Gastrointestinal Manifestations of Disease
The Small Intestine
intestine of the human consists of three portions: duodenum (10
inches), jejunum (8 feet), and ileum (12 feet). The wall
of the intestine is made up of mucosa and submucosa.
The mucosa, in turn, is divided
into three layers: epithelium, lamina propria and
Evaginations of the mucosa, termed villi, project into the intestinal
lumen. Between the villi are crypts; these are minute depressions
of the mucosa that extend into the lamina propria. There are 3 crypts for
The intestinal epithelium is a continuous single layer of cells that covers the entire surface of the intestinal wall facing the intestinal lumen. It covers the villi, the area between the villi as well as the sides and bases of the crypts.
The intestinal epithelium
consists of 4 cell types: the columnar absorptive cell
(making up 90% of the total cells), the goblet cell (9.5%
of total), the Paneth cell and the undifferentiated columnar
Covering the sides and tips
of the villus is the columnar absorptive cell. This cell has, on its luminal
surface, projections termed microvilli. These microvilli in turn,
have projections of glycoprotein molecules which are termed the glycocalyx.
This glycocalyx has enzymatic properties, i.e. it is a saccharidase, alkaline
phosphatase and aminopeptidase. These glycoprotein enzymes have a hydrophobic
end imbedded in the lipid of the cell membrane and a hydrophilic end projecting
into the lumen. This hydrophilic end contains the substrate binding site.
The function of the columnar absorptive cell is the absorption of water,
minerals, amino acids and simple sugars.
The goblet cells are interspersed among the absorptive columnar cells of the epithelium along the sides and tips of the villi. The apical two-thirds of these cells are filled to the point of distention by an accumulation of membrane-bound mucin secretory granules. Once secreted from these unicellular glands the mucous forms a luminal lining lying on top of the glycocalyx of the microvilli. The mucous lubricates and forms a barrier which protects the mucosal epithelium from potentially noxious intraluminal substances. Goblet cell secretion of mucin is induced by enterotoxins of Escherichia coli and Vibrio cholerae as well as by immune complexes.
The Paneth cells occur in small groups at the base of the intestinal crypt. These have both phagocytic and secretory properties and thus provide the first line of immune defense against intestinal microorganisms. They secrete lysozyme (which dissolves the cell wall of bacteria) and secretory IgA.
The undifferentiated columnar cells occur at the base of the crypt where they are interspersed with the Paneth cells. This is the cell production site of the epithelium. These cells are in constant replication; they are the progenitor of the columnar absorptive cell, the goblet cell and Paneth cell.
Underlying the intestinal epithelium is the lamina propria. This is a compact stroma, composed mainly of reticular and elastin fibers. It has extensive beds of blood and lymph capillaries and it is into these that the absorbed food matter passes. Plasma cells and lymphocytic cells are especially numerous in this tissue, the latter often being amassed into solitary or aggregated lymph follicles (Peyer's patches). There is extensive trafficking of lymphocytes through the Peyer's patches. Thus, this presents a second line of immune defense against microbial invasion from the lumen of the intestine.
The muscularis mucosa is a thin bilaminar plexus of circular (inner) and longitudinal (outer) smooth muscle fibers which clearly demarcates the mucosa and submucosa. The muscularis mucosa enables alteration of the focal conformation of the mucosa independent of other movements of the digestive tract, increasing its contact with food.
Most cells formed from the undifferentiated columnar cell at the base of the crypt, migrate along the sides of the villi up to the tip of the villi where they are sloughed off. As they migrate they differentiate into the absorptive columnar cell or the goblet cell. This is a continuous process whereby the cells of the epithelium are replaced every 3 days. The rapidly replicating undifferentiated columnar cells are almost continually undergoing mitosis which makes them especially sensitive to the effects of radiation therapy, cancer chemotherapy and various toxins and enzymes of microbial cells. When their reproduction is interrupted, the other cells of the epithelium continue to migrate and slough off. This disrupts the epithelium which causes 3 major effects: compromization of the first line of microbial defense, malabsorption and diarrhea.
