May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
SECRETION AND ABSORPTION in the INTESTINE
Objectives:
1. Describe the mechanism for salt and water secretion in the small and large
intestine, and what its role is.
2. Understand the importance of the stem cell division and migration cycle in the
maintenance of epithelial integrity.
3. Identify the mechanism of absorption of the primary metabolites.
4. Understand how water absorption can be modified and how such alterations can
lead to diarrhea and constipation.
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.
I.
General Functional Anatomy: Small Intestine
A. Intestinal Villi refers to the extensive foldings observed in the surface of the intestine.
The villi are covered by a layer of epithelial cells with only a few other cell types
interspersed. This folding arrangement dramatically increases surface area providing
an optimal situation for absorption.
B. Crypts of Lieberkuhn are extensive pits found between villi at their base which extend
to the submucosa and are found in all parts of the intestine. The crypts contain
multipotential cells which can differentiate into absorptive epithelial cells as they
migrate towards the villus tip. In addition to these precursor cells, a large variety of
mucus secreting goblet cells, and endocrine cells are found in the crypts. It is likely that
most nutrient sensing endocrine secreting cells are located in these structures
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
II. Cell Growth and Differentiation : Stem cells are located in the crypts. Epithelial cell
turnover at the tip of a villus is high (3-6 day cycle), and a significant rate of migration of cells
from the crypts is necessary to replace lost cells. As cells move from the crypts, changes in cell
function occur: the absorptive capacity and the level of brush border enzymes both increase
dramatically. Therefore, any process that increases cell death at the tip or slows differentiation
in the crypts will reduce absorptive capacity eventually leading to diarrhea. Since mucosal stem
cells divide rapidly, interventions which alter the cell cycle lead to absorptive disorders.
III.
Secretions of the Colon and Small Intestine
Single mucus secreting cells (Goblet cells) are found throughout the intestine. The Crypts
of Lieberkuhn are present but less extensive in the colon. In the colon, crypts contain goblet
cells and stem cells as in the small intestine, however, no endocrine cells are observed.
Mucus represents the largest component of colonic secretions acting to protect the colon
wall and cause fecal material to adhere together. Normally there is net water absorption together
with HCO3 secretion to the lumen in exchange for Cl-. In addition, a low rate of water secretion
at an alkaline pH protects the colon walls from acid produced by bacteria. However, in response
to infection or introduction of a noxious compound into the intestine, fluid secretion into the
lumen can be activated. VIP acting as a neurotransmitter activates water secretion by elevating
cAMP and Cl- conductance (cAMP activated CL- Channel) within colonic and small intestinal
enterocytes. Inflamation of the large intestinal wall generally leads to elevation in cell cAMP
(local histamine release) which sets up an acute secretory response that causes flushing of the
colon. Cholera toxin mediates profound diarrhea through this pathway.
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Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
Figure: Idealized diagram demonstrating the mechanism for active water secretion in the intestines.
IV.
Absorption of Nutrients.
Only monomers and dimers of the initial complex nutrients can be absorbed by the lumenal
cells (enterocytes) of the small intestine. Therefore, in the absence of normal digestion of
complex nutrients, absorption is severely limited.
A. Carbohydrates: The duodenum and upper jejunum have the highest capacity to absorb simple
carbohydrates. Less absorptive capacity exists in lower jejunum and ileum. Glucose
and galactose are absorbed via sodium dependent transport across luminal membranes,
and Na+ independent facilitative transport across the basolateral membrane. Fructose is
transported via an apical Na+-independent transport mechanism. The presence of
enzymes within the brush border completes the breakdown of more complex sugars
into transported species. As indicated in the figure, enzymes for cleaving 1,6
(dextrinase) and 1,4 bonds (glucoamylase) are present. Substantial levels of amylase are
also present in pancreatic secretions, so the brush border enzymes are not critical. On
the other hand, little if any lactase is found in pancreatic secretions, so its presence in
the brush border is important for cleaving lactose to glucose and galactose which can
then be absorbed.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
Mechanisms for carbohydrate uptake across the enterocyte luminal membrane. A method for measuring
the capacity for absorption is to follow uptake of the sugar like Xylose. Xylose is transported into
epithelial cells via the Na+ independent fructose carrier. This sugar is not metabolized, so the amount of
xylose excreted in urine after an oral load reports on the ability of intestinal epithelia to absorb it.
B. Proteins. Protein digestion products are absorbed as amino acids or as dipeptides by specific
transporters. Amino acid absorption occurs primarily in the duodenum and upper
jejunum. A small amount of protein can be absorbed in the form of small peptides by
pinocytosis. Pinocytosis can account for a significant amount of protein uptake (eg. IgG)
in newborn infants but becomes very limited with age.
