Download Lecture Notes - Pitt Honors Human Physiology

NROSCI/BIOSC 1070 and MSNBIO 2070
November 18, 2016
Gastrointestinal 1
Functions of the Digestive Tract.
The digestive system has two primary roles: digestion, or the chemical and mechanical
breakdown of foods into small molecules that can absorbed, or moved across the intestinal
mucosa into the bloodstream. In order to accomplish these functions, the secretion of enzymes,
hormones, mucus, and paracrines by the gastrointestinal organs is needed. Furthermore,
motility, or controlled movement of materials through the digestive tract is required.
In addition to these primary functions, the gastrointestinal tract faces a number of challenges.
Almost 7 liters of fluid must be released into the lumen of the digestive tract per day to allow for
digestion and absorption to occur. Clearly, most of this fluid must be reabsorbed or dehydration
will occur. Furthermore, the inner surface of the digestive tract is technically in contact with
the external environment; for this reason, protective mechanisms are needed. In part, these
mechanisms must protect against the secretions of the GI tract, including acid and enzymes.
Anatomy of the Gastrointestinal
System
November 18, 2016
Page 1
GI 1
The anatomy of the GI system is illustrated in the previous 2 figures. The organs involved in
digestion and absorption include the salivary glands, esophagus, stomach, small intestine,
liver, pancreas, and large intestine. In addition, 7 sphincters control the movement of material
and secretions between the organs. The total length of the GI tract is about 15 feet, of which
13 feet are comprised of intestine. The processed material within the GI tract is referred to
as chyme.
The wall of both the intestines and stomach is similar, in that it contains four (or five) layers:
mucosa, submucosa, muscle layer (sometimes divided into 2 layers), and serosa. The
mucosa is composed of epithelial cells, the lamina propria (connective tissue containing
nerves and muscles), and muscularis mucosa (specialized smooth muscle). The mucosa
has a number of specializations to increase surface area. Within the stomach, these occur
as folds called rugae. Within the small intestine, a number of fingerlike projections, or villi,
are present. The individual cells on the villi have further specializations that increase surface
area; these specializations are called microvilli. In addition, invaginations (called gastric
glands in the stomach and crypts in the intestine) exist in the GI tract. These invaginations
are lined with secretory cells.
Within the stomach, most of the epithelial cells of the mucosa are secretory. Six types of
secretory cells exist in the stomach:
Mucus-secreting cells
Parietal cells (secrete hydrochloric acid)
Chief cells (secrete pepsin)
G cells (secrete the hormone gastrin)
Enterochromaffin cells (secrete histamine)
D Cells (secrete somatostatin)
November 18, 2016
Page 2
GI 1
The submucosal layer contains large blood vessels and lymph vessels, and the submucosal
plexus, a major component of the enteric nervous system. We will discuss the enteric nervous
system in detail later in this lecture.
The muscle layer of the gut is composed of two layers of smooth muscle: an inner circular
layer and an outer longitudinal layer. Contraction of the circular layer decreases the diameter
of the lumen, and contraction of the longitudinal layer shortens the tube. Between the two
layers of muscle is the myenteric plexus, another component of the enteric nervous system.
The outer serosa forms the wall of the GI tract. It is an extension of the peritoneal membrane
that lines the abdominal cavity. Sheets of mesentery connect with the serosa to hold the
intestines in place.
Gastrointestinal Smooth Muscle
The cells in each bundle of smooth muscle are linked by gap junctions; therefore, electrical
signals travel easily from cell to cell. Thus, a layer of gastrointestinal smooth muscle forms a
syncytium, in that an action potential elicited anywhere in a bundle will evoke a contraction
of all surrounding muscle cells.
Three types of electrical activity are important in
control of contraction of gastrointestinal smooth
muscle: slow waves, spikes, and resting
membrane potential. Most gastrointestinal
contractions occur rhythmically, and the slow waves
play a key role in controlling these contractions.
Slow waves are slow oscillations that occur at
different frequencies at different points in the
gut (3/minute in the body of the stomach to 12/
minute in the duodenum). These slow waves are
presumably due to cycling changes in activity in the Na+—K+ pump. The slow waves mainly
reflect the entry of sodium into the smooth muscle cell, and thus in general do not cause
muscle contraction (recall that calcium that triggers smooth muscle contraction enters from
the outside).
