The wall of the colon is similar in structure to the rest of the intestinal tract, though the outer layer of longitudinal muscle is discontinuous. The layers from the outside to the inside are:

• serosa;
• longitudinal muscle layer (taenia);
• circular muscle layer;
• submucosa;
• muscularis mucosae;
• mucosal layer, which includes the lamina propria and a simple columnar epithelial lining.
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The longitudinal muscle is gathered into three bands called taeniae, which maintain constant contraction, shortening the colon and creating the characteristic sac-like bulges known as haustrae.

The lamina propria contains various cells, including fibroblasts, lymphocytes, and other white blood cells, as well as nerve processes and blood vessels, but it lacks lymphatic vessels. This absence of lymphatics is why lymphatic invasion tends to occur later in cases of colon cancer.

The colonic epithelium lacks villi but has numerous crypts that open onto the surface. It is lined by a single layer of columnar epithelial cells (colonocytes), goblet cells, and scattered enteroendocrine cells. Stem cells reside at the base of the crypts. There are also a few Paneth cells in the ascending colon, and their numbers increase in inflammatory bowel disease (IBD).

Goblet cells produce large amounts of mucus that coat the epithelial surface with a protective, hydrated layer, safeguarding against mechanical damage and bacterial invasion. Mucus is mainly composed of polypeptide chains linked by disulfide bonds, which are heavily glycosylated, giving rise to long carbohydrate side chains that attract water and form a slippery gel. Goblet cells also secrete trefoil peptides, which help in epithelial healing and play a role in host defense.

Layer weakness: Blood vessels that supply the colon pass through the circular muscle layer, creating gaps that can be potential weak spots. In the sigmoid colon, these gaps can allow the mucosa to herniate over time, leading to the formation of pouches known as diverticula.