and thyrotropin-releasing hormone [TRH]), the synthesis of cytochrome P-450 enzymes in the liver. It enhances iron absorption (by reducing Fe3+ to Fe2+) and it has well known antioxidant properties.
Absorption and Secretion of Water and Electrolytes
An average adult ingests 1 to 2 L of water per day, but the fluid load to the small intestine is 9 to 10 L, 8 to 9 L being added by the secretions of the GI system. Most absorption of water and electrolytes occurs in the small intestine, with some water absorbed in the colon as well.
Absorption of NaCl (Fig. 22.8)
Na+ is absorbed from the lumen into enterocytes by
– passive diffusion through Na+ channels
– cotransport with glucose and amino acids
– Na+−H+ exchange
– neutral Na+−Cl− cotransport
Cl− is absorbed via
– cotransport with Na+
– Cl−−HCO3− exchange
Aldosterone stimulates Na+ (and Cl−) absorption by stimulating the Na+−K+ ATPase pump.
Fig. 22.8 Na+ and Cl− absorption.
Na+ is absorbed by various mechanisms and the Na+−K+ ATPase in the basolateral membrane is the primary driving mechanism for all of them. Na+ passively diffuses into cells in the duodenum and jejunum via symport carriers, which actively cotrans-port glucose, amino acids, and other compounds (1). A lumen-negative potential forms that drives Cl− out of the lumen (2). Na+ ions in the lumen of the ileum are exchanged for H+ ions (3), while Cl− is exchanged for HCO3− at the same time (4). The H+ and HCO3− combine to form H2O and CO2, which diffuse out of the lumen (not shown in figure). Na+, Cl−, and H2O (by osmosis) are absorbed by this electroneutral transport mechanism. Na+in the colon is mainly absorbed through luminal Na+channels (5). This type of transport is electrogenic and aldosterone-dependent. The lumen-negative potential either leads to K+ secretion or drives Cl− out of the lumen (2).
Absorption of Water
The absorption of solutes (e.g., Na+ and Cl−) makes the lumen of the intestine slightly hypotonic, which then creates the osmotic gradient for water to move paracellularly. This keeps the lumen close to isotonic.
Absorption and Secretion of K+
K+ is absorbed passively in the small intestine. Most of its movement is paracellular. As Na+ and H2O are absorbed, the volume of the luminal contents decreases, resulting in an increase in [K+], permitting passive diffusion.
K+ is secreted in the colon (mechanism is the same as that for K+ secretion in the distal tubule of the kidney). This is stimulated by aldosterone via stimulation of the Na+−K+ ATPase pump.
Note: K+ secretion is a function of the luminal concentration. The colon can absorb or secrete K+ depending on the local conditions.
Absorption of Ca2+
Calcium ions are actively absorbed in the proximal small intestine and passively by paracellular diffusion in the rest of the small intestine. The active absorption is dependent upon 1,25-dihydroxycholecalciferol (1, 25-(OH)2-D3), the active form of vitamin D, which is synthesized in the kidney.
Active transcellular transport of Ca2+ occurs across the apical membrane via channel-like Ca2+ transporter (CaT1), through the cytoplasm via calbindin 9k (CaBP9k), and across the baso-lateral membrane via the Na+−Ca2+exchanger (NCX1), along with the plasma membrane Ca2+ ATPase (PMCA1).
Absorption of Iron
Iron ions are mainly absorbed in the proximal small intestine.
Ingested ferric ions (Fe3+) are reduced to ferrous ions (Fe2+) by acid in the stomach and by the enzyme ferric reductase, which is present on the brush border of the proximal small intestine. Gastric acid also allows iron to form complexes with substances such as ascorbic acid that reduce it to the Fe2+ form.
Free Fe2+ is transported by the divalent metal ion transporter (DMT1) into enterocytes in association with H+. Fe2+ is then transported by ferroportin 1, a transporter on the basolateral membrane, into the blood. This process is facilitated by a protein called hephaestin, which is associated with ferroportin 1. Fe2+ is transported in blood bound to transferrin. It is stored in the liver and transported to the bone marrow for the synthesis of hemoglobin.
The overall absorption and secretion of water and electrolytes in the gut are shown in Fig. 22.9.
