Microscopic colitis develops when the immune system triggers chronic inflammation in the lining of the colon, but the colon looks completely normal during a standard colonoscopy. The damage only shows up under a microscope, which is how the condition gets its name. There isn’t a single cause. Instead, a combination of genetic susceptibility, medication use, immune dysfunction, and lifestyle factors converge to set it off.
The condition primarily affects older adults, with a median age at diagnosis around 63 to 65 years. Women are significantly more likely to develop it than men, particularly the collagenous subtype, where women outnumber men roughly 3 to 1.
Two Types, One Disease
Microscopic colitis comes in two forms: collagenous colitis and lymphocytic colitis. In collagenous colitis, a thick band of collagen protein builds up beneath the surface cells of the colon wall. Normally this layer is about 5 to 7 micrometers thick; in collagenous colitis, it exceeds 10 micrometers. In lymphocytic colitis, that collagen layer stays normal, but an unusually high number of white blood cells (lymphocytes) infiltrate the surface lining of the colon, more than 20 per 100 surface cells.
Both types cause the same primary symptom: chronic, watery, non-bloody diarrhea. They share many of the same triggers and risk factors, though the underlying immune activity differs slightly between them.
Medications That Can Trigger It
Certain common medications are among the strongest identified triggers for microscopic colitis. A systematic review and meta-analysis found that four drug classes carry a statistically significant increased risk:
- Proton pump inhibitors (PPIs) like omeprazole and lansoprazole had the strongest association, with roughly 2.65 times the odds of developing microscopic colitis compared to non-users.
- SSRIs, a widely prescribed class of antidepressants, were associated with about 2.12 times the odds.
- NSAIDs such as ibuprofen and naproxen roughly doubled the risk. These drugs inhibit the production of protective compounds in the gut lining, increasing permeability and allowing bacteria and toxins to penetrate the intestinal wall.
- Statins, used for cholesterol management, were linked to about 1.74 times the odds.
Notably, H2 blockers (another class of acid-reducing medications) did not show a significant association. If you’re taking one of these medications and develop persistent watery diarrhea, the timing of when the drug was started relative to when symptoms began is an important detail to share with your doctor. In some cases, stopping the offending medication resolves symptoms entirely.
Smoking Substantially Raises the Risk
Smoking is one of the clearest lifestyle risk factors. A large study following two cohorts of U.S. women found that current smokers had 2.5 times the risk of developing microscopic colitis compared to people who never smoked. Even past smokers carried an elevated risk, about 1.5 times higher than never-smokers. The risk climbed with more pack-years of smoking.
The encouraging finding is that risk drops after quitting. People who had stopped smoking more than five years earlier had roughly half the risk of current smokers. The association also appears stronger for the collagenous subtype than for lymphocytic colitis.
What Happens Inside the Colon
The inflammation in microscopic colitis is driven by an overactive immune response in the colon wall. The body recruits a mix of immune cells, including certain white blood cells, mast cells (the cells involved in allergic reactions), and eosinophils (inflammatory cells typically associated with allergies and parasitic infections). These cells infiltrate the colon lining and release inflammatory signals.
At the same time, the colon produces less of a natural anti-inflammatory protein called IL-37, which normally keeps immune activity in check. Without enough of this brake on inflammation, the colon’s surface cells release chemical signals that attract even more immune cells, creating a self-reinforcing cycle. In collagenous colitis, specialized cells called myofibroblasts become overactive and deposit excess collagen, thickening the layer beneath the colon’s surface. This thickened barrier disrupts water absorption, contributing directly to the watery diarrhea.
In lymphocytic colitis, the damage is more about increased permeability. The junctions between colon cells loosen, allowing fluid to leak through in both directions. The result is the same: large volumes of watery stool, often 5 to 10 times per day during flares.
Genetics and Autoimmune Connections
There is a clear genetic component, at least for collagenous colitis. A genome-wide association study using UK Biobank data confirmed a strong link to a specific set of immune-system genes on chromosome 6, known as the ancestral MHC 8.1 haplotype. This same genetic region is associated with celiac disease and other autoimmune conditions. Lymphocytic colitis, interestingly, does not show the same genetic association, suggesting the two subtypes may have partially different origins despite their similar symptoms.
About 39% of people with microscopic colitis have at least one other autoimmune condition. The most common is Hashimoto’s thyroiditis, found in roughly 14% of patients in one cohort study. Rheumatoid arthritis and Sjögren’s syndrome each appeared in about 7% of cases. Celiac disease co-occurred in nearly 4% of patients, a rate that makes screening for it worthwhile if you’re diagnosed with microscopic colitis. This clustering of autoimmune diseases supports the idea that microscopic colitis is fundamentally a disorder of immune regulation rather than something caused by a single external factor.
Changes in Gut Bacteria
People with microscopic colitis consistently show an altered gut microbiome. The overall diversity of bacteria in the colon is reduced, and the balance shifts in a specific way: bacteria typically found in the mouth, particularly species of Veillonella, become more abundant in the colon, where they promote inflammation. At the same time, protective bacteria decline. Akkermansia muciniphila, a species that helps maintain the mucus lining of the colon, is depleted. So are several species that produce anti-inflammatory compounds.
It’s not yet clear whether these microbial shifts cause the disease or result from it, but the pattern is consistent across multiple studies and likely contributes to the ongoing inflammation.
Bile Acid Malabsorption
A surprisingly high proportion of microscopic colitis patients also have trouble reabsorbing bile acids, the digestive compounds your liver produces to help break down fats. Normally, bile acids are recycled in the last section of the small intestine. When this recycling fails, excess bile acids reach the colon and irritate it, pulling water into the bowel and worsening diarrhea. Studies have found bile acid malabsorption in up to 60% of people with lymphocytic colitis and up to 44% of those with collagenous colitis. For some patients, this may be a significant contributor to their symptoms, and it can be treated with bile acid binders.
Other Possible Triggers
A previous gastrointestinal infection, whether bacterial or viral, may act as the initial trigger in some cases. The theory is that the infection disrupts the gut’s immune balance or its bacterial ecosystem, and in genetically susceptible people, the immune response never fully returns to normal. This is similar to what happens in some cases of post-infectious irritable bowel syndrome, though the mechanism in microscopic colitis involves a more clearly defined inflammatory process visible on biopsy.
How It’s Diagnosed
Because the colon looks entirely normal on visual inspection, microscopic colitis can only be diagnosed through tissue biopsies taken during a colonoscopy. The biopsies are examined under a microscope for the characteristic findings: a thickened collagen band in collagenous colitis, or elevated lymphocyte counts in the surface lining for lymphocytic colitis. There is also an “incomplete” form of each subtype, where the changes are present but don’t fully meet the standard thresholds. These incomplete forms show milder inflammation and may represent an earlier or less severe stage of the disease.
If you have chronic watery diarrhea lasting more than four weeks, especially if you’re a woman over 50, a non-smoker or current smoker, and you take any of the associated medications, biopsies during colonoscopy are the only way to confirm or rule out microscopic colitis. A colonoscopy that looks “normal” without biopsies is not sufficient to exclude it.