The intestine absorbs both exogenous fluids and its own secretions. The secretions of the intestine and digestive glands are so great that, were they not resorbed, death from dehydration would result in 24 hours.
Daily flux of gut water and
|Transit ileum to colon||
One or more central arterioles carry arterial blood to the tip of a villus, and near the tip the arterioles break into a rich capillary network that descends the villus just beneath the bases of the epithelial cells. Thus, blood shoots up the villus as in a fountain and then falls back around the central stream. This arrangement permits countercurrent exchange of absorbed substances between the descending network and the ascending vessels.
Only a few of the absorptive processes are regulated. The intestine indiscriminately absorbs water, the major electrolytes, and the products of digestion of foodstuffs, but absorption of calcium and iron is adjusted to the body's needs. Three properties of the intestinal mucosa determine its handling of water and electrolytes:
1. Gradient of permeability.
Permeability of the intestinal mucosa to water and electrolytes is high
in the duodenum and jejunum.
It decreases along the length of the intestine until permeability in the ileum is low. The tight junctions between intestinal epithelial
cells are the site of most permeation by water and electrolytes. In the duodenum and jejunum they are "leaky" tight junctions.
Water and electrolytes can pass through them in either direction, depending upon the effective osmotic gradient for water or the
electrochemical gradient for an electrolyte. The tight junctions are cation-selective; that is, cations such as Na+ and K+ pass
through the junctions more rapidly than do anions such as Cl- and HCO3-. The junctions are not, however, absolutely
cation-selective. Divalent ions such as Mg++, Ca++ and SO4-- penetrate the junctions only slightly, if at all, and uncharged
molecules above 200 mW are excluded.
2. Na+ - H+
exchange. Throughout the length of the small intestine there is exchange
of Na+ from the lumen for H+ from the cell
interior across the apical membrane of the intestinal epithelial cells. Na+ is pumped out of a cell across its basolateral border,
and the concentration of Na+ within the cell is relatively low. In addition, the potential difference across the apical membrane is
positive outward and negative inward. Consequently, there is an electrochemical gradient drawing Na+ from the luminal fluid into
the cell. Exit of Na+ from cell to interstitial fluid is accomplished by an energy-consuming pump in the basolateral membrane.
Although a number of H+ ions are extruded equivalent to the number of Na+ ions entering the cells, the gradient of H+
concentration across the apical membrane of the cell is very small; extrusion requires very little energy, and that energy may be
derived from the Na+ gradient. As Na+ is absorbed, Cl- follows passively.
3. Cl- - HCO3-
exchange. In the ileum, but not in the jejunum, there is equal exchange
of Cl- from the luminal fluid for HCO3-,
the cell interior across the apical membrane of the epithelial cells. Cl- entering the cell is extruded across the basolateral border
into interstitial fluid.
The Large Intestine
and the muscularis mucosa of the large intestine do not vary significantly
from that of the small intestine except
for the profusion of lymphocytes, macrophages and plasma cells that locally produce IgA within the lamina propria. This is a
reflection of the more than 500 species of bacteria present in the lumen of the large intestine.
The mucous membrane of the large intestine does differ from that of the small intestine in several aspects:
are no villi.
2. The intestinal crypts are larger, more numerous and more densely packed.
3. One-fourth of the epithelial cells are goblet cells (vs. one-tenth in the small intestine). Thus the large intestine is well lubricated
with a heavy mucous.