Spike potentials occur when voltage-gated channels that pass calcium and sodium open. The
opening of these channels allows calcium to enter the smooth muscle cell, which induces
contraction. These channels have slow kinetics, which results in very long-lasting spikes.
Thus, if the resting membrane potential is sufficiently depolarized, the spike potentials will
occur at the crest of the slow waves.
November 18, 2016
Page 3
GI 1
In other words, control of resting membrane potential is all important in determining whether
gastrointestinal smooth muscle cells will contract.
Depolarization of GI smooth muscle cells can be induced by:
1)
2)
3)
Muscle stretch
Acetylcholine (released by cells of enteric nervous system)
Some specific gastrointestinal hormones
Hyperpolarization of GI smooth muscle cells can be induced by:
Norepinephrine and epinephrine (e.g., the effects of the sympathetic nervous system)
Control of Activity of Gastrointestinal Smooth Muscle
As noted above, two “plexuses” of nerve cells comprise the enteric nervous system of the gut.
The first plexus is in the submucosal layer, and the second plexus is between the longitudinal
and circular smooth muscle (myenteric plexus). These nerve cells receive innervation by the
sympathetic and parasympathetic nervous system, but can function without this input.
It was recognized over 100 years ago that a “coordinating network” of neurons must exist within
the gut. This conclusion was based on the observation that isolated segments of gut (taken
out of the body) could execute coordinated peristalsis. In the 1920s, the British physiologist
Langley speculated that the nerve network in the GI system was a third component of the
autonomic nervous system, and functioned much like the “neural net” of a primitive organism.
However, the enteric nervous system was largely ignored until the 1970s, and most
undergraduate texts don’t even mention it (they incorrectly state that the parasympathetic and
sympathetic systems directly affect GI control). Today, we are beginning to understand that
the functions of the enteric nervous system are indeed very complex. Here is the evidence
to suggest that the enteric nervous system is indeed a “little brain:”
• The neurons of the enteric nervous system release more than 20 neurotransmitters and
neuromodulators, many of which are identical to molecules found in the brain. These
neurotransmitters are sometimes called “non-adrenergic, non-cholinergic” to distinguish
them from the “traditional” autonomic neurotransmitters: norepinephrine and acetylcholine.
The transmitters of the enteric nervous system will be discussed below, but they include
serotonin, Vasoactive Intestinal Peptide (VIP), and Nitric Oxide.
• The support cells of neurons in the enteric nervous system are more similar to the astroglia
of the brain than to the Schwann cells of the peripheral nervous system
November 18, 2016
Page 4
GI 1
• The capillaries that surround ganglia within the enteric nervous system are not very
permeable and create a diffusion barrier that is similar to the blood-brain barrier of cerebral
blood vessels
• Reflexes resulting from stimulation of sensory receptors in GI tract can be integrated and
elicited entirely within the enteric nervous system. Thus, the enteric nervous system must
have the “sophistication” of coordinating these responses.
Organization of the Enteric Nervous System
In general, the enteric nervous system is organized into two sheets, the submucosal plexus
and the myenteric plexus. The submucosal plexus mainly regulates secretory functions and
vasomotor control, whereas the myenteric plexus mainly regulates motility.
In reality, the cell bodies in the submucosal and myenteric plexus are concentrated into
ganglia, with interganglionic fiber tracts interconnecting them.
November 18, 2016
Page 5
GI 1
Why does the Enteric Nervous System Exist?
In large part, the enteric nervous system serves as a “pattern generator” for the carefully
coordinated sequence of contractions that results in motility. By relinquishing this control to the
periphery, the central autonomic systems do not have to worry about coordinating this activity.
In large part, the pacemaker system in the heart serves a similar role. Pattern generators in
the central nervous system like the respiratory pattern generator and the locomotion generator
follow the same idea of “higher centers” relinquishing control of stereotyped functions to lowerlevel coordinators.
