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May 13, 2004 R.M. Lynch, Ph.

D
10:00 AM 626-2472
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ABSORPTION OF IONS AND WATER
Objectives
1. What are the primary pathways for Na
+
and Cl
-
movements across the different
segments of the intestine?
2. What are the important factors in regulating Ca
2+
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 cell
types along the length of the intestine forms the basis for understanding how and where water
moves. In general, there is net fluid secretion from cells located within the intestinal crypts, while
there is net fluid absorption by the enterocytes lining the villi. The surface area of the villi is
massive 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 moist
particularly under resting (inter-digestive) periods.
A. Absorption of Ions
i. Sodium Absorption: Na
+
is absorbed along the entire intestine, though the bulk of Na
+
is
reabsorbed in the jejunum (~80%). H
2
O 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 routes
in proximal intestine) or through Na
+
channels (primary route in colon). Na
+
absorption
is dependent on the Na
+
gradient generated by the basolateral Na-K ATPase which
actively transports it across the basolateral membrane to the interstitial space. Since there
is 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 the
lumen. H
2
O follows NaCl down the osmotic gradient.
ii. Chloride Absorption. The absorption of Cl
-
is passive in the proximal intestine where
junctions between cells are leaky. In the jejunum, Cl
-
moves passively via paracellular
pathways to offset net positive charge movement caused by rapid Na
+
absorption based on
basolateral Na
-
K ATPase activity. However, as the epithelia become less leaky in the distal
intestine, electroneutral Cl
-
transport across the lumenal membrane becomes important for
its absorption to the blood. In the ileum and colon, uptake of Cl
-
across the lumen
membrane occurs through a HCO
3
coupled antiport mechanism which is electroneutral,
and provides increased capacity for buffering bacterial H
+
production. Carbonic
anhydrase has been found in colonic enterocytes, and is likely important in facilitating
May 13, 2004 R.M. Lynch, Ph.D
10:00 AM 626-2472
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HCO
3
-
production, and thereby a favorable chemical gradient for HCO
3
movement to the
lumen coupled to Cl
-
absorption into the cells.
Mechani sm Location
Na
+
Channels Distal Intestine; Colon
Na
+
-Substrate Transporters Decreases from Proximal Intestine
to Ileum
Na
+
/ H
+
High in Proximal Intestine, low in
Colon
: Aldosterone: Increases # Na
+
Channels and NKA and thereby
Increases Na
+
Absorption
which is particularly important for regulating
water absorption in the colon.
Cl
-
Absorption
Paracellular: Proximal Intestine
Cl
-
/ HCO
3
Distal/Colon
May 13, 2004 R.M. Lynch, Ph.D
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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 the
blood via paracellular pathways to maintain electroneutrality. K
+
follows a paracellular route most
likely due to the large concomitant fluid flux (via solvant drag).
Ileal/Colonic Absorption: Na
+
uptake remains the driving force
for water reabsorption. Na
+
coupled co-transporters are much lower,
while apical Na
+
channels provide the primary route for movement into the enterocytes.
Moreover, Cl
-
/HCO
3
exchange is relatively more important due to the need
for net HCO
3
secretion to neutralize H
+
production by bacteria
iii. K
+
Absorption: K
+
absorption along the entire intestine is passive. Absorption in the jejunum
is 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 passive
paracellular K
+
absorption via solvant drag. On the other hand, in the colon K
+
absorption is
transcellular. 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. This
situation occurs as the lumen volume decreases. Since the amount of K
+
remains relatively
constant, as water volume decreases, K
+
concentration increases thereby facilitating passive flux into
May 13, 2004 R.M. Lynch, Ph.D
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eneterocytes via K
+
apical channels. This is a slow process, but under normal conditions movement
through 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
+
is
lost in the stool. In addition, there is evidence for an apical H
+
/K
+
antiport mechanism which also
may promote K
+
absorption in the colon.
