Medical Physiology, 3rd Edition

Overview of Fluid and Electrolyte Movement in the Intestines

The small intestine absorbs ~6.5 L/day of an ~8.5-L fluid load that is presented to it, and the colon absorbs ~1.9 L/day

The fluid content of the average diet is typically 1.5 to 2.5 L/day. However, the fluid load to the small intestine is considerably greater—8 to 9 L/day. The difference between these two sets of figures is accounted for by salivary, gastric, pancreatic, and biliary secretions, as well as the secretions of the small intestine itself (Fig. 44-2). Similarly, the total quantity of electrolytes (Na+, K+, Cl, and image) that enters the lumen of the small intestine also comes from dietary sources in addition to endogenous secretions from the salivary glands, stomach, pancreas, liver, and small intestine.

image

FIGURE 44-2 Fluid balance in the gastrointestinal (GI) tract. For each segment of the GI tract, the figure shows substances flowing into the lumen on the left and substances flowing out of the lumen on the right. Of the ~8.5 L/day that are presented to the small intestine, the small intestine removes ~6.5 L/day, delivering ~2 L/day to the colon. The large intestine removes ~1.9 L/day, leaving ~0.1 L/day in the feces.

We can calculate the absorption of water and electrolytes from the small intestine by comparing the total load that is presented to the lumen of the small intestine (i.e., ~7.5 L/day entering from other organs + ~1.0 L/day secreted by the small intestine = ~8.5 L/day) with that leaving the small intestine (i.e., ileocecal flow). The latter is ~2.0 L/day in normal subjects. Thus, overall small-intestinal water absorption is about 8.5 – 2.0, or ~6.5 L/day. Na+ absorption is ~600 mmol/day. Maximal small-intestinal fluid absorption has not been directly determined but has been estimated to be as great as 15 to 20 L/day.

Colonic fluid absorption is the difference between ileocecal flow (~2.0 L/day) and stool water, which is usually <0.2 L/day (~0.1 L/day). Thus, colonic water absorption is about 2.0 – 0.1, or ~1.9 L/day. In contrast, the maximal colonic water absorptive capacity is between 4 and 5 L/day. As a result, a significant increase in ileocecal flow (e.g., up to perhaps 5 L/day, as occurs with a decrease in small-intestinal fluid absorption) will not exceed the absorptive capacity of the large intestine. Thus, a compensatory increase in colonic fluid absorption can prevent an increase in stool water (i.e., diarrhea) despite substantial decreases in fluid absorption by the small intestine.

The small intestine absorbs net amounts of water, Na+, Cl, and K+ and secretes image, whereas the colon absorbs net amounts of water, Na+, and Cl and secretes both K+ and image

Net ion movement represents the summation of several events. At the level of the entire small or large intestine, substantial movement of ions occurs from the intestinal lumen into the blood and from the blood into the lumen. The net ion movement across the entire epithelium is the difference between these two unidirectional fluxes.

Fluid and electrolyte transport in the intestine varies considerably in two different axes, both along the length of the intestines (segmental heterogeneity) and from the bottom of a crypt to the top of a villus or to the surface cells (crypt-villus/surface heterogeneity). A comparison of two different segments of intestine (e.g., duodenum versus ileum) shows that they differ substantially in function. These differences in function reflect segmental heterogeneity of ion transport processes along the longitudinal axis of the intestine in different macroscopic regions of both the small and the large intestine; these differences are both qualitative and quantitative. For example, image stimulation of Na+ absorption occurs only in the proximal part of the small intestine. In contrast, the so-called electrogenic Na+ absorption (i.e., absorption associated with the development of a transepithelial potential difference) is restricted to the rectosigmoid segment of the colon.

Within an intestinal segment (e.g., a piece of ileum), crypt-villus/surface heterogeneity leads to differences in transport function along the radial axis of the intestine wall. For example, it is generally believed that absorptive function is located in villous cells in the small intestine (and surface epithelial cells in the large intestine), whereas secretory processes reside in the crypt cells. Finally, at a certain level within a single villus or crypt—or within a very small area of the colonic surface epithelium—individual cells may demonstrate further heterogeneity (cellular heterogeneity), with specific transport mechanisms restricted to different cells.

Overall ion movement in any segment of the intestine represents the summation of these various absorptive and secretory events. These events may be paracellular or transcellular, may occur in the villus or crypt, and may be mediated by a goblet cell or an absorptive cell.

Despite the segmental heterogeneity of small-intestinal electrolyte transport, overall water and ion movement in the proximal and distal portions of the small intestine is similar: in health, the small intestine is a net absorber of water, Na+, Cl, and K+, but is a net secretor of image (see Fig. 44-2). Fluid absorption is isosmotic in the small intestine, similar to that observed in the renal proximal tubule (see pp. 758–759). In general, absorptive processes in the small intestine are enhanced in the postprandial state. The human colon carries out net absorption of water, Na+, and Cl with few exceptions, but it carries out net secretion of K+ and image.

