Digestion and Absorption Are Separate, but Related, Processes

Digestion is the process of breaking down complex nutrients into simple molecules. In contrast, absorption is the process of transporting those simple molecules across the intestinal epithelium (Figure 30-1). The two processes are the result of different biochemical events occurring within the gut. Both processes are necessary for the assimilation of nutrients into the body; absorption cannot occur if food is not digested, and the process of digestion is fruitless if the digested nutrients cannot be absorbed.

Disturbances of nutrient assimilation are common in veterinary medicine and may be caused by a variety of diseases, with some affecting digestion and others affecting absorption. The overt signs of failure of nutrient assimilation are often similar, but the biochemical lesions and specific therapies associated with maldigestive disease can be quite different from those associated with malabsorptive disease. Therefore, diagnosing the cause of failure of nutrient assimilation is a frequent challenge faced by veterinary clinicians, a challenge that requires a thorough understanding of the physiology of nutrient digestion and absorption. This chapter first reviews the structural characteristics of the small-intestinal epithelium that are of particular importance to the digestive and absorptive processes.

The Small-Intestinal Mucosa Has a Large Surface Area and Epithelial Cells with “Leaky” Junctions Between Them

Contact between the small-intestinal mucosa and the luminal contents is facilitated by an extensive intestinal surface area. Three levels of surface convolutions serve to expand the surface area of the small intestine (see Figure 27-2). First, large folds of mucosa known as plicae circulares add to the intestinal surface area of some animals, but these are not present in all species. Second, the mucosal surface is covered with fingerlike epithelial projections known as villi. These structures are present in all species and increase the intestinal surface area by tenfold to fourteenfold compared with a flat surface of equal size. Third, the villi themselves are covered with a brushlike surface membrane known as the brush border. The brush border is composed of submicroscopic microvilli that further enlarge the surface area (Figure 30-2). At the base of the villi are glandlike structures known as crypts of Lieberkühn (Figure 30-3). The villi and crypts are covered with a continuous layer of cellular epithelium.

The epithelial cells covering the villi and crypts are called enterocytes. Each enterocyte has two distinct types of cell membranes (Figure 30-4). The cell surface facing the lumen is called the apex and is covered by the apical membrane. The apical membrane contains the microvilli. Under the light microscope, the microvilli give the cell surface its brushlike appearance. This appearance has led to the term brush border, which is synonymous with apical membrane. Attached to the apical membrane are many glycoproteins. These specialized proteins are synthesized within the enterocytes and transferred to the apical membrane. They are the enzymes and transport molecules responsible for the digestive and absorptive functions of the intestinal epithelium. Under the intense magnification of the electron microscope these proteins, which extend into the intestinal lumen, give the microvilli a fuzzy appearance (see Figure 30-2). This rich area of glycoproteins on the surface of the apical membranes is given the name glycocalyx. The apical membrane is a complex cellular membrane with an unusually high protein content.

The remaining portion of the enterocyte plasma membrane, that part not facing the gut lumen, is called the basolateral membrane, referring to the base and sides of the cell. This membrane is not especially unusual and indeed has many similarities to cell membranes of other tissues. Although the basolateral membrane is not in direct contact with ingesta in the gut lumen, it serves an important role in intestinal absorption; nutrients that are absorbed into the enterocytes through the apical membrane must exit the cell through the basolateral membrane before gaining access to the bloodstream.

The attachments between adjacent enterocytes are called tight junctions. These connections serve a special function in the process of digestion and absorption. The tight junctions form a narrow band of attachment between adjacent enterocytes. The band is near the apical end of the cells and divides the apical membrane from the basolateral membrane. The junctions may be called “tight,” but from a molecular standpoint, they are rather loose. This is especially true in the duodenum and jejunum, where the tight junctions are loose enough to allow the free passage of water and small electrolytes. Recent evidence indicates that the relative impermeability, or “tightness,” of the tight junctions is not constant and can be altered by neurohumoral regulatory substances in the gut. These selective changes in permeability can affect the rates of water and ion movement across the gastrointestinal (GI) epithelium, depending on the physiological needs for secretion or absorption. However, the tight junctions are never permeable enough to permit the passage of organic molecules.

The narrow band of tight junctions leaves the majority of the basolateral membrane unattached to its neighboring membrane on the adjacent enterocyte. This arrangement creates a potential space between enterocytes. This area between the lateral surfaces of the enterocytes is called the lateral space. The lateral spaces are normally distended and filled with extracellular fluid (ECF). At the end of the lateral spaces nearest the apical membrane, the ECF is separated from the fluid of the intestinal lumen only by the tight junctions. At the opposite end of the lateral spaces, the ECF is separated from the blood only by the basement membrane of the intestinal capillaries. Both the tight junctions and the capillary endothelium are permeable barriers that allow the free passage of water and small molecules. Thus, there is relatively free flow of water and most electrolytes among the fluid in the lumen of the intestine, the ECF in the lateral spaces, and the blood.

