Secretory, Digestive, and Absorptive Functions of Small and Large Intestines
|DIGESTION OF PROTEIN|
The purpose of the complex enzymatic reactions to which foodstuffs are exposed within the intestinal lumen is to prepare nutrients for transfer into and assimilation within the organism. The lumen of the digestive system, which is the space encompassed by the wall of the digestive tube, belongs, fundamentally speaking, to the outside world, and the processes by which the products of digestion enter and pass through the intestinal wall into the circulation are called secretion and absorption, respectively. The mucosa of the small intestine throughout its length is lined by cells involved with both secretion and absorption: mucus-secreting cells, neuroendocrine cells, and immune active cells. The incredible efficiency of intestinal function is emphasized by the fact that of the approximately 8 L of fluid that enters the small intestine, only 100 to 200 mL is excreted from the rectum, for an efficiency rate in excess of 98%. In disease states, the large and small intestines absorb even more fluid, sometimes exceeding 25 L per day. Alternatively, in secretory dis- orders and infection, the volume of diarrhea lost may rapidly pose a life-threatening risk of dehydration, with the loss of many liters of fluids and their accompanying electrolytes.
The secretory product of the duodenal glands is an alkaline, pale-yellow, viscous fluid, rich in bicarbonates and also containing mucus. Its primary function is protecting the proximal duodenum against the corrosive action of the acidic gastric contents entering the intestine. While there is an increasing relative absorption to secretion as nutrients pass into the jejunum and ileum, secretion persists from epithelial cells, goblet cells, and submucosal glands. The resulting luminal contents, or succus entericus, are constantly being mixed with mucus, bile, and digestive enzyme–laden pancreatic juice. The intestinal secretion contains a wide variety of digestive enzymes, namely, peptidases, nucleases, nucleosidases, phosphatase, lipase, maltase, sucrase, and lactase. Brush-border enterokinase is essential in activating the cascade of proenzymes secreted by the pancreas, including the cascades of trypsinogen to trypsin and chymotrypsinogen to chymotrypsin. The fact that digestion can proceed even in patients who have undergone total pancreatectomy indicates that the brush-border and secreted digestive intestinal enzymes are important. Motility of the small intestinal is activated by parasympathetic nerves, enteric nerves, and a host of enteric hormones acting both locally (paraendocrine hormones) and through the systemic circulation (most notably, cholecystokinin and secretin). These neurologic and hormonal reflexes are stimulated by the presence of acids and nutrients and by distention of the stomach and small intestine. These processes are slowed when nutrients, especially fats and essential amino acids, reach the distal small bowel. There they activate the so-called ileal brake by means of neural mechanisms and release of hormones, including peptide YY and glucagon-like peptide-1. Throughout the digestive process, mucus is being secreted from the intestinal crypts and epithelial cells on the villi to ensure adequate lubrication and protection of the surface epithelial cells.
Mucus is also secreted by colonic epithelium when it has been stimulated mechanically or chemically. The epithelium also secretes an alkaline-rich fluid high in potassium, which is exchanged for sodium as the fecal stream is solidified through dehydration processes.
The normal diet includes a variety of macronutrients composed of carbohydrates, nucleic acids, and proteins that are soluble in water and of fats, which are not. It also contains minerals, vitamins, and other micronutrients. Each requires specific, distinct pathways for digestion in preparation for absorption.
The digestion of proteins is carried out by gastric peptidases, an array of brush-border enzymes, and enzymes secreted by the pancreas. The primary gastric peptidase is pepsin, but chymosin is also active in an acidic environment. Chief cells secrete an inactive sub- stance, pepsinogen, which is activated by acid in the stomach to become pepsin. Pancreatic juices contain a rich supply of proteins that make up over 20 isoforms of 12 distinct enzymes and cofactors, most of which are proteases. All proteases are secreted as inactive proenzymes (zymogens), as are phospholipase and colipase. The proteolytic actions of each protein-splitting enzyme have a highly specific effect. Each attacks only certain linkages of the protein molecule or of the degradation products resulting from the preceding effects of one or more catalytically active compounds. According to their functions, they are typically grouped as either exopeptidases or endopeptidases. Trypsinogen is activated by the brush-border enzyme enterokinase to become its active form, trypsin, which in turn activates other enzymes. Trypsin, chymotrypsin, carboxypeptidase, and the intestinal aminopeptidases act only on polypeptides or peptides containing a free amino group. The dipeptidases act only on dipeptides. As the peptide is digested within the lumen, it diffuses to the epithelial surface, where a number of membrane-bound peptidases continue the digestive process. This cascade of proteolytic effects breaks down the original protein until it has been fragmented into its elementary components, the 26 amino acids, dipeptides, or tripeptides, in preparation for absorption.
