Transcript PowerPoint—November 12

NROSCI 1070-2070
November 12, 2014
Gastrointestinal
2
Clinical Note
• Inhibition of GI enzymes can be used
therapeutically
• An example is Xenical (orlistat), which
reversibly inhibits lipases and prevents
lipids from being absorbed.
• Xenical is used to treat obesity.
• What major side effect would you expect
to be associated with this drug?
Clinical Note
• Lactase levels decease in most individuals as
they age, resulting in inability to digest milk
sugar (lactose intolerance)
• Between 30 and 50 million Americans are
lactose intolerant. Certain ethnic and racial
populations are more widely affected than
others. As many as 75 percent of all African
Americans and American Indians and 90
percent of Asian Americans are lactose
intolerant. The condition is least common
among persons of northern European descent.
Other GI Secretions
• In addition to digestive enzymes, mucus is secreted by
specialized cells in the stomach, small intestine, and
colon.
– This viscous secretion is composed primarily of glycoproteins
that are collectively called mucins.
– Mucus functions to form a protective lining over the GI
mucosa and to lubricate the contents of the gut.
– Mucus is secreted by globlet cells in the stomach and
intestine.
– The release signals for mucus include parasympathetic
innervation, a variety of neuropeptides found in the enteric
nervous system, and cytokines from immune cells.
– Infections of the gut enhance mucus secretion as the
digestive system attempts to protect itself.
Other GI Secretions
• Another secretion that aids in digestion is bile, a non-enzyme
solution secreted by liver cells.
• The key components of bile are: salts for fat digestion, bile
pigments (e.g., bilirubin, a breakdown product of hemoglobin),
and cholesterol.
– The bile salts are formed by the combination of bile acids
(steroid detergents with polar side chains) with amino acids.
• Bile is secreted into the hepatic ducts that lead to the gall
bladder. During a meal, contraction of the gall bladder sends
bile into the duodenum through the common bile duct.
• Bile acts as a surfactant, that allows fats to form small droplets
that have a large surface area for digestion.
• Bile salts are not altered during fat digestion, and are
reabsorbed and taken through the hepatic portal system back to
the liver.
Other GI Secretions
• Hydrochloric acid is released by
parietal cells in the stomach. H+,
which is derived from CO2 and water
(this reaction is catalyzed by carbonic
anhydrase), is actively pumped into
the stomach in exchange for K+.
• Bicarbonate ion, another product of
the reaction, then diffuses into the
extracellular fluid and blood in
exchange for Cl-.
• Acid secretion by the stomach is
needed to denature proteins so they
can be digested. Stomach enzymes
work best at low pH.
Other GI Secretions
• Bicarbonate ions are formed in the
pancreas from CO2, which combines
with water under the influence of
carbonic anhydrase to form carbonic
acid. In turn, the carbonic acid
dissociates to form HCO3- and H+.
• The bicarbonate is pumped from the
pancreas into the lumen by secondary
active transport in exchange for Clions.
• H+ is pumped into the blood, also by
secondary active transport in
exchange for Na+.
• The secretion of HCO3- into the
lumen of the small intestine
neutralizes stomach acid and assures
that the environment remains alkaline.
Control of GI Secretions
• Hormones play the predominant role in the control of GI
secretions.
• In fact, the first hormone every discovered was a GI
hormone (secretin).
• Many gastrointestinal hormones are generally
recognized, or have been proposed. Those that we will
focus on in this course include:
Gastrin
Cholecystokinin (CCK)
Secretin
Vasoactive Intestinal
Peptide (VIP)
Enteroglucagon
Somatostatin
Gastric Inhibitory Protein (also called Glucose-Dependent Inslinotropic
Hormone or GIP)
Control of Gastrin Secretion
• Gastrin is synthesized by G cells in the stomach antrum, and its
secretion is triggered by peptides and amino acids in the lumen of the
stomach and by parasympathetic influences on the enteric nervous
system.