4. There are no Paneth cells.
All that is left of the chyme, which formed the contents of the upper small intestine, by the time it reaches the ileum is the unabsorbable constituents of the diet such as dietary fiber, lignum, waxes, high melting point fats, insoluble or unabsorbable salts and the bodies of the saprophytic bacteria, which inhabit the lower small bowel, plus about 2 liters of water per day containing Na+ in concentrations isotonic with plasma. In contrast to the small intestine, the large intestine absorbs all of the fluid and Na+ that enters it, except for the 100 ml fluid lost per day in the feces and about 4 mmol of Na+. If in excess of 3 liters of water enters the cecum, the upper limit of the colon's absorptive capacity is exceeded and diarrhea results.
Water moves passively with Na+ and Cl-, but neither the movement of these ions nor of water is unidirectional or isotonic. Na+ and its accompanying anion and water diffuse fairly easily back into the lumen, but the net flow is usually in the direction of active absorptions into the portal blood. This is usually 4 times as rapid as back diffusion into the lumen.
Davenport, H.W. 1982. Physiology of the Digestive Tract, 5th Edition. Year Book Medical Publishers, Inc. Chicago, Illinois.
Magee, D.F. and A.F. Dalley II. 1986. Digestion and the Structure and Function of the Gut. S. Karger AG, Basel, Switzerland
Consider the gastrointestinal
tract as a tube through the center of the body extending from the oral
cavity to the anus. The walls of this tube serve as the interface between
the external environment and the body. Through this tube passes all of
the liquid and solid material we ingest. Carried with the ingested material
are bacteria which tend to colonize those parts of the tube that offer
a suitable environment for growth, establishing a "normal" flora for each
part of the tube.
Thus, we see that each end
of the tube, the oral cavity and the colon, are heavily colonized while
the central part of the tube, the esophagus, stomach, duodenum, jejunum
and the proximal half of the ileum, are lightly colonized.
Each portion of the gastrointestinal tract has special anatomic, physiological and biochemical barriers to infection by the normal flora or pathogenic microorganisms. When there barriers are breached by microorganisms or their toxins we have disease. The barriers to infection of the GI tract include:
unbroken mucosal epithelium covering all parts of this system. Under normal
conditions epithelial cells are continually
sloughed off and replaced. As the cells are sloughed off, any microorganisms attached to these cells or within these cells
enter the internal chyme and are excreted from the body. If the sloughing process is interfered with, microorganisms more
easily form foci of infection. If the normal replacement process is interfered with, as in radiation therapy or cancer
chemotherapy, there is ulceration of the mucosa with the resulting clinical symptoms of nausea and vomiting. Infection of the
ulcer will lead to septicemia and fever.
glycocalyx, a glycoprotein and polysaccharide layer that covers the surface
of the epithelial cells. This presents a thick,
relative to the size of bacteria, physical barrier as well as a chemical trap that binds microorganisms.
The mucous plays two roles in disease prevention; it acts as a physical
barrier in preventing bacterial access to the
epithelial cells and it coats the bacteria, making it easier to remove them via peristalsis.
of the stomach. The normal pH of the stomach is less than 4. This acidity
spills into the small intestine establishing a
pH gradient that prevents most bacteria from colonizing the stomach, duodenum, jejunum and upper half of the ileum.
Because of this, the majority of ingested pathogens never reach the intestinal tract. Over 99.9% of ingested bacteria are killed
after 30 minutes exposure to stomach acidity. Alteration of the acid barrier of the stomach by disease, surgery, drugs or
antacids increases the survival of pathogens across this organ and may lead to microbial infection downstream. For example,
the inoculum of Vibrio cholerae required to cause disease is 108 organisms. If gastric acidity is neutralized by 2 gm of sodium
bicarbonate, only 104 ingested organisms are required to cause disease.
