Why do proton‑pump inhibitors raise fecal calprotectin, and how should an elevated result be managed in a patient taking a PPI?

Why PPIs Raise Fecal Calprotectin and How to Manage Elevated Results

Proton pump inhibitors elevate fecal calprotectin by raising gastric pH, which promotes small intestinal bacterial overgrowth, alters the gut microbiome composition, and increases intestinal permeability—all of which trigger low-grade intestinal inflammation that calprotectin detects. 1, 2

Mechanisms of PPI-Induced Calprotectin Elevation

Primary Pathophysiological Pathways

• PPIs eliminate the gastric acid barrier, allowing oral and upper GI tract bacteria to colonize the lower intestinal tract, fundamentally altering the normal microbial ecosystem. 1

• Microbial dysbiosis occurs systematically: PPI users demonstrate significantly lower abundance of normal gut commensals, reduced overall microbial diversity, and a marked increase in Streptococcaceae and other oral bacteria that migrate distally when acid suppression removes the pH barrier. 1

• Small intestinal bacterial overgrowth (SIBO) develops more frequently in PPI users, with bacterial proliferation generating ammonia, endotoxins, and other inflammatory mediators that stimulate neutrophil migration into the intestinal mucosa—the source of calprotectin release. 3

• Increased intestinal permeability and bacterial translocation result from the altered microbiome, triggering systemic inflammation that underlies the calprotectin elevation even in the absence of structural mucosal disease. 3

Supporting Evidence from Clinical Studies

• In a cross-sectional study of 590 patients with normal colonoscopy, 36% had calprotectin >50 µg/g, and PPI use was independently associated with nearly 4-fold higher odds of elevated calprotectin (adjusted OR 3.843; 95% CI 2.338–6.316) after controlling for age and other medications. 2

• A randomized trial demonstrated that 53% of healthy volunteers taking omeprazole 20 mg daily for 2 weeks developed calprotectin >50 µg/g (median 85.3 µg/g; range 51.1–249 µg/g), confirming a direct causal relationship. 4

Clinical Management of Elevated Calprotectin in PPI Users

Step 1: Assess PPI Indication and Consider Discontinuation

• Systematically re-evaluate whether the patient has a valid indication for continued PPI therapy, because up to 70% of PPI use may be inappropriate, and cessation is the most effective strategy to normalize calprotectin. 3, 5

• Patients who should NOT discontinue PPIs include those with Barrett's esophagus, severe erosive esophagitis (LA grade C/D), history of upper GI bleeding on antithrombotic therapy, eosinophilic esophagitis responsive to PPIs, or secondary prevention of peptic ulcer disease. 6

• Patients who SHOULD be considered for PPI discontinuation include those with non-erosive reflux disease, mild erosive esophagitis, or no documented indication—these individuals can undergo a trial of de-prescribing. 6

Step 2: Implement a Washout Period Before Repeat Testing

• If the PPI can be safely discontinued, wait at least 3 weeks before repeating fecal calprotectin, because the randomized trial showed that calprotectin normalized in all participants within 3 weeks of omeprazole cessation. 4

• For patients taking NSAIDs concurrently with PPIs, the washout period remains 3 weeks, as the combination does not prolong the normalization interval beyond omeprazole alone. 4

• Do not repeat calprotectin testing earlier than 3 weeks, as premature retesting will yield persistently elevated results that do not reflect true inflammatory bowel disease. 4

Step 3: Interpret Repeat Calprotectin Results

• If calprotectin normalizes after PPI cessation, the initial elevation was PPI-induced and does not warrant endoscopic evaluation—resume appropriate acid suppression if clinically indicated, using the lowest effective dose. 2, 4

• If calprotectin remains elevated >50 µg/g after a 3-week washout, proceed with colonoscopy and ileoscopy with biopsies to evaluate for inflammatory bowel disease, microscopic colitis, or other mucosal pathology. 3

• A rising calprotectin level on serial testing (e.g., 100 µg/g increase) in a patient with known IBD increases the hazard ratio for clinical recurrence by 18%, making trend analysis more informative than single values. 3

Step 4: Alternative Strategies When PPI Cannot Be Stopped

• If the patient has a definite indication for continued PPI therapy and elevated calprotectin, use endoscopy rather than calprotectin to guide IBD diagnosis, because the biomarker lacks specificity in this context. 3

• Consider switching to an H2-receptor antagonist (e.g., famotidine) for patients with mild GERD symptoms, as H2-blockers do not alter gut microbiota or raise calprotectin and provide adequate acid suppression for non-erosive disease. 5

• For patients requiring potent acid suppression who have failed standard PPIs, vonoprazan (a potassium-competitive acid blocker) may be considered, though data on its effect on calprotectin are not yet available. 5

Common Pitfalls and How to Avoid Them

Pitfall 1: Ordering Colonoscopy Without a PPI Washout

• Many clinicians proceed directly to colonoscopy when calprotectin is elevated in a PPI user, leading to unnecessary procedures with normal findings and missed opportunities to identify PPI as the culprit. 2, 4

• Always attempt a 3-week PPI washout and repeat calprotectin before endoscopy unless the patient has alarm features (rectal bleeding, anemia, weight loss) that mandate immediate visualization. 4

Pitfall 2: Discontinuing PPIs in High-Risk Patients Due to Calprotectin Concerns

• Stopping PPIs in patients with a history of upper GI bleeding on antithrombotic therapy can precipitate life-threatening hemorrhage, which far outweighs any concern about elevated calprotectin. 7, 6

• Document the specific indication for PPI continuation in the medical record to prevent inappropriate discontinuation by other providers who may misinterpret the elevated calprotectin. 5

Pitfall 3: Ignoring Other Medications That Raise Calprotectin

• NSAIDs and aspirin independently elevate calprotectin (adjusted OR 2.411 and 2.934, respectively), and their effects are additive with PPIs. 2

• When evaluating elevated calprotectin, obtain a complete medication history including over-the-counter NSAIDs, aspirin, and PPIs, and consider stopping all three if clinically feasible before repeat testing. 2, 4

Pitfall 4: Using Calprotectin to Monitor IBD Activity in PPI Users

• Fecal calprotectin loses its utility for monitoring Crohn's disease or ulcerative colitis activity in patients who require ongoing PPI therapy, because the PPI effect cannot be distinguished from disease activity. 3

• In IBD patients on PPIs, use endoscopy with mucosal healing as the treatment target rather than relying on calprotectin trends to guide therapy escalation or de-escalation. 3

Age-Related Considerations

• Age independently increases calprotectin levels (adjusted OR 1.051 per year), so elderly patients on PPIs are particularly likely to have values >50 µg/g even without IBD. 2

• In patients ≥65 years with multiple cardiovascular risk factors requiring aspirin or anticoagulation, the indication for PPI continuation typically outweighs concerns about calprotectin elevation, and endoscopy should be pursued if clinical suspicion for IBD remains high after washout. 7