• Its targets are Enterochromaffin cells in the stomach (which release
histamine) and parietal cells in the stomach (which release HCl).
• Acid secretion in the stomach is thus triggered both directly and indirectly
by gastrin release, as the secretion of histamine from Enterochromaffin
cells also enhances gastric acid secretion.
• Histamine in itself does not generally induce HCl secretion, but it greatly
potentiates the effects of Gastrin on the parietal cells.
• Activity of the parasympathetic nervous system can also induce acid
secretion by Parietal cells.
• Gastrin release is inhibited by somatostatin release from D cells in the
stomach. As will be discussed below, this release is induced by the
presence of large amounts of stomach acid. CCK & secretin release
from the intestine have a similar effect.
Summary of Stomach Secretions
Summary of Stomach Secretions
Clinical Note
• A massive drug market exists to limit gastric
acid secretion
• One strategy is to block the histamine receptor
on parietal cells (e.g., cimetadine [Tagament],
ranitidine [Zantac-75], famotidine [Pepcid])
• Another treatment has been inhibitors of the
ATP-ase (H+/K+ ATPase) that pumps H+ out of
the parietal cells (e.g., omeprazole [Prilosec]
and lansoprazole [Prevacid]).
Clinical Note
• The original use of anti-acid therapies was to treat
peptic ulcers, damage to the stomach lining
• However, in the 1980s it was discovered that most
peptic ulcer patients all had a chronic infection of their
stomach wall by the bacterium Helicobactor pylori.
• Apparently, enzymes secreted by this bacterium
break down the mucus layer.
• The “latest and greatest” drugs for treatment of peptic
ulcer are aimed at destroying this bacterium.
Intrinsic Factor & Pernicious Anemia
• In addition to acid, parietal cells release
intrinsic factor
• Intrinsic factor is essential for the
absorption of Vitamin B12
• Lack of intrinsic factor results in
pernicious anemia, as this vitamin is
required to produce red blood cells
Control of CCK Secretion
• CCK is a hormone released by endocrine cells in the small intestine.
Interestingly, it also appears to be a neurotransmitter in both the
enteric nervous system and the brain.
• CCK release is stimulated by the presence of fatty acids and some
amino acids in the duodenum.
• CCK acts on the gall bladder to induce contraction, and the release
of bile into the small intestine (makes sense, as bile acts to emulsify
fats).
• CCK also acts in the stomach (presumably on parietal cells) to
reduce acid secretion; another effect is to reduce gastric motility.
These effects also make sense, because the small intestine can
only digest small amounts of fat at a time (and this response acts to
slow stomach emptying).
• CCK also acts to stimulate bicarbonate secretion from the intestine
and to enhance peristalsis in the small intestine.
• Finally, the hormone is a primary stimulant for pancreatic enzyme
secretion.
Control of Secretin Secretion
• The hormone secretin has some of the same effects as
CCK.
• Like CCK, it is secreted by endocrine cells in the small
intestine.
• Secretin release is stimulated by acid in the small
intestine.
• The effects of this hormone include: a stimulation of
bicarbonate secretion from the pancreas, bile secretion
from the liver, a stimulation of pepsinogen release in the
stomach, and an inhibition of gastric acid secretion.
• Gastric emptying is also inhibited by this hormone.
Control of VIP Secretion
• Vasoactive Intestinal Peptide (VIP) is both a
hormone and a neurotransmitter.
• In the gut, it is produced by cells in the enteric
nervous system.
• The factors leading to VIP release are unknown,
but obviously the release is the result of activity in
the enteric nervous system.
• VIP acts to stimulate somatostatin release from D
cells in the stomach, stimulate bicarbonate
release from the pancreas, and to decrease
motility.
Control of GIP Secretion
• GIP is released from endocrine cells in the small
intestine.
• Although this hormone was once thought to inhibit gastric
acid secretion (hence its original name, gastric inhibitory
peptide), the main role attributed to it today is the
stimulation of insulin release from beta cells of the
pancreas (hence its new name of glucose-dependent
insulinotropic peptide).