For the digestion of nucleoproteins, the pancreas supplies nucleases, ribonuclease, desoxyribonuclease, and other substances that specifically hydrolyze nucleosides: pentose or deoxypentose is conjugated to purines and pyrimidine bases. Intestinal secretion also provides nucleases and, particularly, phosphatases, which split nucleotides (phosphoric esters of nucleosides) into their components.
|DIGESTION OF CARBOHYDRATES|
Dietary carbohydrates may consist of monoglycerides such as glucose and fructose, disaccharides such as lactose and sucrose, or polysaccharides. The processes involved in the digestion of carbohydrates are therefore primarily concerned with the enzymatic cleavage of polysaccharides and oligosaccharides into monosaccharides. Polysaccharides include starch, glycogen, and fibers such as cellulose, gums, and pectins. In human nutrition, the most important carbohydrate is starch, which is a polysaccharide occurring as an energy reservoir in plants, particularly cereals, grains, roots, and tubers. The counterpart in animals is glycogen, another polysaccharide ingested with meat and liver. In both starch and glycogen, a large number of hexoses (monosaccharides) are linked together, forming either a straight chain or a branched chain of molecules. The linkage between these molecules varies, and to open them, the organism is equipped with a variety of specifically active enzymes.
Starch-splitting enzymes called amylases are secreted by the pancreas and, to a lesser extent, by the salivary glands. The digestion of carbohydrates begins in the mouth with the action of salivary amylase. Because salivary amylase is inactivated by gastric acid in the stomach, the actions of the enzyme mainly affect the outer portions of the food mass. Once it reaches the stomach and the gastric acid has penetrated the food mass, digestion of carbohydrates slows or stops until the food mass reaches the duodenum. In the duodenum, carbohydrates are acted on by the more effective enzymes α-amylase and β-amylase, which are synthesized in the pancreas and then secreted in their active forms. The action of the amylases yields the disaccharide maltose and a polysaccharide fragment called dextrin, which cannot be further digested by amylase. Therefore, except during the period of infancy, when the secretory activity of the pancreas has not yet fully developed, the degradation of starch into the disaccharide maltose and the monosaccharide glucose is completed in the lower part of the duodenum and in the jejunum and ileum. The splitting of maltose into two molecules of glucose is catalyzed by maltase, an enzyme formed by the intestinal glands. Disaccharides are primarily digested by intestinal brush-border enzymes such as sucrose-isomaltase, which converts sucrose (common table sugar) into a molecule of glucose and a molecule of fructose, and lactase-phlorizin hydrolase, which converts lactase (milk sugar) into glucose and galactose. Other brush-border disaccharidases include glucoamylase and trehalase. The end products, there-fore, are simple monosaccharides, which the intestinal epithelial cell is prepared to absorb.
|DIGESTION OF FAT|
In humans, cellulose is indigestible, because humans, in contrast to some animals, lack enzymes capable of attacking the specific bonds of cellulose. The enzymes derived from the bacterial flora of the human colonic microbiota can act on cellulose and on the undigested starch reaching the distal gut. This action of the micro- biota produces increased osmotically active substances that attract fluid into the lumen and produce gas through fermentation. Both result in distention that increases colonic motility; when this distention is excessive, it can lead to discomfort interpreted as “gas” and to increased flatulence and bloating.