One clear response that the enteric nervous system produces is the “migrating action
potential complex” (or “migrating motor complex”) which propagates through both normal
gut and that removed from the body and placed in a tissue bath. Many hours after eating a
meal, when the digestive system is not influenced by chemical inputs from the lumen, this
special pattern of activity propagates through the stomach and small intestine about once
every 90 min. Because this response involves a contraction that sweeps through most of
the digestive tract, it must be precisely coordinated. The occurrence of this response, which
apparently takes place to sweep debris out of the gut, shows the extent of influences of the
enteric nervous system. Propulsive and mixing contractions can also take place in the isolated
gut, suggesting that the enteric nervous system also controls these responses.
Connections between the myenteric and submucosal plexus, and extrinsic
influences on the enteric nervous system.
The submucosal and myenteric layers appear to largely subserve different functions: the
submucosal layer participates in regulating secretion and blood flow whereas the myenteric
layer is involved in motility. However, there also seems to be coordination between these
functions. There is good electrophysiological evidence that submucus neurons receive
cholinergic and non-cholinergic excitatory input and non-cholinergic inhibitory inputs from
myenteric neurons. Similarly, a population of submucus neurons project to the myenteric
plexus. The precise role of these interconnections in influencing GI function is currently
unknown.
The enteric nervous system and its target tissues receive inputs from the sympathetic and
parasympathetic nervous systems, which influence motility, secretion and blood flow. Perhaps
these influences are analogous to the sympathetic and parasympathetic influences on the
pacemaker system of the heart (which serve to regulate rate, but not pattern of activity).
The parasympathetic influences to the upper GI tract are mediated by the vagus nerve. In
contrast, the distal half of the colon is innervated by the sacral division of the parasympathetic
nervous system. The postganglionic parasympathetic neurons are components of the enteric
nervous system. The sympathetic nervous system mainly influences motility through inputs
to the enteric nervous system, but to some extent through direct influences on smooth muscle
cells.
November 18, 2016
Page 6
GI 1
Many afferents originating in the gastrointestinal tract influence central nervous system activity.
These afferents can be activated by irritation of the gut mucosa, distension of the gut, or the
presence of specific chemical substances in the gut. Some of these afferents are “local,”
in that their cell bodies and terminations are in the enteric nervous system. Some of these
afferents also make connections in prevertebral sympathetic ganglia. In other cases, the
cell bodies are in the dorsal root ganglia; the axons of these afferents course in sympathetic
nerves. Other gastrointestinal afferents course in the vagus nerve to the brainstem; their cell
bodies are in the nodose ganglion.
A number of hormones affect gastrointestinal motility; some of these agents also affect
secretion. Cholecystokinin is secreted by “I” cells in the mucosa of the small intestine,
mainly in response to breakdown products of fat. As we will see later, this hormone causes
the expulsion of bile from the gall bladder into the stomach. In addition, it inhibits stomach
motility, so that food is emptied from the stomach into the intestine more slowly. Secretin is
secreted by “S” cells in the mucosa of the duodenum, in response to gastric acid released by
the stomach. It acts to inhibit motility throughout the GI tract. Gastric inhibitory peptide,
secreted by the mucosa of the upper small intestine, is similar to cholecystokinin in that it
slows emptying of materials from the stomach. The hormone gastrin, which is released by
cells in the antrum of the stomach in response to the presence of certain foods and stomach
distension, has a mild stimulatory effect on stomach motility.
Patterns of Contraction of GI Smooth Muscle
There are three major types of contractions of gastrointestinal smooth muscle:
1)
2)
3)
Tonic, sustained contractions
Peristaltic contractions
Segmental contractions
Sustained contractions occur in the sphincters, which only occasionally relax to allow
materials through. Peristaltic contractions move materials down the digestive tract. These
movements occur when the circular layer of muscles contracts behind a bolus of food, whereas
the muscles in front of the bolus are relaxed. Segmental contractions occur to mix food.
Alternate segments of intestine contract and relax, propelling materials for short distances in
both directions. Segmental contractions take place through the simultaneous contraction of
circular smooth muscle and relaxation of longitudinal smooth muscle in one segment, and the
opposite pattern of contractions in the next segment.
November 18, 2016
Page 7
GI 1
Movement of Food through the
Gastrointestinal Tract
Mastication and deglutition.