• The main trigger for the release of GIP is glucose and
amino acids in the small intestine.
• The role of GIP in controlling acid secretion is now
debated, as the concentration needed to produce this
effect is extremely high.
Control of Enteroglucagon Secretion
• Another hormone released from endocrine cells
in the small intestine is Enteroglucagon.
• This hormone may act together with GIP, as it
stimulates insulin secretion from the beta cells of
the pancreas.
• It is released when glucose is present in the small
intestine.
Control of Somatostatin Secretion
• A final GI hormone is somatostatin, which is
released from D-cells of the stomach.
• This hormone is not well understood, but seems
to inhibit gastric acid, pepsin, pancreatic enzyme,
and bicarbonate secretion.
• Its release appears to be triggered by acid in the
stomach and perhaps by the hormone VIP.
What Happens During a Meal?
• Digestion has traditionally been divided into three phases: a
cephalic phase, a gastric phase, and an intestinal phase.
– The cephalic phase is due to the effects of the brain on the enteric nervous
system, and begins when a person anticipates eating. During the cephalic
phase, the parasympathetic nervous system induces the G cells to produce
gastrin, the Enterochromaffin cells to release histamine, and the parietal
cells (directly) to release HCl. In addition, Pepsinogen is induced to be
released from chief cells.
– The gastric phase begins when food enters the stomach. The stimulants
for initiation of the gastric phase include distension of the stomach and the
presence of proteins and amino acids in the lumen. Initially, the distention
induces vago-vagal reflexes that result in stomach relaxation to allow a
large meal to enter. Then, the nervous system induces motility to begin.
Acid and pepsinogen release are also reinforced during the gastric phase.
– The intestinal phase of digestion occurs when chyme begins to enter the
small intestine. Feed-back then occurs to the stomach to restrict gastric
motility and to slow the release of materials into the intestine.
The
Intestinal
Phase of
Digestion
Summary:
Control of
Secretion
Blood Supply to
• Virtually all of the blood leaving the GI
the GI Tract
tract travels through the hepatic portal
vein and through the liver.
• Within the liver, reticuloendothelial cells
that line the liver sinusoids remove
bacterial and other large material that
may enter the general blood stream
from the GI tract.
• Most of the non-fat, water soluble
nutrients absorbed from the gut are
also transported to the liver sinusoids.
Here, liver cells absorb and store many
of the nutrients.
• Much intermediate processing of these
nutrients also occurs in the liver.
• Non—water-soluble, fat-based nutrients
are almost all absorbed by the liver
lymphatics and then conducted to the
blood via the lymphatic system.
Control of GI Blood Flow
• Under normal conditions, the blood flow in each area of the
gastrointestinal tract as well as in each layer of the gut wall is
directly related to the level of local activity.
– For example, blood flow to the intestinal villi increases during
absorption, and blood flow to the muscle layers increases
during motility.
• The “local factors” affecting this blood flow are still unclear, but
almost certainly include the gut peptide hormones
(cholecystokinin, vasoactive intestinal peptide, gastrin, and
secretin). These hormones typically induce vasodilation.
• The gut receives a huge blood supply during resting conditions.
This blood supply can be markedly reduced by actions of the
sympathetic nervous system in cases where the blood needs to
be diverted elsewhere (e.g., exercising muscles).
Absorption
by the GI
System
Absorption by GI Tract
• In general, almost all nutrient absorption occurs
in the small intestine; the only substances
absorbed more proximally in the GI tract are lipidsoluble substances, including alcohol and aspirin.
• The colon also is involved in absorbing water and
ions, as well as vitamins produced by the
“intestinal flora”.
• Both active transport and diffusion (both simple
and facilitated) are used to absorb materials in
the gastrointestinal tract.
+
Na
Absorption by GI Tract
• One very important ion to be absorbed is sodium, as large amounts are lost
into the lumen of the gastrointestinal tract in secretions.
