The gastrointestinal tract absorbs vast quantities of fluid and electrolytes. Together, the small and large intestines absorb approximately 9 L of fluid daily, an amount almost equal to the entire extracellular fluid volume! What is the source of this large volume of fluid that is absorbed?
Figure 8-33 shows that there is slightly more than 9 L of fluid in the lumen of the gastrointestinal tract, which is the sum of the volume of liquid in the diet (2 L) plus the combined volume of salivary, gastric, pancreatic, biliary, and intestinal secretions (7 L). Of this 9 L, most is absorbed by the epithelial cells of the small intestine and colon. The small remaining volume that is not absorbed (100 to 200 mL) is excreted in feces. Clearly, a disturbance in the absorptive mechanisms can lead to excessive fluid loss from the gastrointestinal tract (diarrhea). The potential for loss of total body water and electrolytes in diarrhea is enormous.
Figure 8–33 Comparison of volume of fluid ingested and secreted with that absorbed by the intestine. The hatched area shows the small amount of fluid excreted in feces.
The small intestine and colon not only absorb large quantities of electrolytes (Na+, Cl−, HCO3−, and K+) and water, but the epithelial cells lining the crypts of the small intestine also secrete fluid and electrolytes. This additional secretion contributes to the volume already in the intestinal lumen, which then must be absorbed.
The mechanisms for fluid and electrolyte absorption and secretion in the intestine involve cellular and paracellular routes. The permeability of tight junctions between the epithelial cells determines whether fluid and electrolytes will move via the paracellular route or whether they will move via the cellular route. The tight junctions in the small intestine are “leaky” (have low resistance) and permit significant paracellular movement, whereas the tight junctions in the colon are “tight” (have a high resistance) and do not permit paracellular movement.
Intestinal epithelial cells lining the villi absorb large volumes of fluid. The first step in this process is the absorption of solute, followed by the absorption of water. The absorbate (the fluid absorbed) is alwaysisosmotic, meaning that solute and water absorption occur in proportion to each other. The mechanism of this isosmotic absorption is similar to that in the renal proximal tubule. The solute absorptive mechanisms vary among the jejunum, the ileum, and the colon.
The jejunum is the major site for Na+ absorption in the small intestine (Fig. 8-34). The mechanisms for electrolyte transport in the jejunum are identical to those in the early proximal tubule of the kidney and are shown in Figure 8-34A. Na+ enters the epithelial cells of the jejunum via several different Na+-dependent coupled transporters. The apical membrane contains Na+-monosaccharide cotransporters (Na+-glucose and Na+-galactose), Na+-amino acid cotransporters, and Na+-H+ exchange. After Na+ enters the cell on the coupled transporters, it is extruded across the basolateral membrane via the Na+-K+ ATPase. Note that the source of H+ for Na+-H+ exchange is intracellular CO2and H2O, which are converted to H+ and HCO3− in the presence of carbonic anhydrase. The H+ is secreted into the lumen on the Na+-H+exchanger, and the HCO3− is absorbed into blood.
Figure 8–34 Mechanisms of electrolyte transport in the jejunum (A) and in the ileum (B). ATP, Adenosine triphosphate.
The ileum contains the same transport mechanisms as the jejunum plus a Cl−-HCO3− exchange mechanism in the apical membrane and a Cl− transporter, instead of an HCO3− transporter, in the basolateral membrane (see Fig. 8-34B). Thus, when H+ and HCO3− are generated inside the epithelial cells in the ileum, the H+ is secreted into the lumen via the Na+-H+ exchanger, and the HCO3−also is secreted into the lumen via the Cl−-HCO3− exchanger (rather than being absorbed into blood, as in the jejunum). The result of the combined Na+-H+ exchange and Cl−-HCO3− exchange in the apical membrane is net movement of NaCl into the cell, which then is absorbed. Thus, in the ileum, there is net absorption of NaCl, whereas in the jejunum there is net absorption of NaHCO3.
The cellular mechanisms in the colon are similar to those in the principal cells of the late distal tubule and collecting ducts of the kidney (Fig. 8-35). The apical membrane contains Na+ and K+ channels, which are responsible for Na+absorption and K+ secretion. Like the renal principal cells, synthesis of the Na+ channels is induced by aldosterone, which leads to increases in Na+ absorption and, secondarily, to increases in K+ secretion.
Figure 8–35 Mechanism of electrolyte transport in the colon. ATP, Adenosine triphosphate.
The mechanism by which aldosterone increases K+ secretion in the colon is similar to that in the renal principal cells: increased number of Na+ channels, increased Na+ entry across the apical membrane, increased Na+ pumped out across the basolateral membrane by the Na+-K+ ATPase, increased K+ pumped into the cell, and, finally, increased K+ secretion across the apical membrane. Even the flow-rate dependence of K+ secretion seen in the renal principal cells is present in the colon; for example, in diarrhea, the high flow rate of intestinal fluid causes increased colonic K+ secretion, resulting in increased K+ loss in feces and hypokalemia.
The epithelial cells lining the intestinal crypts secrete fluid and electrolytes (compared with the cells lining the villi, which absorb fluid and electrolytes). The mechanism of electrolyte secretion in the crypt cells is shown in Figure 8-36. The apical membrane contains Cl− channels. In addition to having the Na+-K+ ATPase, the basolateral membrane also has an Na+-K+-2Cl− cotransporter similar to that found in the thick ascending limb of the loop of Henle. This three-ion cotransporter brings Na+, Cl−, and K+ into the cells from the blood. Cl− moves into the cells on the Na+-K+-2Cl− cotransporter, and then diffuses into the lumen through Cl− channels in the apical membrane. Na+ follows Cl−secretion passively, moving between the cells. Finally, water is secreted into the lumen, following the secretion of NaCl.
Figure 8–36 Mechanism of Cl− and fluid secretion by epithelial cells in intestinal crypts. The circled numbers correspond to steps described in the text. Cholera toxin activates adenylyl cyclase (AC), increasing cyclic adenosine monophosphate (cAMP) production and opening Cl− channels in the apical membrane. ATP, Adenosine triphosphate; R, receptor; VIP, vasoactive intestinal peptide.
The Cl− channels of the apical membrane usually are closed, but they may open in response to binding of various hormones and neurotransmitters to receptors on the basolateral membrane. These activating substances include, but are not limited to, ACh and VIP. The neurotransmitter or hormone binds to the basolateral receptor, activating adenylyl cyclase and generating cAMP in the crypt cells. cAMP opens the Cl− channels in the apical membrane, initiating Cl− secretion; Na+ and water follow Cl− into the lumen. Normally, the electrolytes and water secreted by intestinal crypt cells are absorbed by intestinal villar cells. However, in diseases in which adenylyl cyclase is maximally stimulated (e.g., cholera), fluid secretion by the crypt cells overwhelms the absorptive capacity of the villar cells and causes severe, life-threatening diarrhea (see later, Secretory Diarrhea).
Diarrhea, which means “to run through,” is a major cause of death worldwide. Serious illness or death may be caused by the rapid loss of large volumes of extracellular-type fluid from the gastrointestinal tract. The previous discussion emphasizes the enormous potential for fluid loss from the gastrointestinal tract, as much as 9 L or more per day.
In diarrhea, the loss of extracellular-type fluid results in decreased extracellular fluid volume, decreased intravascular volume, and decreased arterial pressure. The baroreceptor mechanisms and the renin–angiotensin II–aldosterone system will attempt to restore blood pressure, but these attempts will be futile if the volume of fluid lost from the gastrointestinal tract is too great or if the loss is too rapid.
In addition to circulatory collapse, other disturbances caused by diarrhea are related to the specific electrolytes lost from the body in the diarrheal fluid, particularly HCO3− and K+. Diarrheal fluid has a relatively high concentration of HCO3− because the fluids secreted into the gastrointestinal tract have a high HCO3− content including salivary, pancreatic, and intestinal juices. Loss of HCO3− (relative to Cl−) causes hyperchloremic metabolic acidosis with normal anion gap (see Chapter 7). Diarrheal fluid also has a high concentration of K+ because of flow-rate–dependent K+ secretion by the colon. Excessive loss of K+ from the gastrointestinal tract results in hypokalemia.
The causes of diarrhea include decreased absorptive surface area, osmotic diarrhea, and secretory diarrhea.
Decreased Surface Area for Absorption
Disease processes that result in a decreased absorptive surface area including infection and inflammation of the small intestine cause decreased absorption of fluid by the gastrointestinal tract (see Fig. 8-33).
Osmotic diarrhea is caused by the presence of nonabsorbable solutes in the lumen of the intestine. For example, in lactase deficiency, lactose is not digested to glucose and galactose, the absorbable forms of this carbohydrate. Undigested lactose is not absorbed and remains in the lumen of the intestine, where it retains water and causes osmotic diarrhea. Bacteria in the intestine may degrade lactose to more osmotically active solute particles, further compounding the problem.
In contrast to other forms of diarrhea, which are caused by inadequate absorption of fluid from the intestine, secretory diarrhea (e.g., cholera) is caused by excessive secretion of fluid by crypt cells. The major cause of secretory diarrhea is overgrowth of enteropathic bacteria (pathogenic bacteria of the intestine) such as Vibrio cholerae or Escherichia coli. For example, the bacterial toxin cholera toxin (see Fig. 8-36) enters intestinal crypt cells by crossing the apical membrane (Step 1). Inside the cells, the A subunit of the toxin detaches and moves across the cell to the basolateral membrane. There, it catalyzesadenosine diphosphate (ADP) ribosylation of the αs subunit of the Gsprotein that is coupled to adenylyl cyclase (Step 2). ADP-ribosylation of the αs subunit inhibits its GTPase activity, and as a result, GTP cannot be converted back to GDP. With GTP permanently bound to the αs subunit, adenylyl cyclase is permanently activated (Step 3), cAMP levels remain high, and the Cl− channels in the apical membrane are kept open (Step 4). The resulting Cl− secretion is accompanied by secretion of Na+ and H2O. The volume of fluid secreted into the intestinal lumen overwhelms the absorptive mechanisms of the small intestine and colon, leading to massive diarrhea.