What Is Lymphocytic Colitis? Symptoms, Causes & Treatment

Lymphocytic colitis is a type of inflammatory bowel condition that causes chronic, watery diarrhea even though the colon looks perfectly normal during a colonoscopy. The inflammation only shows up under a microscope, where a pathologist can see an unusually high number of immune cells called lymphocytes infiltrating the lining of the colon. It falls under the broader umbrella of “microscopic colitis,” alongside a closely related condition called collagenous colitis, and it is far more common than most people realize.

How Lymphocytic Colitis Differs From Other Bowel Conditions

The defining hallmark of lymphocytic colitis is what happens at the tissue level. When a pathologist examines a biopsy under a microscope, the surface lining of the colon is packed with lymphocytes at a rate far exceeding what you would see in a healthy colon or in other types of inflammatory bowel disease.¹ Unlike ulcerative colitis or Crohn’s disease, there is no visible ulceration, bleeding, or structural damage to the colon wall. And unlike irritable bowel syndrome, there is an actual measurable inflammatory process happening in the tissue.

Lymphocytic colitis sits alongside collagenous colitis as one of the two main subtypes of microscopic colitis. The two conditions are clinically almost identical in how they present, how old patients tend to be at diagnosis, and how they respond to treatment. The key difference is histological: collagenous colitis features a thickened band of collagen beneath the surface lining, while lymphocytic colitis does not. There is even some histological overlap between the two, with a meaningful fraction of patients showing features of both subtypes.² Some researchers view them as a single disease on a spectrum rather than two distinct entities. In large studies, lymphocytic colitis accounts for roughly half of all microscopic colitis cases.³

Symptoms

The main symptom is chronic, non-bloody, watery diarrhea that can persist for weeks or months.⁴ The diarrhea often comes on gradually rather than all at once, and people frequently describe stools that are loose and urgent rather than the bloody or mucus-filled stools associated with other inflammatory bowel diseases.

Beyond the diarrhea itself, many patients experience abdominal pain, urgency, nocturnal stools that wake them from sleep, fecal incontinence, and unintentional weight loss.⁵ Fatigue is another common complaint and can persist even after the diarrhea improves. In one study comparing patients in clinical remission with healthy controls, fatigue remained significantly more prevalent in the lymphocytic colitis group even when their bowel symptoms had settled down.⁶

Quality of life takes a real hit. Patients with active disease score worse across multiple measures of daily well-being, including social functioning, symptom burden, and general sense of wellness.⁶ The unpredictability of urgent diarrhea makes it difficult to leave the house, travel, or attend social events, and many people describe reorganizing their daily routines around bathroom access.

Who Gets It

Lymphocytic colitis is most commonly diagnosed in middle-aged and older adults. One population-based study found a median age at diagnosis of 59, with a female-to-male ratio of about 2.4 to 1.⁷ Another large study put the mean age at nearly 63.⁸ The female predominance is real but less extreme than in collagenous colitis, where women outnumber men by roughly three to one.

Incidence has been climbing. In a well-known population study from Olmsted County, Minnesota, the incidence of lymphocytic colitis was about 5.5 per 100,000 people per year.⁹ More recent data from Scandinavia show a much steeper rise, with the age-standardized rate for lymphocytic colitis reaching over 15 per 100,000 by 2019.⁸ Some of this increase probably reflects better awareness and more routine biopsy-taking during colonoscopy, but it is not entirely clear whether that accounts for the whole trend.

Causes and Triggers

There is no single cause. Lymphocytic colitis likely develops from a combination of factors in people who are genetically predisposed, with the immune system mounting an exaggerated inflammatory response in the colon lining. What triggers that response in any given person can vary, but a few patterns have emerged clearly from research.