The basic mechanism of amino acid transport is a sodium co-transport mechanism similar
+
to that for glucose. By coupling nutrient uptake to the Na gradient, cells use energy developed
+
by the Na-K ATPase to transport amino acids. In addition, uptake with Na assures net ion flux
to the blood setting the driving force for water absorption.
C.
Fat Absorption. Fat in the diet is emulsified by mixing in the stomach and interacting with
biles salts in the duodenum. As digestion of emulsified fat begins, small fat droplets
coated with bile called micelles form. Micelles diffuse to the epithelial cell surface
coming into contact with the brush border. The micelles are loaded with lipid soluble
digestion products (monoglycerides, fatty acids, cholesterol) allowing them to diffuse
across the enterocyte apical membrane. Bile salts are not absorbed, but rather remain
within the intestinal lumen to ferry more lipid digestion products to the brush border
until they reach the ileum.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
A small amount of short to medium chain length fatty acids (<8 carbons) can be released
from enterocytes directly into the portal blood. However, once inside the epithelial cells,
most fragments of lumenal lipid digestion are resynthesized to triglycerides, cholesterol
esters and phospholipids. The resynthesized fat products are accumulated into vesicles
which are coated with h-lipoprotein to enhance their solubility. This vesicular structure
is referred to as a chylomicron. Chylomicrons are moved from the cell by exocytosis
into the interstitial space of the villus passing from the interstitial space into lymphatic
vessels and eventually into the venous circulation via the thoracic duct. Thus,
lymphatic flow greatly increases during absorption of a fatty meal. In addition to
chylomicrons, very low density lipoproteins (VLDL) also are formed in intestinal
epithelia, and are an important carrier for transport of cholesterol to blood via the
lymphatics. However, chylomicrons are the primary carrier of dietary lipids to the
systemic circulation.
V.
i.
Ion Absorption
+
+
Sodium Absorption: Na is absorbed along the entire intestine, although the bulk of Na is
+
+
reabsorbed in the jejunum (60-80%). Na absorption is dependent on the Na
gradient generated by the basolateral Na-K ATPase. 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 or through Na channels (primary route in jejunum). Na is actively
transported across the basolateral membrane to the interstitial space by the Na-K
ATPase. H2O follows NaCl down the osmotic gradient.
ii. Chloride Absorption. The absorption of Cl- is passive in the proximal intestine where
tight junctions between cells are leaky. In the jejunum, Cl- moves passively through
+
paracellular pathways to offset net positive charge movement caused by rapid Na
uptake coupled with nutrient absorption. As the epithelia become less leaky in the distal
intestine, electroneutral transport of Cl- 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 HCO3 coupled antiport mechanism. This
mechanism 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 HCO3- production, and thereby a favorable chemical gradient
for HCO3 movement to the lumen coupled to Cl- absorption into the cells.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
OVERVIEW
Mechanism
+
Location
Na Channels
Distal Intestine; Colon
Na+ -Substrate Transporters
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- / HCO3
Distal/Colon
The largest fraction of Na+ is absorbed into the villus enterocytes through Na+ channels,
however significant amounts are absorbed via Na+ -coupled co-transporters. The Na-K ATPase
removes this “absorbed” Na+ to the blood. Cl- moves to the blood via paracellular pathways to
maintain electroneutrality.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
Ileal/Colonic Absorption: Na+ uptake remains the driving force for water reabsorption,
however the number of Na+ channels and Na+/H+ exchangers are much lower. Moreover, Cl/HCO3 exchange is relatively more important due to the need for net HCO3 secretion to
neutralize H+ production by bacteria
iv. Calcium Absorption. Ca2+ uptake is critically dependent on active transport via the
basolateral Ca2+ ATPase, as well as, a wide range of Ca2+ binding proteins which reside within
the enterocytes. Transport of calcium from lumen to blood occurs primarily in the proximal
intestine. Initially, calcium moves passively from the lumen into the cell down its
electrochemical gradient. After entry, Ca2+ binds to a range of Ca2+ binding proteins some
which are housed in intracellular stores. This sequestration keeps the free Ca2+ concentration
low within the cell. 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 primarily dependent on the expression of both the level of Ca2+ ATPase and
Ca2+ binding proteins.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
Hormonal Regulation of Ca2+ absorption. Vitamin D3 acts to stimulate the uptake of calcium by
increasing expression of Ca2+ binding proteins and Ca2+ ATPase molecules. Parathyroid
Hormone acts to promote calcium uptake by enhancing renal formation of Vitamin D3 (1, 25
dihydroxycholecalciferol).
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 H2O per day.
Rapid equilibration of H2O 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 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 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.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
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.
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.
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May 29, 2004
Intestinal Secretion and Absorption
Ron Lynch, Ph.D
626-2472
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 Clchannel 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.
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