Lipids include a variety of heterogeneous molecules often described as fats. The term includes triglycerides, phospholipids, cholesterol, steroids, and fat-soluble vitamins. From the dietary point of view, the triglycerides are of major importance due to their high-energy value. Triglycerides, whether of plant origin (unsaturated) or animal origin (mostly saturated), are esters of glycerol and fatty acids. The esters are named triglycerides because the three alcoholic hydroxyl groups of glycerol are bound in an ester linkage to the carboxyl group (the group that determines the acid character) of either saturated or unsaturated organic acids, such as palmitic, stearic, oleic, or linoleic acid. The term neutral fat has also been used to describe these important nutrients because no acidic group is free. In an aqueous milieu, fats align with their hydrophobic groups adjacent to each other and their polar groups facing the surrounding water. This arrangement creates bilayers or micelles. Nonpolar lipids accumulate in the inner portions of these micelles. Further digestion of fats requires access to these molecules within the micelle. Bile salts and the coenzyme colipase are essential factors that facilitate this access. Triglycerides are digested by hydrolyzation of the ester linkage, yielding the components of the esters, namely, glycerol and the various fatty the triglycerides lose first one of their three acid molecules, leaving a diglyceride (i.e., a glycerol ester containing only two acids), and this, in turn, is hydrolyzed to a monoglyceride, which possesses only one acid molecule.
The hydrolysis of triglycerides and phospholipids is accomplished by lipases and phospholipases, respectively, that are secreted by the salivary glands, stomach, pancreas, and intestinal glands. A limited amount of fat is digested in the stomach by a lingual lipase originating in saliva and the gastric lipase originating from the chief cells in the stomach. The gastric lipase can function in an acidic environment, in contrast to other lipases, which act in a nearly neutral environment. In most adults, this gastric lipase is of limited significance, but it is important in patients with pancreatic insufficiency; it is also important in infants, in whom it is capable of hydrolyzing the highly emulsified fat of milk. The pancreas is the major source of bicarbonate, which serves to neutralize gastric acidity, and of lipase activity. It also is the source of colipase, which plays an important role as a cofactor at the interface of water, bile salt, and lipid by enhancing lipolysis. The phospholipids undergo hydrolysis into their component parts by secretions of a proenzyme from the pancreas that is activated by trypsin to produce phospholipase A. This hydrolysis produces glycerol, fatty acids, phosphate, and the special compound characteristic of the particular phospholipid (choline, serine, inositol, or ethanolamine). In contrast to the enzymes involved in protein and carbo- hydrate digestion, which act with a high degree of specificity on certain compounds or chemically well- defined groups or bonds, the action of lipases of animal or plant origin is far less specific.
In the lower duodenum, fat is mixed with bile and dispersed into a fine emulsion. The components of bile responsible for this action are the bile acids, mostly glycocholic acid and taurocholic acid, which act as detergents. The result of the emulsification of fat in the aqueous medium of the intestinal chyme is an enormous increase of the surface of the fat particles, facilitating the hydrolytic action of the pancreatic and intestinal lipases. The fatty acids, whether ingested with food or arising as split products of fat hydrolysis, combine in the intestine with bile salts and cations, forming soluble soaps with sodium and potassium and insoluble soaps with calcium and magnesium. Bile is important for the emulsification of ingested water-insoluble or less-soluble fats in the digestion mixture.
Insoluble soaps, the monoglycerides, are “ferried” through the lumen to the cellular barrier with complexes of colipase and bile acids. The soluble alkali soaps aid in the emulsification of fat and the stabilization of emulsified lipids by the same principle that makes soap useful in the household for cleansing and detergent effects.
Much of ingested cholesterol is not esterified in the lumen, although some hydrolysis occurs through the action of cholesterol esterase. Instead, cholesterol can be taken up intact through specific facilitated transport. Other lipids, such as vitamin A (and its provitamin, carotene), vitamins E and K, and other steroids, including vitamin D, are not broken down within the intestine.
The absorption of nearly all nutrients is achieved by the small intestinal cells of the duodenal, jejunal, and ileal epithelia. The small, but important, amount of nutrient absorption and the significant amount of water and electrolyte absorption that take place in the colon are described at the end of this section. Selective absorption also occurs across the oral and gastric epithelia. The epithelial lining of the small intestine is preeminently and specifically equipped for its function by its length and its large surface area. The surface area of the intestinal tube is increased by the presence of luminal folds, villi, and, most importantly, microvilli. Small intestinal folds are arrayed in a special circular design perpendicular to the axis of the lumen which enhances the turbulent flow of the luminal contents, known as the plicae circulares. Villi further increase the surface area 15- to 30-fold, and microvilli increase the surface area an additional 20- to 40-fold.