Mechanical digestion of food begins in the
oral cavity with chewing. The lips, tongue
and teeth contribute to mastication of food,
creating a softened mass that can be easily
swallowed. Mastication is an important
process, as it increases the surface area
of food that will be exposed to digestive
enzymes.
Swallowing (deglutition) occurs in three
stages:
1)
A voluntary stage, which initiates
the swallowing process
2)
An involuntary pharyngeal stage
3)
An esophageal stage
The voluntary stage of swallowing involves
the moving of food into the pharynx by the
actions of the tongue.
November 18, 2016
Page 8
GI 1
The involuntary pharyngeal stage of swallowing is triggered by the stimulation of receptors near
the opening of the pharynx, whose axons terminate in nucleus tractus solitarius. Stimulation
of these receptors evokes a coordinated response that involves outflow along cranial nerves
5, 9, 10 and 12. Contraction of pharyngeal muscles causes closing of the glottis, the opening
between the pharynx and larynx, so that no materials move into the airway. At the same time,
respiration is inhibited and the upper esophageal sphincter relaxes.
The esophageal stage of swallowing has two components: primary peristalsis and secondary
peristalsis. Primary peristalsis is a continuation of the swallowing reflex that began in the
pharynx. Secondary peristalsis is initiated by distention of the esophagus by a large bolus
of food, which triggers reflex contractions. The afferents that evoke secondary peristalsis
send their axons through the vagus nerve, which also carries the efferent outflow from the
brainstem to the esophagus. The musculature of the upper third if the esophagus, like that
of the pharynx, is striated muscle, which is controlled by the vagus nerve. The lower twothirds of the esophagus contains smooth muscle, whose activity is mainly controlled by the
enteric nervous system (but influenced by the parasympathetic nervous system). Thus, even
if the vagus nerve is sectioned, swallowing can occur if food reaches the lower part of the
esophagus (but note that the striated muscle of the pharynx and upper esophagus requires
neural input to contract).
The activity of the enteric nervous system also causes the relaxation of the lower esophageal
sphincter when a bolus of food approaches. The tight closing of this sphincter is needed to
prevent reflux of acid from the stomach into the esophagus.
Stomach Motility.
When food enters the stomach, it stimulates receptors, and through a “vasovagal reflex”
induces relaxation of the stomach wall so the stomach can be distended with food. The
contractions of the stomach are mainly weak, and for the purpose of mixing food with stomach
secretions. At the antrum of the stomach, contractions are more intense, and aid in stomach
emptying. With each slow wave some materials are pushed through the pyloric sphincter
into the duodenum. Typically, the pyloric sphincter is only partially contracted, which allows
liquid materials to pass along. The degree of constriction of the pylorus can be increased or
decreased by nervous and hormonal signals.
Motility in the stomach is influenced most prominently by the hormonal factors listed above
(gastrin release from the stomach has a stimulatory effect, whereas cholecystokinin, secretin
and gastric inhibitory peptide release from the duodenum inhibit stomach motility).
Motility in the Small Intestine.
As discussed above, both mixing and propulsive contractions occur in the small intestine. These
contractions occur no more rapidly than a rate of 12/minute, the frequency of occurrence of
slow waves in the small bowel. The rate of motility is influenced by distension of the intestine,
which effects the excitability of cells of the enteric nervous system. A number of hormones
released from the small intestine also modestly enhance motility in the small intestine.
November 18, 2016
Page 9
GI 1
Under unusual conditions, however, irritation of the bowel wall or central nervous system
influences can induce the enteric nervous system to rapidly empty the digestive system. This
“peristaltic rush” helps to remove toxins when they are present.
The ileocecal valve permits one way movement of materials from the small intestine into the
colon. Its physical structure of overlapping “lips” assists with this process.
Motility in the Colon.
The regulation of motility in the colon is similar to that in the small intestine. The main functions
of the colon are to absorb water from residual products of digestion and to store the material
until elimination. Mixing contractions, which are called haustrations in the colon, can be very
intense, but are needed to expose the fecal material to the intestine wall to permit reabsorption
of water. Strong propulsive movements occur in the distal part of the colon to force feces into
the rectum.
Defecation.