Fig. 22.9 Water and electrolyte absorption and secretion.
H2O is primarily absorbed in the jejunum and the ileum, with smaller amounts being absorbed in the colon. When solutes (e.g., Na+ and Cl−) are absorbed, H2O follows by osmosis. Na+ reabsorption in the colon is dependent on aldosterone. This also causes the secretion of K+. HCO3− is secreted throughout the GI system except the jejunum, where it is absorbed. Ca2+ and Fe2+ are absorbed in the duodenum. Active Ca2+ absorption requires calcitriol.
Iron deficiency anemia
Iron deficiency anemia is a condition in which there is insufficient hemoglobin in red blood cells due to a lack of iron (which is an essential component of heme). Approximately two thirds of the iron content of the body is bound to hemoglobin. It is usually caused by blood loss from menses in premenopausal women, but it can also be due to inadequate dietary intake of iron, GI bleeding (e.g., from peptic ulcers, long-term nonsteroidal antiinflammatory drug use, or certain GI cancers), from GI conditions that decrease the absorption of iron (e.g., Crohn disease), or by pregnancy (in which the need for iron is increased due to the increase in maternal blood volume and for fetal hemoglobin synthesis). Treatment involves replenishment of iron in the form of ferrous sulfate tablets.
Hemochromatosis
Hemochromatosis is a condition in which there is failure of regulation of iron absorption in the bowel. This leads to excessive iron in the body, which then gets deposited in organs such as the liver, heart, pancreas, and the pituitary gland. Iron toxicity causes lipid peroxidation of cell membranes, DNA damage, and increased collagen formation. Signs include fatigue, arthralgia, skin pigmentation, liver disease (cirrhosis and carcinoma), cardiomyopathy, heart failure, arrhythmias, diabetes, and infertility. Management is by the drainage of venous blood until the patient is iron deficient.
Cholera
Cholera is an infectious disease caused by Vibrio cholerae, a gram-negative bacteria. It is spread via the fecal-oral route. V. cholerae toxin increases cyclic adenosine monophosphate (cAMP) concentrations in intestinal mucosal cells, causing the opening of Cl− channels and massive secretion of Cl−. This results in the production of a profuse amount of watery diarrhea, which, in turn, causes severe dehydration. This can lead to kidney failure, shock, coma, and death. Treatment requires rapid replacement of lost body fluids with oral or intravenous solutions containing salts and sugar. Tetracycline reduces fluid loss and diminishes transmission of the bacteria.
Diarrhea
Exudative diarrhea is a consequence of gross structural damage to the intestinal or colonic mucosa. It is characterized by the presence of blood in feces and frequent passage of a small volume of feces. Examples of causes of exudative diarrhea are inflammatory bowel diseases such as ulcerative colitis and Crohn disease, mucosal invasion by a protozoan (e.g., Entamoeba histolytica), and certain bacterial infections (e.g., Shigella and Salmonella).
Secretory diarrhea occurs in disorders in which there is increased secretion of fluids and electrolytes (e.g., cholera) or inhibited reabsorption of fluids and electrolytes.
Osmotic diarrhea occurs when ingested solutes that are osmotically active are retained in the lumen of the GI system. Because water must also be retained to maintain isotonicity, the volume of fluid delivered to the colon may exceed its absorptive capacity. Osmotic diarrhea may result from ingestion of substances that are difficult to absorb (e.g., MgSO4, a common ingredient in laxatives), limited absorption of solutes, or resection of the jejunum or ileum, which decreases the surface area for absorption of digested food. It may also occur if bile salts enter the colon, both because they are irritants and because they present an osmotic load.
Antibiotic-associated pseudomembranous colitis
Pseudomembranous colitis is inflammation of the colon due to superinfection with Clostridium difficile, a gram-positive bacillus. It typically occurs following a course of antibiotic treatment in which the normal gut commensal bacteria are eradicated, allowing C. difficile to colonize the gut unimpeded. The most common antibiotics that cause this condition are the penicillins, cephalosporins, fluoroquinolone, and clindamycin. Symptoms of pseudomembranous colitis include diarrhea, fever, and abdominal pain. It is treated with metronidazole or vancomycin.