Medications

Several commonly used drug classes are associated with a higher risk of developing microscopic colitis. A systematic review and meta-analysis found that people taking proton pump inhibitors (the acid-reducing drugs used for heartburn and reflux) were roughly two and a half times more likely to develop microscopic colitis. Similar elevations in risk were found for SSRIs (a common class of antidepressants), NSAIDs (like ibuprofen and naproxen), and statins (cholesterol-lowering drugs).¹⁰ A large UK case series found that over 40% of lymphocytic colitis patients were taking a PPI and a similar proportion were on a statin at the time of diagnosis, rates well above what you would expect from the general population.¹¹

This does not mean these medications directly cause the disease in every case. Many of these drugs are extremely widely used, and the vast majority of people taking them never develop lymphocytic colitis. But when someone is newly diagnosed, gastroenterologists will typically review the medication list to see whether any of these drugs can be stopped or switched, since discontinuation sometimes leads to improvement on its own.

Smoking

Cigarette smoking increases the risk of microscopic colitis overall. One case-control study found that current smokers had over four times the odds of developing any type of microscopic colitis compared to never-smokers.¹² A large prospective cohort study found a more modest but still meaningful association, with current smoking roughly doubling the risk of microscopic colitis and past smoking raising it by about 50%.¹³ The risk diminished after quitting, which is consistent with smoking playing a genuine causal role rather than just being a marker for something else. The smoking connection appears stronger for collagenous colitis than for lymphocytic colitis specifically, but it applies to both.

Autoimmune Connections

People with lymphocytic colitis are substantially more likely to have other autoimmune conditions. A large Danish case-control study found significantly increased odds of 16 different autoimmune diseases in microscopic colitis patients, with the strongest associations seen for celiac disease, ulcerative colitis, and Crohn’s disease.¹⁴ In another study, about 39% of microscopic colitis patients had at least one autoimmune condition in their history, compared to 19% of patients with other forms of inflammatory bowel disease.¹⁵ This clustering suggests that the immune dysregulation behind lymphocytic colitis is not limited to the colon alone.

What Is Happening in the Colon

Research into the underlying mechanism has pointed to a breakdown in the colon’s barrier function. Normally, the cells lining the colon are held tightly together by structures called tight junctions, which prevent the contents of the intestine from leaking through. In lymphocytic colitis, several of the key proteins that maintain these junctions are reduced or physically displaced away from where they need to be. Inflammatory signaling molecules drive this disruption, causing the intestinal lining to become “leaky.” Water and electrolytes then flow into the intestinal space more freely than they should, producing the characteristic watery diarrhea.¹⁶

How It Is Diagnosed

Diagnosis requires a colonoscopy with biopsies, and this is non-negotiable. The colon typically looks entirely normal or near-normal during the procedure, which is why biopsies are essential. In some cases, subtle findings like unusual vascular patterns or mild mucosal changes may be visible, but these are inconsistent and cannot be relied on.¹⁷ The diagnosis is made when the pathologist sees the characteristic increase in lymphocytes in the tissue samples.

Where the biopsies are taken matters. A systematic review of biopsy protocols found that sampling from both the ascending colon (right side) and descending colon (left side) yields the highest diagnostic accuracy, with a recommendation of at least six biopsies total, three from each site.¹⁸ When biopsies from both sites were combined, one study found that every single case was identified.¹⁹ The right colon tends to be more reliably positive than the left, so skipping the right side during biopsy-taking reduces the chance of catching the diagnosis.²⁰

The IBS Misdiagnosis Problem

Because lymphocytic colitis produces diarrhea with a normal-looking colon, it is frequently mistaken for diarrhea-predominant irritable bowel syndrome. One study of 247 patients who had been diagnosed with IBS-D found that about 6% actually had microscopic colitis when biopsies were taken, with the majority of those cases being lymphocytic colitis.²¹ A case series of older adults diagnosed with microscopic colitis found that every single patient had previously been told they had IBS, with diagnostic delays ranging from a couple of months to six years.²²

The practical takeaway here is straightforward. If you are an older adult with persistent watery diarrhea that has been labeled as IBS, particularly if it started after age 50 and has not responded to typical IBS treatments, it is worth asking whether biopsies were taken during your colonoscopy. If they were not, the diagnosis of microscopic colitis has not been ruled out.

Treatment

Budesonide

Budesonide, a locally acting steroid, is the first-line treatment and the only drug with strong trial evidence behind it for lymphocytic colitis. In a randomized, double-blind, placebo-controlled trial, 86% of patients given budesonide achieved clinical remission within six weeks, compared with 48% on placebo. Histological improvement followed the same pattern.²³ Most patients feel dramatically better within the first few weeks of treatment.