Bile solubilizes lipids; it thus inactivates those organism having a lipid
envelope. All enveloped viruses and many bacteria
are thus prevented from growing in areas of high bile salts. Obstruction of the flow of bile due, for example, to gallstones has
two effects: downstream from the blockage and into the intestine non-normal flora (i.e., organisms with an outer lipid
membrane) can proliferate and cause disease and upstream from the block bile salts accumulate and initiate a cycle of
inflammation and damage to the gallbladder wall which often becomes a site of infection (cholecystitis)
F. IgA. Secretary IgA helps prevent colonization by certain species of bacteria.
G. In children lactoferrin in the mother's milk has a similar function to IgA.
blood cells, especially neutrophils, have their final stopping point in
the intestine. They play an undetermined role in
controlling pathogens and maintaining the balance of normal flora.
I. Gut motility. Peristalsis contributes to the health of the gut by:
1. Aiding in the fluid absorption process
2. Maintaining appropriate dilution of indigenous enteric microflora
3. Ridding the host of pathogenic microorganism by hindering adherence of micro-organisms to receptors in the epithelial wall.
patches. These are whitish unencapsulated patches of lymph follicles in
the mucosa and sub-mucosa of the small
intestine which provide a "gut-homing" site for lymphocytes. This allows certain antigen-specific lymphocytes to come into
contact with their appropriate antigen in the microenvironment of the Peyer's patches. In addition there is non-specific
lymphocyte trafficking through the Peyer's patches; about 1-2% of the lymphocyte pool recirculate each hour providing a ready
source of white blood cells. The intestinal mucosa demonstrates a state of "physiologic inflammation" in the lamina propria,
with neutrophils, macrophages, plasma cells and lymphocytes present - suggesting a constant battle to maintain the integrity
of the mucosa.
flora. Of the normal microflora, 99.9% are anaerobes, mainly members of
Peptostreptococcus. The remaining organisms are aerobes or facultative cells of the genera Escherichia, Proteus and
Pseudomonas as well as other less numerous species. These normal non-pathogenic flora compete with potential pathogens
for nutrients and intestinal receptor sites, thus keeping them from causing disease.
The gastrointestinal tract is subjected to continual challenge by pathogenic microorganisms but is well protected by the various barriers discussed above. It is only when one or more of these barriers is breached that we have disease. Some of the more common factors that compromise the human are:
of antacids which neutralize stomach and upper intestinal acidity and allow
microorganisms to proliferate on areas
that are normally lightly colonized.
B. Antibiotic therapy which destroys the normal flora and thus reduces competition that pathogens are normally subjected to.
C. Glucosteroid therapy which reduces the immune reaction.
D. Cancer chemotherapy which reduces both normal flora and cellular and humoral immunity and intestinal epithelium integrity.
E. Radiation therapy which affects immunity and sometimes upsets the balance of normal flora and intestinal epithelium integrity.
F. Ingestion of pre-formed toxins with food and/or water.
G. Ingestion of microorganisms which produce toxins/enzymes/ immune suppression factors in situ.
alterations. Obstructions to the flow of liquids remove one of the most
powerful defensive mechanisms of the
gastrointestinal tract. Thus, stones in the gallbladder that impede the flow of bile predispose the biliary tree to infections. The
presence of large diverticuli or the surgical formation of intestinal "blind loops" create sites with reduced flow of intestinal
contents, leading to bacterial overgrowth and metabolic derangements.
1. Gross examination (watery, mucoid or bloody)
2. Microscopic examination
a. Fecal leukocytes (non-inflammatory reaction vs. inflammatory reaction)
b. Sudan stain for fat globules (large fat globules indicates malabsorption)
c. Eosin stain (stains undigested muscle fibers, indicating pancreatic insufficiency and maldigestion)
d. pH (acidic pH indicates lactose intolerance in children) - normal pH is greater than 7.
e. Copper sulfate reaction - presence of reducing sugars indicates carbohydrate malabsorption.
f. Occult blood test
g. Culture for enteric pathogens
B. Blood culture for septicemia
C. Serological tests (e.g., typhoid fever, amebiasis)
D. Toxin assays - Rabbit loop test, Sereny test, adrenal cell assay
E. Elisa test for LT of E. coli and Vibrio cholerae