Proton pump inhibitors are not associated with an increased risk of Clostridioides difficile infection: a systematic review and meta-analysis of randomized controlled trials.

Observational studies reported conflicting results regarding the association between proton pump inhibitors (PPIs) and intestinal dysbiosis. We assessed the risk of enteric infections, including Clostridioides difficile infection (CDI), and small intestinal bacterial overgrowth (SIBO) among PPI users compared to non-users in randomized controlled trials (RCTs). A systematic search was conducted on April 15th, 2025 (CRD42023403322). Eligible RCTs compared adults treated with PPIs versusplacebo or alternative therapies. Risk ratios (RR) with corresponding 95% confidence interval (CI) were calculated using random effects models. Eight RCTs with 29,880 participants reported CDI rates. No significant difference was observed between PPI users and non-users (RR = 1.19, 95% CI: 0.75; 1.89). Four RCTs totaling 27,254 participants compared PPIs to H2-receptor blockers, showing no significant difference in CDI risk (RR = 0.72, 95% CI: 0.49; 1.07). Similarly, three RCTs (1,645 participants) comparing PPIs with potassium-competitive acid blockers found no significant difference (RR = 1.23, 95% CI: 0.43; 3.55). The qualitative synthesis found that other enteric infections and SIBO may be more common in PPI users. Data from RCTs suggest that PPIs do not seem to increase the risk of CDI compared to placebo and other acid-suppressive medications.