The catch is relapse. A meta-analysis found that over half of patients relapse after budesonide is stopped, whether they were finishing an initial course or a longer maintenance period.²⁴ This means many people end up on low-dose budesonide long term to keep their symptoms under control. Because budesonide is designed to act locally in the gut with less absorption into the rest of the body compared to other steroids, it tends to be better tolerated for extended use. But long-term steroid use of any kind still carries considerations for bone health and other side effects, and doctors typically try to find the lowest effective maintenance dose.

Bile Acid Sequestrants

A separate treatment approach uses bile acid sequestrants, medications originally designed to lower cholesterol that also bind bile acids in the gut. These can be useful because bile acid malabsorption is relatively common in microscopic colitis. In one large retrospective study of 282 patients treated with bile acid sequestrants, about half achieved a complete response and another 16% had a partial response.²⁵ The response rate was not as high as budesonide, and about a quarter of patients did not respond at all, but bile acid sequestrants offer an alternative for people who want to avoid steroids or who cannot tolerate them.

When Standard Treatments Fail

A small fraction of patients do not respond adequately to budesonide or cannot stay on it. For these refractory cases, immunosuppressive drugs or biologic therapies are sometimes tried, though the evidence base is thin. A multicenter study of biologic therapy (primarily anti-TNF agents) in budesonide-refractory microscopic colitis found some patients responding, though many ultimately needed second or even third lines of biologic treatment.²⁶ A case report also documented successful treatment of refractory lymphocytic colitis with upadacitinib, a newer class of oral immunosuppressant, though this remains experimental.²⁷ For the vast majority of patients, however, budesonide and bile acid sequestrants are sufficient to manage symptoms.

Long-Term Outlook

The prognosis for lymphocytic colitis is generally reassuring, particularly compared to other inflammatory bowel diseases. A large Danish nationwide cohort study found that about 71% of lymphocytic colitis patients had a self-limiting or transient disease course, meaning their symptoms eventually resolved or became intermittent without requiring ongoing aggressive treatment. Fewer than 5% had disease refractory enough to need immunomodulators or biologic therapy.²⁸

One question patients commonly have is whether lymphocytic colitis increases their risk of colon cancer. The evidence is actually reassuring on this front. The same Danish study found that microscopic colitis patients had a lower risk of colorectal cancer than the general population, not a higher one.²⁸ This is a meaningful distinction from ulcerative colitis and Crohn’s disease, where long-standing inflammation does raise colorectal cancer risk. A separate large analysis also found that microscopic colitis patients had significantly fewer colonic adenomas (pre-cancerous polyps) than control patients.³

Mortality overall is modestly higher in microscopic colitis patients with severe disease compared to the general population, though interpreting this is tricky because the patients tend to be older and have other health conditions. For most people with lymphocytic colitis, the condition is a chronic nuisance rather than a life-threatening illness.

The Celiac Disease Connection

The overlap between lymphocytic colitis and celiac disease deserves special attention because it has practical implications for treatment. A meta-analysis found that celiac disease is about eight times more prevalent among microscopic colitis patients than in the general population, with roughly 6% of lymphocytic colitis patients also having celiac disease.²⁹ An earlier study in lymphocytic colitis patients specifically found celiac disease in 15% of cases, a rate vastly higher than the background prevalence.³⁰

This matters because if someone has both conditions, the diarrhea may not improve with budesonide alone. Untreated celiac disease will continue to drive symptoms regardless of what you do for the colitis. Current clinical thinking is that celiac disease should be ruled out in anyone diagnosed with lymphocytic colitis, especially if they are not responding well to standard treatment. The screening test is a blood test for celiac antibodies, followed by small-bowel biopsy if positive.