iv. Calcium and Magnesium Absorption. Ca
2+
and Mg
2+
uptake are critically dependent on active
transport via the basolateral Ca
2+
ATPase, as well as, a wide range of Ca
2+
binding proteins which
reside within the enterocytes. Transport of Ca
2+
from lumen to blood occurs primarily in the
proximal intestine. Initially, Ca
2+
moves passively from the lumen into the cell down its
electrochemical gradient. After entry, Ca
2+
binds to a range of Ca
2+
binding proteins some which are
housed in intracellular stores. This sequestration keeps the free Ca
2+
concentration low within the
cell. Calcium is pumped to the blood primarily via a Ca
2+
ATPase and secondarily by Na
+
-Ca
2+
exchange on the basolateral membrane. Therefore, the capacity for Ca
2+
uptake is primarily
dependent on the expression of both the level of Ca
2+
ATPase and Ca
2+
binding proteins. Mg
2+
interacts competitively with calcium transport. Therefore, high levels of Mg
2+
in the lumen (some
antacids; Mg(OH)
2
) will diminish net Ca
2+
uptake. There also is evidence of a Ca
2+
-independent
mechanism for Mg
2+
absorption, however details of this process are lacking.
Hormonal Regulation of Ca
2+
absorption. Vitamin D3 acts to stimulate the uptake of calcium by
increasing expression of Ca
2+
binding proteins and Ca
2+
ATPase molecules. Parathyroid Hormone
acts to promote calcium uptake by enhancing renal formation of Vitamin D3 (1, 25
dihydroxycholecalciferol).
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iv. Absorption of Water: About 90 - 95% of water (re)absorption takes place in the small
intestine in association with nutrient (ion linked) absorption. The remaining 1-2 L/day is
absorbed in the colon. Water permeability in the colon is low, so it is at this level that
regulation of stool water content takes place under normal conditions. A normal colon can
reabsorb a maximum of about 4.5 liters of H
2
O per day.
Rapid equilibration of H
2
O between lumen and blood occurs in the proximal intestinal
tract following the rules of osmosis. In the duodenum chyme is quickly brought to
isotonicity. Ingestion of a hypotonic meal leads to rapid movement of water to blood with
isotonicity of the chyme reached prior to the jejunum. Water permeability decreases from
proximal to distal small intestine, and the colon has the lowest permeability. The
mechanism of H
2
O 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 lumenal
end of the lateral intercellular space creating a gradient for water movement into the lateral
spaces.
Summary of Gastrointestinal Tract Secrtion Volumes
DAILY SECRETION OF INTESTINAL JUICES
(Daily Volume)
(ml.) pH
Saliva 1200 7.0-8.0
Gastric secretion 2000 1.0 -3.5
Pancreatic secretion 1200 8.0-8.3
Bile 700 7.8
Succus entericus (intestine) 2000 7.8-8.0
Brunner's gland secretion 50 (?) 8.0-8.9
Large intestinal secretion 60 7.5-8.0
Total 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 alterations
can lead to diarrhea and constipation.
The causes of Diarrhea can be delineated into 3 categories which may be inter-related depending on
the type of primary insult: Defects in Absorption, Secretion, or Motility. Since intestinal contents
are 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 canal
will effect the consistency of the fecal contents. Therefore, decreases in motility are
correlated with constipation (more time for water removal), whereas increases in
motility 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 the
enterocytes of the small intestine will lead to elevated water flux to the colon. If this
flux is greater than 4.5 L/day, then diarrhea will ensue. Generally, the volume of
diarrhea 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 stimulate
secretion.
c. Celiac disease (Sprue; gluten sensitivity) Wheat flour contains gluten. In the
absence 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 in
Motility in the small intestine which occur after surgery (use of anticholinergics) can
lead to migration of bacteria into the small intestine, and this in turn can lead to a
decrease in eneterocyte viability and absorptive diarrhea. Furthermore, patients using
H2 antagonists or other inhibitors of HCl secretion are susceptible to parasitic and
bacterial infections which can lead to absorptive problems.
3. Secretory. The primary mechanism for active secretion of water into the colon is
coupled to the opening of apical Cl
-
channels. This is the "cystic fibrosis" channel. In
addition, digestive (bacterial) products of bile salts act as secretagogues, though their
mechanism of action is as yet unknown.
Specific effectors which alter cAMP levels in enterocytes can lead to excessive
secretion 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 cAMP
in these cells during the post-prandial period. For this reason, VIP-oma's are
correlated with massive secretory diarrhea. Cholera toxin stimulates intestinal
secretion through the same mechanism, i.e., elevating cAMP.