• Sodium is actively transported from intestinal epithelial cells into the
bloodstream.
• Because the epithelial cells are constantly pumping sodium into the blood,
there is a concentration gradient for this ion that causes it to diffuse from the
gut lumen into the epithelial cells.
• The gastrointestinal tract makes use of this concentration gradient to move
other substances.
• The transport protein on the lumen side of the epithelial cells will only pass
sodium if it combines with another appropriate substance, which is usually
glucose.
• Through this mechanism, glucose is moved into the epithelial cell. In other
words, the initial active transport of sodium through the basolateral membrane
provides the “force” that drags glucose into the epithelial cell.
• A facilitated carrier for glucose exists on the basolateral membrane to move
this sugar into the blood.
• Similarly, co-transport mechanisms that use the Na+ gradient are mainly
responsible for amino acid absorption.
H2O Absorption by GI Tract
• In all parts of the body,
water is transported
through simple diffusion.
However, the
concentration gradient
that is set-up in the
epithelial cells by the
active transport of sodium
at the basolateral
membrane tends to “pull”
water in from the lumen,
and move it to the blood.
Fat Absorption by GI Tract
• Fats are digested to small
droplets composed of
monoglycerides and free fatty
acids, which are called micelles.
• Bile plays a critical role in this
process. Fats are not soluble in
water, the major constituent of
chyme. However, the bile salts
surround the micelle and make
the fats soluble.
• However, when a micelle becomes adjacent to the villi, it experiences a local
acidic environment because of transport occurring at the membrane. The
acidity causes the micelle to disintegrate, releasing the free fatty acids and
monoglycerides that diffuse into the epithelial cell (as they are lipophilic).
• Cholesterol is transported on a specific, energy-dependent membrane
transporter.
• Thus, micelles formed by bile are critical in transporting fats and cholesterol to
the intestinal brush border for absorption; without bile the fats were pass
through the colon undigested.
Fat Absorption by GI Tract
• Once in the cytoplasm of the endothelial cell, monoglycerides
and free fatty acids move to the smooth endoplasmic
reticulum, where they are re-synthesized into triglycerides.
• They then combine with cholesterol and proteins into large
droplets called chylomicrons. Formation of chylomicrons is
necessary to solubilize the fats.
• Because of their size, chylomicrons must be packaged into
secretory vesicles in order to leave the epithelial cells by
exocytosis.
• These particles are too large to cross the basement
membrane of capillaries, and are instead absorbed into
lymph vessels of the intestine.
• However, a few shorter fatty acids are able to diffuse across
the capillary wall and into the blood.
Clinical Note
• A new drug, Zetia (Ezetimibe), blocks the
absorption of Cholesterol from the GI
tract
• Zetia is effective in cases where blocking
cholesterol synthesis is not adequate
Absorption of Materials by the Colon
• As discussed previously, considerable water and ion absorption
occurs in the colon.
• Furthermore, many bacteria typically live in the colon. These
bacteria normally derive their energy supply by digesting
cellulose, which is not broken down in the colon and stomach.
An end result of this digestion are vitamin K and B12. In
particular, the vitamin K production can be important, as we
typically consume too little of this important substance.
• These bacteria also generate gases, including carbon dioxide,
hydrogen gas, and methane. Fermentation of some particular
undigested foods can lead to a production of large amounts of
these gases, and other foul-smelling products, which can have
undesirable social consequences.
• In general, movement of materials across epithelial cells in the
gastrointestinal system is achieved through very similar
mechanisms as used in the kidney.
What Isn’t Absorbed?
• Large molecules that can’t be digested (e.g.,
indigestible plant material such as cellulose) are
eliminated as feces.
• Typical, feces are composed of about 25% water
and 75% solids.
• The solid matter is composed, in addition to
undigested foods, of dead bacteria, sloughed
epithelial cells, and dried constituents of digestive
juices.
• The color of feces comes from derivatives of
bilirubin, a breakdown product of hemoglobin that
is a constituent of bile.