Elimination of wastes is usually triggered by the entry of material into the rectum. Afferent
signals affect the enteric nervous system of the distal colon, causing propulsive movements
of further materials towards the anus. The enteric nervous system also causes the relaxation
of the internal anal sphincter. At the same time, afferents whose cell bodies are in the sacral
dorsal root ganglia evoke a conscious sensation of a filled rectum. These inputs can induce
a voluntary relaxation of the external anal sphincter, which is composed of striated muscle.
Thus, both conscious and autonomic activity is required for defecation to take place.
Secretion in the Digestive System
As noted previously, about 7 liters of secretions enter the GI system per day, as summarized
in the following table:
Salivary Glands
1.5 L
Liver (Bile)
0.5 L
Stomach Secretions
2.0 L
Pancreas Secretions
1.5 L
Intestine Secretions
1.5 L
———7.0 L
Obviously, most of this fluid most be reabsorbed or dehydration will occur. Most of the absorption occurs in the small intestine, although some occurs in the colon. Only about 0.15 L
of water per day are lost in the feces.
November 18, 2016
Page 10
GI 1
Digestive Enzymes.
Digestive enzymes are secreted by exocrine glands (salivary glands and the pancreas) or by
epithelial cells in the stomach and small intestine. These enzymes are proteins, and are packaged by the Golgi apparatus into secretory vesicles and stored within the cell until needed.
On demand, they are released into the extracellular space by exocytosis. Some of these
enzymes become mixed with chyme, and others are attached to the brush border (microvilli)
on the epithelial cells.
Some digestive enzymes are secreted in an inactive proenzyme form, and must be activated
by other agents. Amongst these enzymes are pepsinogen in the stomach and the pancreatic
enzymes chymotrypsinogen, procarboxypeptidase, procolipase, and prophospholipase.
These pancreatic enzymes are converted to their active form by trypsin, a conversion product
of the pancreatic enzyme trypsinogen. Trypsinogen is converted to trypsin through the actions of the brush border enzyme enteropeptidase (also called enterokinase).
Left diagram: Activation of pepsinogen in stomach.
Right diagram: Activation of pancreatic enzymes.
Question for discussion: Why are some digestive enzymes released in an
inactive form?
November 18, 2016
Page 11
GI 1
The following table summarizes the major digestive enzymes:
November 18, 2016
Page 12
GI 1
We will discuss the factors that influence the secretion of digestive enzymes below. In fact,
a number of control mechanisms exist. Salivary secretion is under neural control (mainly
parasympathetic control via cranial nerves VII and IX). In contrast, stomach and intestine
secretions are both under neural and hormonal control.
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 specialized mucus
cells in the stomach and globlet cells in the 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.
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.
Active transport processes are involved in moving ions into and out of epithelial cells. Two very
important ions that are secreted in high concentration is H+ in the stomach and HCO3- from
the pancreas into the small intestine. These secretions are important, because enzymes in
the stomach work well at low pH, whereas those secreted into the small intestine work best
at alkaline pH.
November 18, 2016
Page 13
GI 1
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-.
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 Cl- ions. H+ is pumped
into the blood, also by secondary active transport
in exchange for Na+.
Control of Secretion in the GI System
Obviously, both neural activity and the release of hormones play a role in the control of gut
secretions (since all other physiological processes are controlled by these mechanisms).
Although the enteric nervous system acts as a “little brain,” its functions are profoundly affected
by the central nervous system. For example, Pavlov demonstrated that acid secretion in the
stomach could be conditioned, and could be triggered by the sounding of a bell. Gastrointestinal
physiologists often speak of the cephalic phase of digestion, in which the sight, smell or
anticipation of food initiate secretion even before eating begins. Obviously, these effects are
an efficient adaptation, as the GI tract is prepared for the receipt of food. Sometimes, these
effects are also called “long reflexes,” to distinguish them from the “short reflexes” mediated
exclusively by the enteric nervous system.
Hormones also play a huge role in the control of secretion in the gastrointestinal system.