Lymphocytic Colitis Versus Collagenous Colitis

Since the two subtypes of microscopic colitis are so closely related, people diagnosed with one often want to know how it compares to the other. One earlier clinical study found that patients with lymphocytic colitis tended to present somewhat sooner after symptom onset, were less likely to be current smokers, and had a slightly better overall prognosis. Resolution or significant improvement occurred in 84% of lymphocytic colitis patients compared to 74% of those with collagenous colitis.³¹ Collagenous colitis also has a stronger female predominance. But overall, the two conditions are far more alike than they are different. They share the same risk factors, the same association with autoimmune diseases, similar rates of bile acid malabsorption, and they respond identically to budesonide.² If you have been diagnosed with one and read information about the other, most of it will apply to you as well.

1
PubMed. Lymphocytic (“microscopic”) colitis: a comparative histopathologic study with particular reference to collagenous colitis
2
PubMed. Systematic review: are lymphocytic colitis and collagenous colitis two subtypes of the same disease – microscopic colitis?
3
PubMed. Lymphocytic and collagenous colitis: epidemiologic differences and similarities
4
PubMed. Clinical presentation, diagnosis, pathogenesis and treatment options for lymphocytic colitis
5
PubMed. Lymphocytic colitis: clinical features, treatment, and outcomes
6
PubMed. Long-term prognosis of clinical symptoms and health-related quality of life in microscopic colitis: a case-control study
7
PubMed Central. Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients
8
PubMed. Regional differences in the incidence of lymphocytic and collagenous colitis over time
9
PubMed Central. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota
10
PubMed Central. Are Drugs Associated with Microscopic Colitis? A Systematic Review and Meta-Analysis
11
Journal of Crohn’s and Colitis. P1139 Lymphocytic Colitis: A large case series in the United Kingdom
12
PubMed. Current and past cigarette smoking significantly increase risk for microscopic colitis
13
PubMed Central. Smoking is Associated with an Increased Risk of Microscopic Colitis: Results From Two Large Prospective Cohort Studies of US Women
14
PubMed. Autoimmune diseases in microscopic colitis: A Danish nationwide case-control study
15
PubMed Central. Contrasting Autoimmune Comorbidities in Microscopic Colitis and Inflammatory Bowel Diseases
16
PubMed. Epithelial barrier dysfunction in lymphocytic colitis through cytokine-dependent internalization of claudin-5 and -8
17
Gut and Liver. Does Lymphocytic Colitis Always Present with Normal Endoscopic Findings?
18
European Journal of Gastroenterology & Hepatology. Estimating the optimum number of colon biopsies for diagnosing microscopic colitis: a systematic review
19
Clinical Gastroenterology and Hepatology. Biopsies From Ascending and Descending Colon Are Sufficient for Diagnosis of Microscopic Colitis
20
PubMed Central. Right biopsy protocol for microscopic colitis: Reduced workload and carbon footprint while maintaining diagnostic accuracy
21
PubMed Central. Microscopic colitis – a missed diagnosis in diarrhea-predominant irritable bowel syndrome
22
Arquivos de Gastroenterologia. WARNING TO DELAY IN DIAGNOSING MICROSCOPIC COLITIS IN OLDER ADULTS. A SERIES OF CASES
23
PubMed. Budesonide is effective in treating lymphocytic colitis: a randomized double-blind placebo-controlled study
24
Inflammatory Bowel Diseases. Effectiveness and Safety Profile of Budesonide Maintenance in Microscopic Colitis: A Systematic Review and Meta-Analysis
25
Clinical Gastroenterology and Hepatology. Bile Acid Sequestrants in Microscopic Colitis: Clinical Outcomes and Utility of Bile Acid Testing
26
Journal of Crohn’s and Colitis. Biologic Therapy for Budesonide-refractory, -dependent or -intolerant Microscopic Colitis: a Multicentre Cohort Study from the GETAID
27
PubMed Central. Medically Refractory Lymphocytic Colitis Successfully Treated With Upadacitinib
28
Journal of Crohn’s and Colitis. Disease Activity Patterns, Mortality, and Colorectal Cancer Risk in Microscopic Colitis: A Danish Nationwide Cohort Study, 2001 to 2016
29
PubMed Central. The association between microscopic colitis and celiac disease: a systematic review and meta-analysis
30
PubMed. Celiac disease is highly prevalent in lymphocytic colitis
31
Gut. Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis