Medical Physiology, 3rd Edition

Regulation of Intestinal Ion Transport

Chemical mediators from the enteric nervous system, endocrine cells, and immune cells in the lamina propria may be either secretagogues or absorptagogues

Numerous chemical mediators from several different sources regulate intestinal electrolyte transport. Some of these agonists are important both in health and in diarrheal disorders, and at times only quantitative differences separate normal regulatory control from the pathophysiology of diarrhea. These mediators may function in one or more modes: neural, endocrine, paracrine, and perhaps autocrine (see p. 47). Most of these agonists (i.e., secretagogues) promote secretion, whereas some others (i.e., absorptagogues) enhance absorption.

The enteric nervous system (ENS), discussed on pages 339–340 and 855–856, is important in the normal regulation of intestinal epithelial electrolyte transport. Activation of enteric secretomotor neurons results in the release of acetylcholine from mucosal neurons and in the induction of active Cl⁻ secretion (see Fig. 44-5). Additional neurotransmitters, including VIP, 5-HT, and histamine, mediate ENS regulation of epithelial ion transport.

An example of regulation mediated by the endocrine system is the release of aldosterone from the adrenal cortex and the subsequent formation of angiotensin II; both dehydration and volume contraction stimulate this renin-angiotensin-aldosterone axis (see pp. 841–842). Both angiotensin and aldosterone regulate total-body Na⁺ homeostasis by stimulating Na⁺ absorption, angiotensin in the small intestine, and aldosterone in the colon. Their effects on cellular Na⁺ absorption differ. In the small intestine, angiotensin enhances electroneutral NaCl absorption (see Fig. 44-3C), probably by upregulating apical membrane Na-H exchange. In the colon, aldosterone stimulates electrogenic Na⁺ absorption (see Fig. 44-3D).

The response of the intestine to angiotensin and aldosterone represents a classic endocrine feedback loop: dehydration results in increased levels of angiotensin and aldosterone, the primary effects of which are to stimulate fluid and Na⁺ absorption by both the renal tubules (see pp. 765–766) and the intestines. The result is restoration of total-body fluid and Na⁺ content.

Regulation of intestinal transport also occurs by paracrine effects. Endocrine cells constitute a small fraction of the total population of mucosal cells in the intestines. These endocrine cells contain several peptides and bioactive amines that are released in response to various stimuli. Relatively little is known about the biology of these cells, but gut distention can induce the release of one or more of these agonists (e.g., 5-HT). The effect of these agonists on adjacent surface epithelial cells represents a paracrine action.

Another example of paracrine regulation of intestinal fluid and electrolyte transport is the influence of immune cells in the lamina propria (see Fig. 44-1). Table 44-3 lists these immune cells and some of the agonists that they release. The same agonist may be released from more than one cell, and individual cells produce multiple agonists. These agonists may activate epithelial cells directly or may activate other immune cells or enteric neurons. For example, reactive oxygen radicals released by mast cells affect epithelial-cell function by acting on enteric neurons and fibroblasts, and they also have direct action on surface and crypt epithelial cells.

A single agonist usually has multiple sites of action. For example, the histamine released from mast cells can induce fluid secretion as a result of its interaction with receptors on surface epithelial cells (Fig. 44-7). However, histamine can also activate ENS motor neurons, which can in turn alter epithelial-cell ion transport as well as intestinal smooth-muscle tone and blood flow. As a consequence, the effects of histamine on intestinal ion transport are multiple and amplified.

FIGURE 44-7 Mast cell activation. Activation of mast cells in the lamina propria triggers the release of histamine, which either directly affects epithelial cells or stimulates an enteric neuron and thus has an indirect effect. The neuron modulates the epithelium (secretion), intestinal smooth muscle (motility), or vascular smooth muscle (blood flow). ACh, acetylcholine; EP₂ receptor, prostaglandin E₂ receptor; IL-1, interleukin-1; PGE₂, prostaglandin E₂.

Secretagogues can be classified by their type and by the intracellular second-messenger system that they stimulate

Several agonists induce the accumulation of fluid and electrolytes in the intestinal lumen (i.e., net secretion). These secretagogues are a diverse, heterogeneous group of compounds, but they can be effectively classified in two different ways: by the type of secretagogue and by the intracellular second messenger that these agonists activate.

Grouped according to type, the secretagogues fall into four categories: (1) bacterial exotoxins (i.e., enterotoxins), (2) hormones and neurotransmitters, (3) products of cells of the immune system, and (4) laxatives. Table 44-2 provides a partial list of these secretagogues. A bacterial exotoxin is a peptide that is produced and excreted by bacteria that can produce effects independently of the bacteria. An enterotoxin is an exotoxin that induces changes in intestinal fluid and electrolyte movement. For example, E. coli produces two distinct enterotoxins (the so-called heat-labile and heat-stable toxins) that induce fluid and electrolyte secretion via two distinct receptors and second-messenger systems.

We can also classify secretagogues according to the signal-transduction system that they activate after binding to a specific membrane receptor. As summarized in Table 44-2, the second messengers of these signal-transduction systems include cAMP, cGMP, and Ca²⁺. For example, the heat-labile toxin of E. coli binds to apical membrane receptors, becomes internalized, and then activates basolateral adenylyl cyclase. The resulting increase in [cAMP]_i activates protein kinase A. VIP also acts by this route (Fig. 44-8). The heat-stable toxin of E. coli binds to and activates an apical receptor guanylyl cyclase, similar to the atrial natriuretic peptide (ANP) receptor (see p. 66). The newly produced cGMP activates protein kinase G and may also activate protein kinase A. The natural agonist for this pathway is guanylin, a 15–amino-acid peptide secreted by mucosal cells of the small and large intestine. Still other secretory agonists (e.g., 5-HT) produce their effects by increasing [Ca²⁺]_i and thus activating protein kinase C or Ca²⁺-calmodulin–dependent protein kinases. One way that secretagogues can increase [Ca²⁺]_i is by stimulating phospholipase C, which leads to the production of inositol 1,4,5-trisphosphate (IP₃) and the release of Ca²⁺ from intracellular stores (see p. 60). Secretagogues can also increase [Ca²⁺]_i by activating protein kinases, which may stimulate basolateral Ca²⁺ channels.

FIGURE 44-8 Action of secretagogues. Secretagogues (agents that stimulate the net secretion of fluid and electrolytes into the intestinal lumen) act by any of the mechanisms numbered 1, 2, or 3. AC, adenylyl cyclase; CaM, calmodulin; DAG, diacylglycerol; ER, endoplasmic reticulum; G_q and G_s, α-subunit types of G proteins; GPCRs, G protein–coupled receptors; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, cGMP-dependent protein kinase; PLC, phospholipase C.

Although the secretagogues listed in Table 44-2 stimulate fluid and electrolyte secretion via one of three distinct second messengers (i.e., cAMP, cGMP, and Ca²⁺), the end effects are quite similar. As summarized in Table 44-4, all three second-messenger systems stimulate active Cl⁻ secretion (see Fig. 44-5) and inhibit electroneutral NaCl absorption (see Fig. 44-3C). The abilities of cAMP and Ca²⁺ to stimulate Cl⁻ secretion and inhibit electroneutral NaCl absorption are almost identical. In contrast, cGMP's ability to stimulate Cl⁻ secretion is somewhat less, although its effects on electroneutral NaCl absorption are quantitatively similar to those of cAMP and Ca²⁺. Both stimulation of Cl⁻ secretion and inhibition of electroneutral NaCl absorption have the same overall effect: net secretion of fluid and electrolytes. It is uncertain whether the observed decrease in electroneutral NaCl absorption is the result of inhibiting Na-H exchange, Cl-HCO₃ exchange, or both inasmuch as electroneutral NaCl absorption represents the coupling of separate Na-H and Cl-HCO₃ exchange processes via pH_i (see Fig. 44-3C).

Mineralocorticoids, glucocorticoids, and somatostatin are absorptagogues

Although multiple secretagogues exist, relatively few agonists can be found that enhance fluid and electrolyte absorption. The cellular effects of these absorptagogues are less well understood than those of the secretagogues. Those few absorptagogues that have been identified increase intestinal fluid and electrolyte absorption by either a paracrine or an endocrine mechanism.

Corticosteroids are the primary hormones that enhance intestinal fluid and electrolyte absorption. Mineralocorticoids (e.g., aldosterone) stimulate Na⁺ absorption and K⁺ secretion in the distal end of the colon; they do not affect ion transport in the small intestine. Their cellular actions are outlined on page 1027. Aldosterone induces both apical membrane Na⁺ channels (a process that is inhibited by the diuretic amiloride) and basolateral Na-K pumps; this action results in substantial enhancement of colonic “electrogenic” Na⁺ absorption. Although the effects of glucocorticoids on ion transport have most often been considered a result of crossover binding to the mineralocorticoid receptor (see p. 766), it is now evident that glucocorticoids also have potent actions on ion transport via their own receptor and that these changes in ion transport are distinct from those of the mineralocorticoids. Glucocorticoids stimulate electroneutral NaCl absorption (see Fig. 44-3C) throughout the large and small intestine without any effect on either K⁺secretion or electrogenic Na⁺ absorption. Both corticosteroids act, at least in part, by genomic mechanisms (see pp. 71–72).

Other agonists appear to stimulate fluid and electrolyte absorption by stimulating electroneutral NaCl absorption and inhibiting electrogenic  secretion; both these changes enhance fluid absorption. Among these absorptagogues are somatostatin, which is released from endocrine cells in the intestinal mucosa (see pp. 993–994), and the enkephalins and norepinephrine, which are neurotransmitters of enteric neurons. The limited information available suggests that these agonists affect ion transport by decreasing [Ca²⁺]_i, probably by blocking Ca²⁺ channels. Thus, it appears that fluctuations in [Ca²⁺]_i regulate Na⁺ and Cl⁻ transport in both the absorptive (low [Ca²⁺]_i) and secretory (high [Ca²⁺]_i) directions. Therefore, Ca²⁺ is clearly a critical modulator of intestinal ion transport.