In fact , some of the earliest studies of hormones were conducted by gastrointestinal
physiologists. In the early 1900s, Baylis and Starling discovered that acid entering the small
intestine triggers the release of pancreatic juices even after the neural innervation of the gut is
severed. They speculated that a blood-borne agent released from the duodenum had effects
on the pancreas. Furthermore, they showed that extracts of the duodenum, when placed
November 18, 2016
Page 14
GI 1
on the pancreas, induced secretion. They termed the hormone released from the duodenum
“secretin”. Starling then coined the name “hormone,” from the Greek word meaning “I excite,”
to describe substances like secretin.
Many gastrointestinal hormones are recognized, or have been proposed. Those that we
will focus on in this course include: Gastrin, Cholecystokinin (CCK), Secretin, Vasoactive
Intestinal Peptide (VIP), Gastric Inhibitory Protein (also called Glucose-Dependent
Inslinotropic Hormone or GIP), Enteroglucagon, and Somatostatin.
These hormones are typically separated into three classes:
Gastrin Family
—
Includes CCK and Gastrin
Secretin Family —
Includes Secretin, VIP, and GIP
Others —
Includes Enteroglucagons and
Somatostatin
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.
One of the most common “ills” is peptic ulceration, damage to the stomach wall by acid
when the protective mucus barrier breaks down. A very common modern treatment for
peptic ulcers has been antihistamines (e.g., cimetadine [Tagament], ranitidine [Zantac-75],
famotidine [Pepcid]) that block the H2 receptors on parietal cells. Another treatment has been
inhibitors of the ATP-ase that pumps H+ out of the parietal cells (e.g., omeprazole [Prilosec]
and lansoprazole [Prevacid]). 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.
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 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 has a number of effects. It 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). It 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
November 18, 2016
Page 15
GI 1
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.
Another interesting effect of CCK occurs in the brain. This hormone apparently is “monitored”
by the brain (probably binds to receptors in a circumventricular organ like Area Postrema).
The physiological role of CCK actions in the brain are not well understood, although high blood
concentrations of the peptide are known to induce nausea.
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.
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.
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.
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.
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.
Integration of GI Function — 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.
November 18, 2016
Page 16
GI 1
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. For example, the release of secretin and CCK from the small
intestine act to inhibit motility and acid secretion. If the meal contains carbohydrates, then
GIP is released, which may inhibit acid secretion if the concentration is high enough. The
mixture of acid, enzymes, and digested food in chyme usually forms a hyperosmotic solution.
Osmoreceptors in the wall of the intestine detect this osmolarity, and inhibit gastric emptying.
The hormone mediating this effect has not been identified.
November 18, 2016
Page 17
GI 1
Synthesis of Information — Control of Stomach Function
November 18, 2016
Page 18
GI 1
Blood Supply to the Gut
Virtually all of the blood leaving the GI
tract travels through the hepatic portal
vein and through the liver. Here, blood
travels through liver sinusoids and finally
leaves the liver by way of the hepatic
veins that empty into the vena cava.
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, thus preventing access of
harmful agents to the body. 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—watersoluble, fat-based nutrients are almost all
absorbed by the liver lymphatics and then
conducted to the blood via the lymphatic
system.
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.
Recall from the cardiovascular lectures that 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).
November 18, 2016
Page 19
GI 1
Absorption of materials in the GI tract
In general, almost all nutrient absorption occurs in the small intestine; the only substances
absorbed more proximally in the GI tract are lipid-soluble 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.
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.
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.
November 18, 2016
Page 20
GI 1
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, energydependent 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.
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.
Nucleic acids are digested into bases and monosaccharides. The bases are absorbed by
active transport. Fat-soluble vitamins (A, D, E, and K) are absorbed along with fats. The
water soluble vitamins are absorbed via mediated transport. A noted exception is vitamin
B12. This vitamin must be complexed to a protein called intrinsic factor, which is released
along with HCl by parietal cells of the stomach, in order to be recognized by its transporter.
People with severe damage to the stomach wall, and who lack intrinsic factor production, have
a great deal of difficulty in absorbing this vitamin. B12 is required for red blood cell synthesis,
so people lacking this vitamin suffer from anemia.
November 18, 2016
Page 21
GI 1
A special note is required about absorption in 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 75% water and 25% 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.
November 18, 2016
Page 22
GI 1