Absorption of Ions and Water

May 13, 2004 R.M. Lynch, Ph.D 10:00 AM 626-2472

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ABSORPTION OF IONS AND WATERObjectives

1. What are the primary pathways for Na+ and Cl- movements across the differentsegments of the intestine?

2. What are the important factors in regulating Ca2+ absorption?3. Where is most K+ absorbed and what is the primary mechanism for its

absorption?

Water movement follows the movement of osmolytes including ions and nutrients. Therefore,understanding the mechanisms of osmolyte transport and the anatomical distribution of specific celltypes along the length of the intestine forms the basis for understanding how and where watermoves. In general, there is net fluid secretion from cells located within the intestinal crypts, whilethere is net fluid absorption by the enterocytes lining the villi. The surface area of the villi ismassive compared to the crypts such that net water absorption is normally favored. However,continuous secretion of water, and therefore osmolytes is required to maintain the intestine moistparticularly under resting (inter-digestive) periods.

A. Absorption of Ionsi. Sodium Absorption: Na+ is absorbed along the entire intestine, though the bulk of Na+ is

reabsorbed in the jejunum (~80%). H2O movement is critically linked to Na+ absorption.

Na+ moves into epithelial cells down its electrochemical gradient through the apical(luminal) membrane by co-transport with nutrients, via Na+/H+ exchange (primary routesin proximal intestine) or through Na+ channels (primary route in colon). Na+ absorptionis dependent on the Na+ gradient generated by the basolateral Na-K ATPase whichactively transports it across the basolateral membrane to the interstitial space. Since thereis net movement of positive charge from the lumen to the blood (3Na+ to blood for 2K+

into cell), the interstitial compartment becomes slightly more positive with respect to thelumen. H2O follows NaCl down the osmotic gradient.

ii. Chloride Absorption. The absorption of Cl- is passive in the proximal intestine wherejunctions between cells are leaky. In the jejunum, Cl- moves passively via paracellularpathways to offset net positive charge movement caused by rapid Na+ absorption based onbasolateral Na-K ATPase activity. However, as the epithelia become less leaky in the distalintestine, electroneutral Cl- transport across the lumenal membrane becomes important forits absorption to the blood. In the ileum and colon, uptake of Cl- across the lumenmembrane occurs through a HCO3 coupled antiport mechanism which is electroneutral,and provides increased capacity for buffering bacterial H+ production. Carbonicanhydrase has been found in colonic enterocytes, and is likely important in facilitating


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HCO3- production, and thereby a favorable chemical gradient for HCO3 movement to thelumen coupled to Cl- absorption into the cells.

Mechanism LocationNa+ Channels Distal Intestine; Colon

Na+ -Substrate Transporters Decreases from Proximal Intestineto Ileum

Na+ / H+ High in Proximal Intestine, low inColon: Aldosterone: Increases # Na+ Channels and NKA and therebyIncreases Na+Absorption which is particularly important for regulatingwater absorption in the colon.Cl- AbsorptionParacellular: Proximal Intestine

Cl- / HCO3 Distal/Colon


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The largest fraction of Na+ is absorbed into the villus enterocytes through Na+ -coupled co-transporters. The Na-K ATPase removes this absorbed Na+ load to the blood. Cl- moves to theblood via paracellular pathways to maintain electroneutrality. K+ follows a paracellular route mostlikely due to the large concomitant fluid flux (via solvant drag).

Ileal/Colonic Absorption: Na+ uptake remains the driving forcefor water reabsorption. Na+ coupled co-transporters are much lower,while apical Na+ channels provide the primary route for movement into the enterocytes.Moreover, Cl-/HCO3 exchange is relatively more important due to the needfor net HCO3 secretion to neutralize H+ production by bacteria

iii. K+ Absorption: K+ absorption along the entire intestine is passive. Absorption in the jejunumis primarily through paracellular pathways. K+ is low in the intercellular space and the large para-cellular fluid flux during active transcellular salt (NaCl) absorption is believed to drive passiveparacellular K+ absorption via solvant drag. On the other hand, in the colon K+ absorption istranscellular. Since intracellular K+ is high, K+ absorption can only occur when the lumenal K+

concentration become elevated and a lumenal to intracellular K+ gradient is established. Thissituation occurs as the lumen volume decreases. Since the amount of K+ remains relativelyconstant, as water volume decreases, K+ concentration increases thereby facilitating passive flux into


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eneterocytes via K+ apical channels. This is a slow process, but under normal conditions movementthrough the colon is slow. However, under conditions where colonic transit increases (diarrhea), K+

concentration does not increase substantially, and little time is available for absorption, so net K+ islost in the stool. In addition, there is evidence for an apical H+/K+ antiport mechanism which alsomay promote K+ absorption in the colon.

iv. Calcium and Magnesium Absorption. Ca2+ and Mg2+ uptake are critically dependent on activetransport via the basolateral Ca2+ ATPase, as well as, a wide range of Ca2+ binding proteins whichreside within the enterocytes. Transport of Ca2+ from lumen to blood occurs primarily in theproximal intestine. Initially, Ca2+ moves passively from the lumen into the cell down itselectrochemical gradient. After entry, Ca2+ binds to a range of Ca2+ binding proteins some which arehoused in intracellular stores. This sequestration keeps the free Ca2+ concentration low within thecell. Calcium is pumped to the blood primarily via a Ca2+ ATPase and secondarily by Na+-Ca2+

exchange on the basolateral membrane. Therefore, the capacity for Ca2+ uptake is primarilydependent on the expression of both the level of Ca2+ ATPase and Ca2+ binding proteins. Mg2+

interacts competitively with calcium transport. Therefore, high levels of Mg2+ in the lumen (someantacids; Mg(OH)2) will diminish net Ca

2+ uptake. There also is evidence of a Ca2+-independentmechanism for Mg2+ absorption, however details of this process are lacking.

Hormonal Regulation of Ca2+ absorption. Vitamin D3 acts to stimulate the uptake of calcium byincreasing expression of Ca2+ binding proteins and Ca2+ ATPase molecules. Parathyroid Hormoneacts to promote calcium uptake by enhancing renal formation of Vitamin D3 (1, 25dihydroxycholecalciferol).


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iv. Absorption of Water: About 90 - 95% of water (re)absorption takes place in the smallintestine in association with nutrient (ion linked) absorption. The remaining 1-2 L/day isabsorbed in the colon. Water permeability in the colon is low, so it is at this level thatregulation of stool water content takes place under normal conditions. A normal colon canreabsorb a maximum of about 4.5 liters of H2O per day.

Rapid equilibration of H2O between lumen and blood occurs in the proximal intestinaltract following the rules of osmosis. In the duodenum chyme is quickly brought toisotonicity. Ingestion of a hypotonic meal leads to rapid movement of water to blood withisotonicity of the chyme reached prior to the jejunum. Water permeability decreases fromproximal to distal small intestine, and the colon has the lowest permeability. Themechanism of H2O absorption is based on the Theory of Standing Gradient Osmosis.The driving force is the Na+ that is pumped into the lateral extracellular space by the Na+ -K+ ATPase. Cl- follows Na+ by diffusion through intercellular junctions, or facilitative


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transport as in the colon. These ion movements create hypertonic fluid near the lumenalend of the lateral intercellular space creating a gradient for water movement into the lateralspaces.

Summary of Gastrointestinal Tract Secrtion VolumesDAILY SECRETION OF INTESTINAL JUICES

(Daily Volume)(ml.) pH

Saliva 1200 7.0-8.0Gastric secretion 2000 1.0 -3.5Pancreatic secretion 1200 8.0-8.3Bile 700 7.8Succus entericus (intestine) 2000 7.8-8.0Brunner's gland secretion 50 (?) 8.0-8.9Large intestinal secretion 60 7.5-8.0Total 7210

Pathophysiology of Diarrhea.

Objectives:1. Identify why changes in motility, absorption and secretion work together to

alter colonic transit.

2. Understand how water absorption can be modified and how such alterationscan lead to diarrhea and constipation.

The causes of Diarrhea can be delineated into 3 categories which may be inter-related depending onthe type of primary insult: Defects in Absorption, Secretion, or Motility. Since intestinal contentsare relatively high in K+, profound diarrhea is associated with both hypokalemia, as well as,systemic dehydration.

1. Motility. Factors that alter the normal transit of a meal through the alimentary canalwill effect the consistency of the fecal contents. Therefore, decreases in motility arecorrelated with constipation (more time for water removal), whereas increases inmotility are correlated with diarrhea. Sedatives (codeine) and pregnancy(progesterone) elicit decreases in motility and are associated with constipation.

2. Absorptive. Any treatment or infection which alters the viability and/or function of theenterocytes of the small intestine will lead to elevated water flux to the colon. If thisflux is greater than 4.5 L/day, then diarrhea will ensue. Generally, the volume ofdiarrhea is only moderate with absorptive disorders, and is diminsihed upon fasting.

a. Lactase deficiency: Lactose in diary products is not digested, and therefore,can not be absorbed leading to an osmotic diarrhea.


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b. Ileal resection; terminal ileal disease: elevated bile salts and their metabolites(bacterial produced) in the colon are strong osmotic agents and also stimulatesecretion.

c. Celiac disease (Sprue; gluten sensitivity) Wheat flour contains gluten. In theabsence of gluten hydrolase, gluten is converted to a toxic metabolite gliadin.Gliaden causes the destruction of enterocytes, and mucosal endocrine cells,severely limiting absorption in the jejunum.

Normal motility keeps bacteria restricted mostly to the colon. Significant decreases inMotility in the small intestine which occur after surgery (use of anticholinergics) canlead to migration of bacteria into the small intestine, and this in turn can lead to adecrease in eneterocyte viability and absorptive diarrhea. Furthermore, patients usingH2 antagonists or other inhibitors of HCl secretion are susceptible to parasitic andbacterial infections which can lead to absorptive problems.

3. Secretory. The primary mechanism for active secretion of water into the colon iscoupled to the opening of apical Cl- channels. This is the "cystic fibrosis" channel. Inaddition, digestive (bacterial) products of bile salts act as secretagogues, though theirmechanism of action is as yet unknown.

Specific effectors which alter cAMP levels in enterocytes can lead to excessivesecretion of ions and fluid into the colon. cAMP appears to regulate (open) the Cl-channel in the colonic enterocyte luminal membrane. VIP is known to elevate cAMPin these cells during the post-prandial period. For this reason, VIP-oma's arecorrelated with massive secretory diarrhea. Cholera toxin stimulates intestinalsecretion through the same mechanism, i.e., elevating cAMP.

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Absorption of Ions and Water