The Intestinal Surface Microenvironment Consists of Glycocalyx, Mucus, and an Unstirred Water Layer

Liberally interspersed among the enterocytes are goblet cells, which secrete a rich layer of mucus that covers the mucosa. At the brush border surface, the mucus blends into the glycocalyx, with the two layers forming a viscous coating that tends to trap molecules near the apical membrane. In addition to the mucus and glycocalyx layers, there is an area near the intestinal surface known as the unstirred water layer. With respect to the unstirred water layer, the intestine can be likened to a large stream or river; that is, the water in the center flows relatively rapidly, whereas the water near the edge or bank is quiet and flows slowly. Because of the same fluid-friction phenomenon that causes the water on the banks of rivers to be less turbulent and to flow at a slower rate than water in center stream, the water very near the intestinal surface is quiet and flows at a much slower rate than water in the central part of the lumen. The unstirred water layer, mucus, and glycocalyx form an important diffusion barrier through which nutrients must pass before entering the enterocytes.

Chemical Digestion Results in the Reduction of Complex Nutrients into Simpler Molecules

Chemical digestion of each major nutrient is accomplished by the process of hydrolysis, the splitting of a chemical bond by the insertion of a water molecule. Glycosidic linkages in carbohydrates, peptide bonds in proteins, ester bonds in fats, and phosphodiester bonds in nucleic acids are all cleaved by hydrolysis during digestion. Figure 30-5 illustrates hydrolytic splitting of these various chemical bonds.

Hydrolysis in the digestive tract is catalyzed by the action of enzymes. There are two general classes of digestive enzymes: those that act within the lumen of the gut, and those that act at the membrane surface of the epithelium. Enzymes acting within the lumen originate from the major GI glands, including the salivary gland, gastric glands, and especially the pancreas. The secretions of these glands become thoroughly mixed with ingesta and exert their actions throughout the lumen of their associated gut segments; thus the actions they catalyze are referred to as the luminal phase of digestion. In general, luminal-phase digestion results in the incomplete hydrolysis of nutrients, resulting in the formation of short-chain polymers from the original macromolecules (Figure 30-6).

The hydrolytic process is completed by enzymes that are chemically bound to the surface epithelium of the small intestine. These enzymes break the short-chain polymers resulting from luminal-phase digestion into monomers that can be absorbed across the epithelium. This final phase, which occurs at the epithelial membrane surface, is referred to as the membranous phase of digestion. Membranous-phase digestion is followed closely by absorption.

Luminal-Phase Carbohydrate Digestion Results in the Production of Short-Chain Polysaccharides

Carbohydrates are nutrients containing carbon, hydrogen, and oxygen atoms arranged as long chains of repeating simple-sugar molecules. Dietary carbohydrates originate primarily from plants. There are three general types of plant carbohydrates: fibers, sugars, and starches. Fibers, the structural parts of plants, form an important energy source for herbivorous animals; however, plant fibers are not subject to hydrolytic digestion by mammalian enzymes and therefore cannot be digested directly by animals (see Chapter 31).

Sugars are energy-transport molecules in plants. Sugars, or saccharides, may be simple (made up of a single molecular unit, monosaccharides) or complex (made up of two or more repeating saccharide subunits, polysaccharides). Glucose, galactose, and fructose are the most important simple sugars in animal diets. These monosaccharides are present, preformed in small quantities, in normal diets; however, most monosaccharides absorbed from the gut arise from the enzymatic hydrolysis of more complex carbohydrates. Complex sugars are referred to as disaccharides, trisaccharides, and oligosaccharides, depending on the number of repeating simple-sugar subunits. Oligosaccharides contain several monomer units, usually between 3 and 10. Important complex sugars in animal diets are lactose, or milk sugar, and sucrose, or table sugar. Lactose is a disaccharide composed of glucose and galactose, whereas sucrose is a disaccharide composed of glucose and fructose. Other important complex sugars are maltose, isomaltose, and maltotriose; these three sugars are composed of two or three repeating glucose units (Figure 30-7). They are seldom present preformed in the diet but rather are formed in the gut as intermediate products of starch digestion.

Starch is an energy-storage carbohydrate of plants that forms the major energy-yielding nutrient in the diets of many omnivorous animals, such as pigs, rats, and primates. There are two chemical forms of starch, amylose and amylopectin. Both are long-chain glucose polymers, but amylose is a straight-chain molecule containing glucose monomers linked by α[1-4] glycosidic linkages. Amylopectin also contains glucose chains joined by α[1-4] glycosidic linkages, but the amylopectin chains are branched, having an α[1-6] linkage at each branch point (see Figure 30-7). Although the chemical structure of starch is limited to these two molecular types, the physical structure and encapsulation of starches vary among plant sources. This variation results in the unique characteristics of starches from different sources, such as wheat, corn, and barley.

