The four layers of the GI wall

GI tract is a hollow tube that extends all the way from the esophagus to the anus. In a living human, the distance from the mouth to anus is about 450cm long, with about 390cm of the length taken up by the small and large intestines. However, after death, the longitudinal muscles of the GI tract relax. This makes the intestinal length made during autopsies almost double that of a normal living adult human.

The wall of the GI tract has four layers namely:

  1. Mucosa
  2. Submucosa
  3. Muscularis externa
  4. Connective tissue covering called serosa

Although the arrangement of the layers is the same for all sections of the GI tract, slight variations exist from one section of the GI tract to another. The variation in arrangement of tissues in the wall of different sections of the GI tract accounts for the functional peculiarities of each section of the GI tract.

1. Mucosa

The mucosa is the inner lining of the gastrointestinal tract. Three principal structures make up the mucosa of the GI wall. These are:

a. a single layer of epithelial cells

b. lamina propria, a sub-epithelial connective tissue that underlies the epithelium and helps to hold the epithelium in place

c. Muscularis mucosa, a thin layer of smooth muscle

Along the length of the GI tract, there are several structural modifications, which serve to increase the mucosal surface area to enhance absorption.

The entire wall of the gut (i.e. the region that extends from the stomach to the anus) crumples into several folds called rugae in the stomach and plicae in the intestine. Moreover, the mucosa of the small and large intestines projects into the lumen in small finger-like extensions called villi.

The mucosa forms numerous tubular invaginations along the wall of the stomach and the intestines. The invaginations extend deep into the supporting connective tissue layer to form gastric glands in the stomach and crypts in the intestines. The deepest invaginations reach into the submucosa to form secretory submucosal glands, which open into the lumen through ducts. These glands release their products into the lumen of the gut directly, through ducts.

a. GI epithelial cells

Epithelial cells are arguably the most variable feature of the GI tract. They show significant changes from section to section. Three classes of epithelial cells exist along the GI mucosa.

  1. Transporting epithelial cells
  2. Secretory epithelial cells
  3. Stem cells called GI stem cells

Transporting epithelial cells both absorb water, ions, and nutrients into the extracellular space, and move water and ions into the lumen of the GI tract.

Secretory cells are present along the wall of the GI tract. At the mucosal surface, secretory cells secrete mucus, enzymes, and paracrine modulators into the GI lumen. Along the basolateral surface (serosal surface), secretory cells secrete hormone into blood where they travel to target organs. Moreover, secretory cells found along the basolateral surface secrete paracrine messengers (signal molecules) into the interstitial fluid where they act on neighboring cells.

GI stem cells are undifferentiated cells that rapidly divide to continuously produce new epithelium for the GI tract. GI stem cells lie deep in the gastric glands and the intestinal crypts.

The average life span of an epithelial cell along the GI tract is only a few days due their location and function. GI stem cells divide at a very high rate to ensure that there is a rapid turnover of new cells to replace senile GI epithelial cells. The rapid turnover and high rate of cell division that occurs in the GI tract makes these organs susceptible to developing cancers. Nowadays colorectal cancers (cancers of the colon and rectum) are becoming very common and accounts for majority of cancer deaths in the developed countries.

GI epithelial cells form tight junctions with each other, however, the degree of tightness of the cell-to-cell junctions vary from section to section. The cell-to-cell junctions formed by GI epithelial cells of the stomach and colon are so tight that they almost prevent the passage of materials between the cells. In contrast, the junctional complexes formed by epithelial cells of the small intestine are not so tight and allow for the easy passage of considerable amounts of water and some solutes along the paracellular route (i.e. between the epithelial cells rather than through them).

b. Lamina propria

Lamina propria is a connective tissue that lies under the GI epithelium. It forms the second layer of the mucosa.