The intestines absorb and secrete solutes by both active and passive mechanisms

As discussed on pages 136–140, intestinal epithelial cells are polar; that is, they have two very different membranes—an apical membrane and a basolateral membrane—separated from one another by tight junctions. The transport processes present in the small and large intestine are quite similar to those present in other epithelia, such as the renal tubules, with only some organ-specific specialization to distinguish them. The transepithelial movement of a solute across the entire epithelium can be either absorptive or secretory. In each case, the movement can be either transcellular or paracellular. In transcellular movement, the solute must cross the two cell membranes in series. In general, movement of the solute across at least one of these membranes must be active (i.e., against an electrochemical gradient). In paracellular movement, the solute moves passively between adjacent epithelial cells through the tight junctions.

All transcellular Na+ absorption is mediated by the Na-K pump (i.e., Na,K-ATPase) located at the basolateral membrane. This enzyme is responsible for Na+ extrusion across the basolateral membrane and results in a relatively low [Na+]i (~15 mM) and an intracellular-negative membrane potential. This Na+ gradient serves as the driving force, in large part, for Na+ entry into the epithelial cell across the luminal (apical) membrane, a process mediated either by Na+ channels or by Na+-coupled transporters (e.g., Na/glucose cotransport, Na-H exchange). The epithelial cell may also use this Na+ gradient to energize other transport processes at the apical or basolateral membrane.

Intestinal fluid movement is always coupled to solute movement, and sometimes solute movement is coupled to fluid movement by solvent drag

Fluid movement is always coupled to active solute movement. imageN44-1 The model of the osmotic coupling of fluid movement to solute movement in the intestine is similar to that in all or most epithelial cells (see p. 139). It is likely that the water movement occurs predominantly by a paracellular route imageN44-2 rather than by a transcellular route. imageN44-3

N44-1

Nonosmotic Coupling of Water and Solute Movement in the Intestine

Contributed by Emile Boulpaep, Walter Boron

The classical view, presented in the text, is that water transport always osmotically follows solute transport—that is, there is no such thing as a water pump (see pp. 127–136). However, Loo, Wright, and Zeuthen have suggested that the Na/glucose cotransporter SGLT1 can transport >200 water molecules for every two Na+ ions and one glucose molecule that it transports. imageN44-5 In the specific case of the small intestine, these authors propose that SGLT1 can cotransport enough water to account for ~50% of the total water absorption across the brush border of the human small intestine. On the other hand, Lapointe and colleagues have argued that the observed water movement is in fact secondary to local osmotic gradients that drive water movement via the classical pathway.

References

Lapointe J-Y, Gagnon M, Poirier S, Bissonnette P. The presence of local osmotic gradients can account for the water flux driven by the Na+-glucose cotransporter. J Physiol. 2002;542:61–62.

Loo DDF, Wright EM, Zeuthen T. Water pumps. J Physiol. 2002;542:53–60.

Loo DDF, Zeuthen T, Chandy G, et al. Cotransport of water by the Na+/glucose cotransporter. Proc Natl Acad Sci U S A. 1996;93:13367–13370.

N44–5

The Water-Pump Controversy

Contributed by Emile Boulpaep, Walter Boron

Loo and colleagues have proposed that the Na/glucose cotransporter SGLT1 in the human small intestine cotransports not only Na+ and glucose, but water as well. In other words, with each cycle, SGLT1 would move 2 Na+ ions, 1 glucose molecule, and >200 water molecules. The authors envisage that the Na+ ions and glucose molecule—along with the water molecules—would diffuse from the extracellular fluid into a pore within the cotransporter protein. The cotransporter would then undergo a conformational change that would close an outer gate and thereby occlude these ions and molecules from the extracellular fluid. By opening an inner gate, the cotransporter would deocclude these particles and allow the 2 Na+ ions, the glucose molecule, and the 200+ water molecules to enter the cytoplasm of the intestinal cell (i.e., enterocyte). There is no controversy that this general model—minus the water—explains how SGLT1 works. The question is whether each cycle of the cotransporter also moves a fixed number of water molecules through the membrane protein along with the Na+ and glucose. Loo and colleagues suggest that the water pumped by SGLT1 would account for about half of the water taken up by the small intestine.

On the other hand, Lapointe and colleagues have challenged the conclusion of Loo and colleagues, suggesting that the data of Loo and colleagues can more easily be explained by the classical model. That is, as SGLT1 cotransports Na+ and glucose from the extracellular to the intracellular fluid, water would follow osmotically.

References

Lapointe J-Y, Gagnon M, Poirier S, Bissonnette P. The presence of local osmotic gradients can account for the water flux driven by the Na+–glucose cotransporter. J Physiol. 2002;542:61–62.