Ions are transported across the epithelium by ion channels and ion exchangers and by cotransporters that facilitate diffusion, osmosis, and solvent drag. Other complex molecular transport mechanisms involve specific receptor-mediated transport proteins and other active transport mechanisms. The presence of transport proteins on the apical surface and the tight junctions between cells permit movement of fluid as the epithelium actively transports substances against a concentration gradient. Ion-specific channel proteins permit the movement of hydrophilic ions through the hydrophobic bilayer of the cell membrane along concentration gradients (facilitated diffusion). These ion channels are also “gated”, so that they permit transport only for a brief period in which the channel is open; then the gate closes.
Water crosses the intestinal wall in both directions, depending on hydraulic and osmotic forces based on the osmolality of luminal contents and the location within the small intestine. This occurs across the cell membrane and between cells in the paracellular channels that are exquisitely regulated by tight junctions and their regulatory and contractile proteins. Aquaporin water channels are less common in the gut than in the renal tubules. If the aqueous phase of the intestinal contents is hypotonic, water moves from the lumen through the cells and between the cells through para-cellular spaces into the blood. Alternatively, if the luminal content is hypertonic, water will be transferred from the blood into the lumen. As solutes enter the wall, an obligatory transport of water from the lumen occurs to keep the solution within the tube isosmotic.
Most minerals, such as the salts composed of sodium, potassium, and chloride ions, move with the water across channels, but, in addition, specific ion pumps, exchangers, and cotransport mechanisms exist to bring needed ions into the epithelial cells and then into the circulation, often against a steep concentration gradient. Active transport by ion pumps requires energy expenditure through the hydrolysis of adenosine triphosphate. Carrier proteins can couple electrolyte transport with specific nutrients, including glucose and amino acids. For example, the cotransport of each molecule of glucose brings two molecules of sodium into the epithelial cell. Chloride is transported into the lumen by means of the chloride channel on the apical cell membrane, primarily the cystic fibrosis transmembrane conductance regulator. It is absorbed across tight junctions and via exchange proteins with bicarbonate.
Calcium must be solubilized before it can be absorbed through acidification in the stomach or at the brush-border surface by the action of the Na+-H+ exchanger. Absorption through channels or by carriers is tightly regulated through vitamin D–mediated processes. Once in the lumen, it is bound by a calcium-binding protein, calbindin-D9k.
Like calcium, magnesium is absorbed by both passive and active processes, primarily in the duodenum and upper jejunum. Magnesium absorption is much less efficient than is calcium absorption; this accounts for the efficacy of its salts to function as osmotic laxatives.
A man absorbs 1 mg of iron daily; 2 mg of iron daily is absorbed by menstruating females, again primarily through the duodenum. Ferric iron must be solubilized to ferrous iron to be absorbed. This occurs through the effect of gastric acid, ascorbic acid, or brush-border reductases. The divalent brush-border transporter transports this essential nutrient into the cell, where it is oxidized by heme-oxidase before being transported out of the cell. Its absorption is tightly regulated by the hepatic synthesis of the peptide hepcidin, based on the needs of the body.
The concentration of bile in the intestine diminishes as the chyme enters the distal intestine. Effective active transport of bile acids by the distal ileum is necessary to maintain healthy concentrations of these complex molecules. Malabsorption will lead to bile salt diarrhea.
The products of protein digestion formed by the combination of gastric, pancreatic, and brush-border peptidases result in dipeptides or tripeptides and amino acids that can diffuse to the cell membrane surface. There they are brought into the cell by more than a dozen specific sodium-coupled transport mechanisms. The rate of absorption for various amino acids is different, and quantitatively most may be absorbed as dipeptides and tripeptides. Once in the enterocyte, all are degraded further to isolated amino acids. Although some amino acids entering the cells are synthesized within them, most are transported by the basolateral membrane directly into the circulation. Under special circumstances, intact protein molecules may be absorbed through specialized channels and the process of pinocytosis associated with M cells as part of the gut immune regulatory system.
Carbohydrates are absorbed almost exclusively in the form of monosaccharides, that is, as hexoses (glucose, fructose, and galactose) or pentoses (ribose and deoxy- ribose). Monosaccharides are absorbed via specific sodium-coupled cotransport proteins that recognize only the D isomer of the molecule. Galactose is more rapidly absorbed than is glucose. Fructose is absorbed via facilitated transport down a concentration gradient via its own specific transport protein, GLUT5. Within fairly wide limits, the rate of hexose transfer is independent of the intraluminal concentration. The presence of enzymes (hexokinases) catalyzing the conversion of hexoses to hexose phosphates in the intestinal mucosa and the reduction of glucose and galactose absorption can occur when the hexokinases are inhibited by phlorizin. The picture of the absorption of pentoses is still less clear. The transfer of xylose, used now as an indicator of the efficiency of intestinal absorption, may involve diffusion or phosphorylation, or both.