Lamina propria contains small blood vessels and small lymphatics into which absorbed nutrients pass. In addition to the vessels, lamina propria contains nerve fibers. A special feature of the lamina propria is the presence of wandering immune cells like macrophages, and lymphocytes, which are on surveillance against pathogenic invaders that may enter through breaks in the epithelium. In the intestine, pockets of lymphoid tissues form small lymph nodules and larger lymphoid collections called Peyer’s patches creating visible bumps in the mucosal layer. Together, these lymphoid aggregations form a significant part of the gut-associated-lymphoid tissue (GALT).

Of note, the GI tract contains the largest collection of lymphoid tissues in the body because it needs the immune cells of lymphoid tissues to combat potential invaders since the GI tract has a large vulnerable surface area facing the external environment.

c. Muscularis mucosa

Muscularis mucosa is the third and final layer of the mucosa. This layer separates the mucosa from the submucosa. As its name implies, the muscularis mucosa is a thin layer of smooth muscle in the mucosa of the GI wall. Contraction of the muscularis mucosa alters the surface are available for absorption by rocking the villi back and forth much like the waving tentacles of a sea anemone.

2. Submucosa


The submucosa is the layer of the gut wall adjacent to the mucosa. The submucosa is a layer of connective tissue much like the lamina propria. However, the submucosa contains larger blood vessels and lymphatics.

Interestingly, the submucosa contains a nerve plexus called submucosal plexus or Meissner’s plexus. Meissner’s plexus is one of the two major nerve networks of the enteric nervous system the other being the Auerbach’s plexus.

The submucosal plexus controls mainly the secretory functions of each small segment of the gastrointestinal wall. Submucosal plexus receives sensory signals from the gastrointestinal epithelium, integrates these signals before sending out motor signals to help control local secretions of the GI epithelium and absorptive ability of the epithelium. Although the submucosal plexus controls secretory functions mainly, it also controls the contraction of submucosal muscles. Contraction of the submucosal muscles causes various degrees of infolding of the GI mucosa.

The enteric nervous system coordinates and integrates digestive functions. The submucosal plexus innervates GI epithelial cells and the smooth muscles of the muscularis mucosa.

3. Muscularis externa


Muscularis externa is the outer wall of the GI tract. Muscularis externa lies between the submucosa and the serosa. Muscularis externa primarily consists of two smooth muscle layers: an inner circular layer and an outer longitudinal layer. The circular muscle layer contracts to reduce the diameter of the lumen whereas the longitudinal muscle layer contracts to shorten the tube. In the stomach, there is an incomplete layer of oblique smooth muscle between the circular muscles and the submucosa.

Muscularis externa contains the second nerve network of the enteric nervous system called the myenteric plexus. The myenteric plexus also called Auerbach’s plexus lies between the longitudinal and circular muscle layer. Because of its location, the myenteric or Auerbach’s plexus coordinates and controls primarily the motor activities of the gastrointestinal tract.

For instance, the myenteric plexus controls tonic contractions of the gut (i.e. gut tone), rhythmical contractions of the gut wall, as well as the rate and rhythm of the gut wall contractions. Generally, the stimulation of the myenteric neurons has excitatory effects on the GI muscles and increases gut motility. Perhaps, a handful of neurons of the myenteric nerve plexus inhibit certain GI muscles by releasing inhibitory peptides at their nerve endings. Thus, the stimulation of the inhibitory fibers of the myenteric nerve plexus relaxes GI muscles, which they innervate. This inhibition is physiologically important because it relaxes sphincters which otherwise would resist movement of GI content along successive regions of the GI tract. Among these sphincters is the pyloric sphincter, which controls the rate at which stomach empties into the duodenum.

The myenteric plexus constitutes many interconnected neurons that form a linear chain that extends the entire length of the gastrointestinal tract.

4. Serosa


The serosa, which forms the outer covering of the entire gastrointestinal tract is a connective tissue membrane that continues as the peritoneal membrane (peritoneum) lining the abdominal cavity. In addition to lining the abdominal cavity, the peritoneal membrane forms sheets of mesentery that holds the intestines in place to prevent them from tangling as they move.

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