Epithelial Cell Defense Mechanisms
of the Digestive System
The potential for
intraluminal contents to cause severe, even lethal, injury to the patient
warrants highly specialized and effective cellular and noncellular defense
mechanisms against the “tube within the tube.” An increasingly recognized
characteristic of individuals who are susceptible to digestive diseases is the
degree to which the epithelial lining provides an ineffective barrier and,
thus, a “leaky gut.” This occurs in patients with Crohn disease, celiac
disease, food allergies, and food intolerance.
The first line of defense from intraluminal contents is the partial
barrier created by the glycocalyx coat secreted by submucosal glands, goblet
cells, and epithelial cells throughout the length of the gut. This thick mucoid
substance is a complex mixture of mucins, glycoproteins, and trefoil factor like
peptides. Its slippery nature serves as a lubricant to reduce the shearing
forces produced by contractions and swallowed solids. In the stomach, mucus retards
the diffusion of bicarbonate away from the epithelium to create a pH gradient
that ranges from 1.0 at the surface of the mucus to a neutral 7.0 at the
epithelial cell surface. In the intestine, it serves to retard diffusion of
foreign antigens and microorganisms toward the surface while retaining
secretory IgA molecules that have been released into the lumen, at the surface.
This glycocalyx can also trap antigens within this sticky material to
eventually be passed in stool.
The heterogeneous cells lining the gut all share the ability to provide
an effective physical barrier that is resistant to invasion of microorganisms
and toxins and to diffusion of electrolytes. Intestinal epithelial cells can also influence the immune response by
secreting pro- inflammatory mediators, including cytokines, chemokines, and
adhesion molecules. They can also process invading microorganisms or absorbed
toxins, neutralize them, and then serve as antigen-presenting cells to T cells
in the lamina propria’s immune system. Finally, it is important to mention the
intricate systems within epithelial cells that are able to recognize when a
cell is being overcome by antigen excess, triggering intracellular messengers
to produce apoptosis. These dying cells are extruded constantly into the lumen
and replaced by new, healthy cells. Interposed between epithelial cells are
podocytes of subepithelial dendritic cells, which are highly efficient antigen-
presenting cells.
Microorganisms can invade the gut by crossing epithelial cells
(transcellular) or by passing between cells in the process of translocation.
Key to preventing such invasions are the cell-cell adhesion molecules, particularly
tight junctions (zonulae occludentes). Tight junctions are complex yet dynamic
structures that selectively control the paracellular movement of antigens and
fluid to the underlying intraepithelial lymphocytes and lamina propria. When
these gates to the paracellular space’s protective mechanisms are impaired,
cells can become damaged. In the upper gastrointestinal tract, medications
commonly damage tight junctions, permit- ting back diffusion of acid and
submucosal injury that can lead to ulcerations. In the intestine,
translocational invasion is partially controlled by intraepithelial
lymphocytes.
The ongoing “controlled inflammatory response” associated with the
epithelial cell damage, apoptosis, and exfoliation is occurring constantly to
maintain an effective biologic shield against its external environment within
the tube of the gut. Cell replacement must be common and robust to provide the
billions of healthy epithelial cells that coat the gut. When ongoing cellular
replacement is impaired, health is threatened. In the esophagus, the
nonkeratinized squamous cell epithelium is under the constant influence of
shearing forces related to swallowed food and strong esophageal con- tractions
as well as the caustic effects of gastroesophageal reflux. The increased rate
of cellular replacement in response to injury can be identified by the enlargement
of the rete pegs. Mucosal breaks, ulcerations, and bleeding result when this
cellular replacement process is overwhelmed. Inadequate replacement of the
columnar epithelium of the stomach and intestines occurs commonly in a more
wholesale fashion in the setting of hypotension and shock. In shock, the
normally robust supply of nutrients and oxygen provided to the gut by its rich
vascular supply is diverted to the heart, kidneys, and brain. Under such
circumstances, if cells continue to be damaged but are not replaced rapidly
enough, the gut’s integrity can be lost. When this occurs in the stomach,
diffuse hemorrhagic gastritis may result. In the gut, mesenteric ischemia leads
to increased leakiness and translocation; if it is not corrected, it results in
the many potentially lethal complications of mesenteric ischemia, including
sepsis, bleeding, and, if not corrected,
perforation.
