Gao M, Yin RR, Mao X, Shao ZX, Shi YY. Association between proton pump inhibitor use and the risk of inflammatory bowel disease: A systematic review and meta-analysis. World J Gastroenterol 2026; 32(22): 116469 [DOI: 10.3748/wjg.v32.i22.116469]
Corresponding Author of This Article
Yan-Yan Shi, MD, Professor, Research Center of Clinical Epidemiology, Peking University Third Hospital, No. 49 Garden North Road, Haidian District, Beijing 100191, China. shiyanyan@bjmu.edu.cn
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Gastroenterology & Hepatology
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research-article
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Gao M, Yin RR, Mao X, Shao ZX, Shi YY. Association between proton pump inhibitor use and the risk of inflammatory bowel disease: A systematic review and meta-analysis. World J Gastroenterol 2026; 32(22): 116469 [DOI: 10.3748/wjg.v32.i22.116469]
World J Gastroenterol. Jun 14, 2026; 32(22): 116469 Published online Jun 14, 2026. doi: 10.3748/wjg.v32.i22.116469
Association between proton pump inhibitor use and the risk of inflammatory bowel disease: A systematic review and meta-analysis
Min Gao, Rui-Rui Yin, Xin Mao, Zong-Xin Shao, Yan-Yan Shi
Min Gao, Rui-Rui Yin, Zong-Xin Shao, Yan-Yan Shi, Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
Xin Mao, Peking University Health Science Center, Peking University, Beijing 100191, China
Co-first authors: Min Gao and Rui-Rui Yin.
Author contributions: Gao M and Yin RR contributed to investigation and drafting the manuscript as co-first authors; Mao X and Shao ZX contributed to discussion; Shi YY was responsible for designing and revising this meta-analysis; all authors have read and approved the article.
AI contribution statement: AI tools were used solely for language refinement to improve the clarity and readability of the manuscript. These tools did not contribute to the generation of scientific ideas, research content, data analysis, image creation, or any experimental or computational procedures. The study design, data collection, data interpretation, and scientific conclusions were carried out entirely by the authors.
Supported by Beijing Natural Science Foundation of China, No. J230002.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Yan-Yan Shi, MD, Professor, Research Center of Clinical Epidemiology, Peking University Third Hospital, No. 49 Garden North Road, Haidian District, Beijing 100191, China. shiyanyan@bjmu.edu.cn
Received: November 13, 2025 Revised: January 11, 2026 Accepted: February 28, 2026 Published online: June 14, 2026 Processing time: 198 Days and 0.7 Hours
Abstract
BACKGROUND
The worldwide prevalence of inflammatory bowel disease (IBD) continues to rise, motivating extensive exploration into possible contributing factors. Proton pump inhibitors (PPIs) are frequently prescribed medications for managing various gastrointestinal disorders. However, uncertainties persist regarding the implications of chronic PPI therapy and its potential association with the onset of IBD.
AIM
To assess the association between PPI use and incident IBD risk via a systematic review and meta-analysis of observational studies.
METHODS
A comprehensive literature search was performed in databases including PubMed, EMBASE, and Web of Science, covering the period from inception to February 13, 2025. Search terms included “proton pump inhibitors” and “inflammatory bowel disease”. Eligible were observational studies (cohort, case-control, and cross-sectional studies) reporting adjusted effect estimates for the association between PPI use and incident IBD. Study quality was assessed using the Newcastle-Ottawa Scale. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, and heterogeneity was quantified with the I2 statistic.
RESULTS
A total of five observational studies, encompassing 48058263 participants across diverse age groups, were included in this meta-analysis. Findings revealed that participants with PPI exposure had a significantly higher risk of developing IBD than those without exposure (OR = 1.85; 95%CI: 1.11-3.09, P < 0.05). However, sensitivity analyses revealed that this association was unstable; excluding one large cross-sectional study reduced the OR to 1.40 (95%CI: 0.98-1.98), which was no longer statistically significant. Moreover, there was notable heterogeneity among the included studies (I2 = 97.6%, P < 0.001). Subgroup analyses indicated that variations in participant age and study methodology notably contributed to the observed heterogeneity.
CONCLUSION
The statistically significant association between PPI use and IBD risk is non-robust and unstable, driven by extreme heterogeneity and studies prone to protopathic bias. Well-designed prospective studies are required to validate these findings.
Core Tip: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications worldwide, yet their long-term safety remains under debate. This systematic review and meta-analysis demonstrate a statistically significant association between PPI use and an increased risk of incident inflammatory bowel disease. However, substantial heterogeneity and sensitivity analyses suggest that this association may be influenced by study design, age differences, and protopathic bias, thereby limiting causal inference. Clinicians should interpret this association cautiously, and future prospective studies with rigorous bias control are needed to determine whether PPI use contributes to inflammatory bowel disease pathogenesis.
