Since white blood cells involved in the immune process are the cells that release various chemicals can result in increased intestinal permeability, the presence of increased numbers of these cells are a microscopic clue that the gut is leaky. Typical cells seen are lymphocytes but may also include eosinophils and mast cells in certain conditions. These cells release chemical mediators that attract more cells to the area. Lymphocytes in particular release a chemical tumor necrosis factor (TNF) that increases the numbers of lymphocytes in the villi.

Obvious visually apparent defects of the lining of the intestine or mucosa such as ulcerations and erosions or atrophy are associated with increased intestinal permeability. However, ultra structural studies have shown that areas of the intestine lining can have gaps in its barrier. That is, your gut can be leaky though it may look visibly normal during an endoscopy by a doctor who may fail to sample the tissue assuming it is normal. Furthermore, even if the doctor samples normal appearing tissue, it may look normal to a pathologist examining it using a microscope that has been stained with standard tissue stains. However, special staining techniques including those that stain specialized immune cells may reveal abnormal cells and injury to the lining resulting in leaky gut. Electron microscope exams, usually done in research, also can reveal ultra structural abnormalities, below standard light microscope detection. Such ultra structural abnormalities have been proven associated with problems with absorption and increased permeability leading to disease.

Probiotics appear to be helpful in protecting against leaky gut and bowel inflammation. Various good bacteria that constitute probiotics maintain the health of the intestinal lining cells. In doing so, they help maintain tight junctions that prevent leaky gut from occurring. Alternatively, bad bacteria in the gut injure the intestinal lining cells and cause leaky gut. Probiotics suppress bad bacteria levels by several mechanisms. Some good bacteria actually produce a natural antibiotic that kills bad bacteria. For example acidophilus bacteria produce acidophilin that has this effect and promotes gut health. Probiotics are gaining acceptance or interest in the prevention and treatment of both inflammatory bowel diseases (Crohn’s and colitis) as well as irritable bowel syndrome (IBS). They are also being touted to prevent or treat antibiotic associated diarrhea.

Chronic gluten exposure has been shown to activate zonulin resulting in increased intestinal permeability (or leaky gut) even in the absence of celiac disease. Intestinal permeability with malabsorption has been described in celiac patients and their relatives who don’t have atrophy of the intestine on biopsy but only increased inflammatory cells known as lymphocytes or increased intraepithelial lymphocytosis (IEL). In celiac disease, genetically predisposed people can have marked increased and sustained leaky gut from gluten. This combined with other factors results in the characteristic abnormal blood tests, damaged intestine seen on biopsy, and symptoms and signs of celiac disease including malabsorption of nutrients and diarrhea.

Lymphocytic enteritis is a relatively new term for this small intestine biopsy finding of increased lymphocytes in the tips of the intestinal villi without other signs of intestinal damage. See also intraepithelial lymphocytosis reviewed elsewhere. More than 30 lymphocytes per 100 epithelial enterocytes cells in the intestine defining intraepithelial lymphocytosis, the earliest sign of celiac disease thought not specific for it. Levels of lymphocytes above 20 per 100 enterocytes may be abnormal.  Release of TNF in the intestinal lining by lymphocytes attracts more lymphocytes, increasing gut permeability and causing intestinal injury resulting in malabsorption. The leaky gut resulting increases the risk of celiac and Crohn’s disease specifically in genetically predisposed individuals. If altered gut bacteria and yeast levels are present the risks appear to be much higher. Therefore, lymphocytic enteritis maybe the earliest microscopic sign of leaky gut and celiac disease.

Tumor necrosis factor is a chemical released by white blood cells, especially lymphocytes, intended to destroy tumor cells and foreign invaders like bacteria and viruses. It can damage the intestine and result in leaky gut. Interestingly, anti-tumor necrosis factor (anti-TNF) therapy in the form of remicade (infliximab) and humira (adalimubab) are highly effective in treating Crohn’s disease, rheumatoid arthritis and more recently ulcerative colitis. Unfortunately, such therapy is directed at the already released TNF not the underlying cause or predisposition.

The small intestine lining has projections called villi that dramatically increase the surface area of the intestine. Each villous is lined with a single layer of enterocytes and globet cells. The enterocytes of the small intestine have projections on their surfaces known as microvilli where digestive enzymes reside. 

The intestinal lining cells, called enterocytes in small intestine (a type of epithelial cell) are “shoulder to shoulder” next to each other. They are actually joined to each other by proteins that form a type actively moving “scaffolding or R bar” that can move opening the space between the cells to selectively allow particles and fluid through into the body. This tight junction area is called the zonula occludens (occlusion zone). Though it is normally barrier to various proteins including those derived from foods, bacteria and yeast, sometimes the barrier abnormally opens allowing potentially dangerous proteins access into the gut wall and direct contact with immune system cells. Normally, signals open up the spaces between the cells, the paracellular space, as part of normal digestion

Abnormal tight junctions result in increase intestinal permeability or a leaky gut. This altered intestinal permeability or barrier function is implicated in several diseases, especially celiac disease and the inflammatory bowel diseases ulcerative colitis and Crohn’s disease. Chemicals released as part of the innate immune system can increase gut permeability. Some bacteria, yeast and virus cause toxic injury to intestinal cells resulting in increased permeability. Some medications, such as ibuprofen (Motrin, Advil) can increase intestinal permeability. Stress has implicated in increased intestinal permeability. In fact one of research models for Crohn’s disease is a rat that when water stressed develops increased intestinal permeability allowing certain bacteria through the bowel wall resulting in Crohn’s like disease that is used to study this disease in humans.

Occludin and claudin are structural proteins that maintain the tight junctions or zonula occludens. The structure of the tight junctions is also known as a cytoskeleton that is formed by these proteins acting like scaffolding or R bar holding the intestinal cells tight against each other except during brief openings of the normally closed paracelluar spaces. These proteins are regulated at least in part by another protein, zonulin.