Long-term use of proton pump inhibitors is associated with an increased risk of enteric infections, with the strongest and most consistent evidence linking these drugs to Clostridioides difficile infection. L. Clifford McDonald Centers for Disease Control and Prevention has highlighted acid suppression as a modifiable risk factor for C. difficile in surveillance and guidance documents, and Mark H. Wilcox Leeds Teaching Hospitals NHS Trust has reviewed clinical studies showing higher rates of C. difficile among PPI users. The association is strongest for hospitalized, older, or antibiotic-exposed patients, but it is observed across settings.
Evidence from clinical research
Observational studies and systematic reviews repeatedly report an association between PPI use and enteric infections. Much of the literature focuses on C. difficile because of its clear clinical impact, but population studies also report higher risks of non-typhoidal Salmonella and Campylobacter infections among people taking acid-suppressing medications. Randomized trials directly assessing infection risk are limited for ethical and feasibility reasons, so the evidence base is primarily observational and adjusted for confounders. This means causality is supported by biological plausibility and consistency, but absolute risk varies by population.
Mechanisms and implications
Biologically, acid suppression reduces the stomach’s barrier function, allowing more ingested bacteria and spores to survive transit. Long-term PPIs also alter the gut microbiota, reducing diversity and promoting overgrowth of opportunistic organisms. These mechanisms explain why concurrent antibiotic exposure, immunosuppression, advanced age, or hospitalization amplifies risk. In regions with higher burdens of enteric pathogens or limited sanitation, the practical consequences of acid suppression may be greater at a population level.
Clinical and public-health relevance
Consequences include increased morbidity, healthcare utilization, and recurrence of C. difficile disease. For individuals, the absolute risk for enteric infection remains modest if they are young and otherwise healthy, but higher-risk groups face tangible harms. Stewardship measures recommended by infectious disease and gastroenterology experts include limiting PPI duration to indicated uses, using the lowest effective dose, reassessing ongoing need, and considering alternatives when appropriate. Clinicians should balance symptomatic benefit against infection risk, and policy efforts in territories with high enteric disease prevalence should incorporate medication review into prevention strategies.