Luminal-Phase Digestion of Carbohydrates Applies Only to Starches, Because Sugars Are Digested in the Membranous Phase

The enzyme involved in luminal starch digestion is α-amylase, which is actually a mixture of several similar molecules. This enzyme arises from the pancreas in all species, as well as from the salivary glands of some species (see Chapter 29). The α[1-4] linkages of either amylose or amylopectin are attacked by α-amylase. Characteristic of luminal-phase digestion, α-amylase does not break off, or cleave, single glucose units from the ends of the chain. Rather, the starch chains are broken in their midsections, resulting in the production of polysaccharides of intermediate chain length, known as dextrins. These chains continue to be attacked until disaccharide (maltose) and trisaccharide (maltotriose) units are formed.

This digestive process proceeds for amylopectin in the same way as it does for amylose, except that the α[1-6] linkages at the chain branch points of amylopectin are not hydrolyzed. Because these branch points are not hydrolyzed, branch-chain oligosaccharides, known as limit dextrins, as well as an α[1-6]-linked disaccharide, known as isomaltose, are formed (see Figure 30-7). The end result of luminal-phase carbohydrate digestion is the creation of many disaccharides, trisaccharides, and oligosaccharides from large starch molecules. These complex sugars are not hydrolyzed further in the luminal phase.

Proteins Are Digested by a Variety of Luminal-Phase Enzymes

Proteins are a source of amino acids, which are essential components of all animal diets. Dietary proteins come from both plant and animal sources. The general pattern of protein digestion is similar to that of carbohydrate digestion, in that large molecular proteins are broken down into small peptide chains by luminal digestion. Subsequent digestion of the peptide chains to individual amino acids occurs to a large extent by membranous-phase digestion, although unlike in carbohydrate digestion, a portion of free monomers, that is, amino acids, is released in the luminal phase.

A major difference between protein digestion and carbohydrate digestion is in the number of different enzyme types involved. The relatively larger number of enzymes involved in protein digestion is expected, considering that starch molecules are made up of only one type of monomer, glucose, and protein molecules are made up of a variety of amino acids. Therefore, only bonds between glucose molecules need to be broken in the case of starch. On the other hand, proteins are made up of infinite combinations of up to 20 individual types of amino acids; the various proteolytic enzymes are necessary for digestion because they differ in their efficiency in cleaving peptide bonds between specific types of amino acids.

The major luminal-phase proteolytic enzymes are listed in Table 30-1. Most proteolytic enzymes are endopeptidases, meaning that they break proteins at internal points along the amino acid chains, resulting in the production of short-chain peptides from complex proteins. Endopeptidases produce essentially no free amino acids. Two exopeptidases, which release individual amino acids from ends of peptide chains, are secreted also from the pancreas and are active in luminal-phase digestion.

The proteolytic enzymes are secreted from the stomach glands or pancreas in the form of inactive zymogens (see Chapter 29), which are activated in the stomach or intestinal lumen, respectively. These enzymes must be secreted in an inactive form; otherwise, the active enzymes would digest the cells in which they are synthesized. Activation of the zymogens occurs in the gut lumen. The proteolytic zymogens of the stomach, pepsinogen and chymosinogen, are activated by hydrochloric acid (HCl) in the stomach lumen. Pepsinogen is also activated by pepsin in an autocatalytic feedback loop. Trypsinogen from the pancreas is activated by enterokinase, an enzyme elaborated by duodenal mucosal cells. The active enzyme, trypsin, then serves as an autocatalytic agent to activate additional trypsinogen as well as the other pancreatic protein-digesting enzymes. Figure 30-8 illustrates the cascade of intraluminal zymogen activation.

Luminal-phase protein digestion begins in the stomach. Gastric digestion of protein is facilitated not only by the stomach enzymes but also by HCl, which has hydrolytic properties of its own. The acid environment of the stomach is suited to the action of pepsin, which has its optimal activity at pH 1 to 3. Gastric hydrolysis of protein is probably important to the physical as well as the chemical digestion of protein, because most connective tissue of animal origin is protein; digestion of connective tissue aids in breaking food down into particles small enough to pass the pylorus. Although stomach action is important in initiating protein digestion, it is not essential; animals without stomachs can digest proteins, provided they have a functional pancreas and are fed small, frequent meals of soft, moist food. Luminal-phase digestion of proteins is completed in the small intestine by the action of pancreatic enzymes.