Lipolysis hydrolyzes fats to diglycerides, then monoglycerides, and then completely hydrolyzed fat components, glycerol, and fatty acids that enter the cell through a specific transport mechanism, including fatty acid translocase CD36. Once absorbed, the split products are transported in the cell by fatty acid–binding proteins to the endoplasmic reticulum, where they are resynthesized back to triglycerides. Other lipids are added, including apolipoproteins, in the Golgi apparatus, and the product is packaged into secretory granules. These leave the cell by exocytosis as chylomicrons, moving into the lymphatics to the rest of the body. Some lipids exit the cell in very low density lipoproteins. Other lipids and some phospholipids may be further degraded, leave the cell, and enter the portal system. Similarly, cholesterol is transported into the cell by specific transport proteins located on the apical brush borders. It is processed within the cell and exits in chylomicrons or very low density lipoproteins.
The absorption of other lipids, cholesterol, phosphatides, and fat-soluble vitamins is intimately related to the mechanisms of fat absorption. Although some cholesterol may be esterified in the lumen, most is transported into the cell through receptor-mediated trans- port. Free cholesterol and the cholesterol esters leave the intestinal cells by way of the lymph stream. The absorption of the hydrolytic products of phospholipid digestion (see above) follows the line indicated for fat absorption.
Vitamin A is a water-insoluble lipid derived from dietary carotenoid. The vitamin is actually made up of a family of biologically active retinoids. These retinoids are esterified to long-chain fatty acids that are hydrolyzed by pancreatic enzymes. Absorption occurs via passive, noncarrier-mediated transport into the cell, where the vitamin is further oxidized and eventually bound to retinol-binding protein for distribution to the rest of the body. Active vitamin D is the result of a complex series of steps, including actions in the kidney, liver, and skin. Although the skin can synthesize vitamin D under adequate exposure to sunlight, in more northern climates, absorption of the inactive unesterified sterol precursors vitamin D3 (cholecalciferol) and D2 (ergocalciferol) is important for their nutrient value. After absorption by the enterocyte, they are exported in chylomicrons to the circulation, where they become bound to transport proteins. In the liver, they are metabolized to 25-hydroxyvitamin D and then to 1,25-dihdroxy vitamin D3 by the kidney.
The mechanisms involved in the absorption of the water-soluble vitamins (thiamine, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, ascorbic acid, and cyanocobalamin [vitamin B12]) involve vitamin-specific, complex, receptor-mediated mechanisms after partial intraluminal metabolism. As discussed elsewhere, vitamin B12 is absorbed by complex interactions of two binding proteins. The salivary glands secrete a pH-dependent binding protein (R protein) known as haptocorrin that protects the vitamin from intragastric digestion. Once the complex reaches the duodenum, proteolysis releases haptocorrin, permitting the intrinsic factor secreted by the gastric parietal cells to bind B12 and facilitate its protection until absorbed in the distal ileum. The intrinsic factor–vitamin B12 complex is bound to the cubam receptor on ileal epithelium. There the complex is actively absorbed by endocytosis into the ileum.
Unlike other important nutrients and vitamins, vitamin K is primarily derived from synthetic actions of the microbiota and is absorbed by the colonic epithelium. Although malabsorption of most fat-soluble vitamins is due to a deficiency of pancreatic enzymes or bile salts, vitamin K deficiency more commonly results from inadequate nutrition and the deleterious effects of antibiotics on the microbiota.
As mentioned, the role of the colon in absorbing nutrients to be used by the rest of the body is negligible. Colonic epithelial cells, however, are able to absorb short-chain fatty acids that are a major source of energy for the epithelial cells. Effective absorption of fluid and electrolytes by the colon is important and serves to limit the loss of fluid in the stool by nearly a liter under normal circumstances and by more when small intestinal fluid delivery to the colon increases during disease states. It also limits the volume of fluid loss and the inconvenience of frequent defecations.