Regular Use of Proton Pump Inhibitor and the Risk of Inflammatory Bowel Disease: Pooled Analysis of 3 Prospective Cohorts

Gastroenterology. 2021 Dec;161(6):1842-1852.e10. doi: 10.1053/j.gastro.2021.08.005. Epub 2021 Aug 11.


Background & aims: Proton pump inhibitors (PPIs) have a major impact on gut microbiome and immune function, which in turn, may increase the risk of inflammatory bowel disease (IBD). Our aim in this study was to evaluate PPI use and subsequent risk of IBD and subtypes (ie, Crohn's disease and ulcerative colitis).

Methods: This was a pooled analysis of the Nurses' Health Study (NHS, n = 82,869), NHS II (n = 95,141), and UK Biobank (n = 469,397). We included participants with information on personal use of PPIs and free of IBD or cancer at baseline. We evaluated hazard ratios and 95% confidence intervals (CIs) with Cox regression adjusting for lifestyle factors, PPI indications, comorbidities, and other medications.

Results: We documented 271 cases of IBD (median follow-up, 12 years) in the pooled NHS cohorts and 1419 cases (median follow-up, 8.1 years) in the UK Biobank. For both pooled NHS cohorts and UK Biobank, regular use of PPIs consistently showed a significantly positive association with IBD, Crohn's disease, and ulcerative colitis risk. Combined analyses of 3 cohorts showed that regular PPI users had an increased risk of IBD as compared with nonusers (hazard ratio, 1.42; 95% CI, 1.22-1.65; number needed to harm, 3770; 95% CI, 3668-4369). Direct comparison with H2 receptor antagonist, a less potent acid suppressor, showed that PPI use was also associated with higher IBD risk (hazard ratio, 1.38; 95% CI, 1.16-1.65).

Conclusions: Regular use of PPIs was associated with an increased risk of IBD and its subtypes. The findings should be interpreted with caution because the absolute risk was low and the clinical benefits of PPIs are substantial.

Keywords: Cohort; Inflammatory Bowel Disease; Proton Pump Inhibitor; Risk Factor.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Colitis, Ulcerative / diagnosis
  • Colitis, Ulcerative / epidemiology*
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / microbiology
  • Crohn Disease / diagnosis
  • Crohn Disease / epidemiology*
  • Crohn Disease / immunology
  • Crohn Disease / microbiology
  • Dysbiosis
  • Female
  • Gastrointestinal Microbiome / drug effects
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Prognosis
  • Prospective Studies
  • Proton Pump Inhibitors / adverse effects*
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • United Kingdom / epidemiology
  • United States / epidemiology


  • Proton Pump Inhibitors