Membranous-Phase Digestive Enzymes Are a Structural Part of the Intestinal Surface Membrane

Membranous-phase digestion, as with its luminal counterpart, occurs because of the hydrolytic action of enzymes. The difference between the two phases is that membranous-phase enzymes are chemically bound to the surface membrane of the intestine. They constitute a large and important portion of the glycocalyx. The substrates for these enzymes must diffuse into the glycocalyx before hydrolysis can occur. These membrane-bound digestive enzymes are synthesized within the enterocytes and subsequently transported to the luminal surface of the apical membrane. They remain attached to the surface by a short anchor segment, whereas the large, catalytic portion of the enzyme molecule projects away from the surface, toward the gut lumen.

Membranous-Phase Digestion Occurs Within the Microenvironment of the Unstirred Water Layer, Intestinal Mucus, and Glycocalyx

As previously described, the unstirred water layer, mucus, and glycocalyx form a diffuse zone separating the mucosal surface from the lumen of the intestine. The membranous-phase digestive enzymes project from the apical membrane into this surface layer. The quiet surface layer forms a microenvironment in which membranous-phase digestion occurs. Peptides and polysaccharides in the intestinal lumen must diffuse into the surface layer before membranous-phase digestion can take place. Furthermore, most of the products of membranous-phase digestion never diffuse away from the surface environment back into the lumen of the intestine; instead, they are absorbed, soon after formation, into the underlying epithelial cells. This arrangement is efficient because it ensures that the final products of carbohydrate and protein digestion are formed near their site of absorption, avoiding the need for long diffusion distances (Figure 30-9).

A Specific Membranous-Phase Enzyme Exists for the Digestion of Each Type of Polysaccharide

The membranous-phase enzymes of carbohydrate digestion have as their substrates dietary complex carbohydrates, such as sucrose and lactose, as well as the polysaccharide products of luminal-phase starch digestion, including maltose and isomaltose. The specific membranous-phase enzymes are named according to their substrates and include maltase, isomaltase, sucrase, and lactase. The sole product of maltose and isomaltose digestion is glucose, whereas in addition to glucose, fructose and galactose are produced from the digestion of sucrose and lactose, respectively. All polysaccharides are digested to monosaccharides before absorption (Figure 30-10).

Complete Digestion of Peptides to Free Amino Acids Takes Place Both on the Enterocyte Surface and Within the Cells

Membranous-phase digestion of peptides is, in some respects, similar to that of carbohydrates; peptide-digesting enzymes, or peptidases, are present on the enterocyte surface membrane and extend into the glycocalyx. These enzymes hydrolyze the peptide products of luminal-phase protein digestion, yielding free amino acids. Some of the longer-chain peptides are incompletely digested, yielding dipeptides and tripeptides. A large portion of dietary amino acids is absorbed directly in the form of dipeptides and tripeptides. This mode of absorption contrasts with that of carbohydrates, in which only monomeric, simple sugars may pass the apical membrane. Dipeptides and tripeptides that are absorbed intact are subsequently hydrolyzed by the action of intracellular peptidases, which results in the formation of free amino acids that are then available for passage into the blood. Thus the final digestion of peptides to free amino acids may occur at either of two sites: on the surface membrane of the enterocyte or within the cell. In either case, the final product of protein digestion is free amino acid (Figure 30-11).

Specialized Nutrient Transport Systems Exist in the Apical and Basolateral Membranes

Specialized transport mechanisms exist for the movement of molecules across membranes in the intestinal epithelium. These mechanisms are interactions of events involving specific proteins that lie embedded in the matrix of the cell membranes of the epithelial cells. These proteins provide the transport pathway for the passage of ions and organic molecules across the plasma membranes of cells. As discussed here, there are many transport pathways. In general, the different pathways are polarized within the enterocytes, meaning that specific transport pathways exist on either the apical or the basolateral membrane, but not both. The transport pathway proteins chemically interact with specific organic nutrients and inorganic ions to affect their transport across the membrane. The transport mechanisms can be classified as active transport, secondary active transport, tertiary active transport, and passive transport.

Active transport involves the direct consumption of metabolic energy. During active transport, energy stored as ATP is expended to move ions or molecules across membranes against an electrical or chemical gradient. In the large and small intestine, the active transport pathway of greatest importance is the Na⁺,K⁺-ATPase pump. This protein pathway lies on the basolateral membrane and uses energy from the hydrolysis of one molecule of ATP to drive three ions of sodium out of the cell, in exchange for the entry of two potassium ions into the cell. This important transport pathway exists in a wide variety of cells, in addition to enterocytes. The Na⁺,K⁺-ATPase pump is the mechanism by which (1) the interior of cells is kept electrically negative with respect to the extracellular fluid and (2) the concentration of sodium is kept very low in the intracellular fluid (see Chapter 1).