Loo DDF, Wright EM, Zeuthen T. Water pumps. J Physiol. 2002;542:53–60.

Loo DDF, Zeuthen T, Chandy G, Wright EM. Cotransport of water by the Na+/glucose cotransporter. Proc Natl Acad Sci U S A. 1996;93:13367–13370.

N44-2

Pathways of Intestinal Water Movement

Contributed by Emile Boulpaep, Walter Boron

Pappenheimer and Reiss have estimated that about 50% of the fluid absorption in the small intestine occurs by a paracellular route. Moreover, they concluded that solvent drag—the entrainment of solutes by the paracellular flow of water—is a major pathway for the absorption of glucose and amino acids in the small intestine.

In his 1988 review, Pappenheimer proposed the following model: Na+-coupled glucose uptake into the intestinal cell—followed by the deposition of solute in the lateral intercellular spaces between epithelial cells—provides the osmotic driving force for paracellular H2O movement, and hence solvent drag. Moreover, he speculated that Na+-coupled glucose transport somehow causes contraction of a ring of actomyosin just beneath the apical membrane, which pulls the tight junction apart slightly and increases the paracellular conductance to H2O.

As far as the transcellular component of H2O movement is concerned, the aquaporins AQP7 and AQP8 are present in the apical membranes of the small intestine and may play a role in transcellular H2O movement. Aquaporins are present in the colon, although their role there is not established.

References

Pappenheimer JR. Physiological regulation of epithelial junctions in intestinal epithelia. Acta Physiology Scand Suppl. 1988;571:43–51.

Pappenheimer JR, Reiss KZ. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J Membrane Biol. 1987;100:123–136.

Tritto S, Gastaldi G, Zelenin S, et al. Osmotic water permeability of rat intestinal brush border membrane vesicles: Involvement of aquaporin-7 and aquaporin-8 and effect of metal ions. Biochem Cell Biol. 2007;85:675–684.

N44-3

Aquaporins in the Apical Membranes of the Gastrointestinal Tract

Contributed by Emile Boulpaep, Walter Boron

The aquaporins AQP7 and AQP8 are present in the apical membranes of the small intestine and may play a role in transcellular H2O movement. Although aquaporins are present in the colon, their role is not established.

References

Schnermann J, Chou C-L, Ma T, et al. Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc Natl Acad Sci U S A. 1998;95:9660–9664.

Tritto S, Gastaldi G, Zelenin S, et al. Osmotic water permeability of rat intestinal brush border membrane vesicles: Involvement of aquaporin-7 and aquaporin-8 and effect of metal ions. Biochem Cell Biol. 2007;85:675–684.

Solute movement is the driving force for fluid movement. However, the converse may also be true: solute movement may be coupled to fluid movement by solvent drag, a phenomenon in which the dissolved solute is swept along by bulk movement of the solvent (i.e., water). Solvent drag accounts for a significant fraction of the Na+ and urea absorbed in the human jejunum (but not in the more distal segments of the small intestine or the large intestine). For all intents and purposes, solvent drag occurs through the paracellular route, and it depends on the permeability properties of the tight junctions (reflection coefficient; see p. 468) and the magnitude of the convective water flow. Thus, solvent drag contributes primarily to the absorption of relatively small, water-soluble molecules, such as urea and Na+, and it does so mainly in epithelia with relatively high permeability. The transepithelial permeability of the jejunum is considerably greater than that of the ileum or colon, as evidenced by its lower spontaneous transepithelial voltage difference (Vte), higher passive movement of NaCl, and larger apparent pore size.

The resistance of the tight junctions primarily determines the transepithelial resistance of intestinal epithelia

Epithelial permeability is an inverse function of transepithelial resistance. In epithelial structures such as the small and large intestine, transepithelial resistance is determined by cellular resistance and paracellular resistance, which are arranged in parallel (see pp. 136–137). Paracellular resistance is considerably lower than transcellular resistance; therefore, overall mucosal resistance primarily reflects paracellular resistance, which in turn depends primarily on the properties of the tight junctions. Therefore, intestinal permeability is essentially a function of tight-junction structure. Just as transport function varies greatly throughout the intestine, major differences in transepithelial permeability and the properties of tight junctions are also present throughout the intestinal tract. In general, resistance increases in the aboral direction (i.e., moving away from the mouth). Thus, the resistance of the jejunum is considerably lower than that of the distal end of the colon. Evidence also indicates that the permeability of the tight junctions in the crypt is greater than that in the villus.

 

SMALL INTESTINE

LARGE INTESTINE

Length (m)

6

2.4

Area of apical plasma membrane (m2)

~200

~25

Folds

Yes

Yes

Villi

Yes

No

Crypts or glands

Yes

Yes

Microvilli

Yes

Yes

Nutrient absorption

Yes

No

Active Na+ absorption

Yes

Yes

Active K+ secretion

No

Yes