A Systematic Review of the Adverse Effects of Long-Term Proton Pump Inhibitor Use on the Gastrointestinal System in the Adult Population

• Published in: Curēus (Palo Alto, CA) Vol. 17; no. 8
• Main Authors: Sekar Lakshmisai, Sandeep, Bheemaneni, Roshitha S, Nwachukwu, Evangeline C, Nigam, Aahana, Sakarkar, Priyanka, Khan, Safeera
• Format: Journal Article
• Language: English
• Published: Palo Alto Springer Nature B.V 20.08.2025; Cureus
• Subjects: Chronic illnesses; Family/General Practice; Gastroenterology; Gastroesophageal reflux; Internal Medicine; Mortality; Protons; United Kingdom > UK
• ISSN: 2168-8184; 2168-8184
• DOI: 10.7759/cureus.90606

Proton pump inhibitors (PPIs) have been the first-line drug of choice for acid-peptic diseases for a long time. While literature is abundant on the efficacy of the drug, the adverse effects of this drug, especially in the gastrointestinal (GI) system, have been a topic of ongoing research interest. The long-term safety profile remains controversial. PPIs have been found to cause polyps, malignancies, and pre-cancerous conditions such as intestinal metaplasia, enteric infections such as Clostridium difficile, and microscopic colitis. Furthermore, long-term use is seen to be associated with decreased iron absorption and disruption in gut microbiota. This systematic review aims to perform a qualitative synthesis of the literature on the long-term adverse effects of PPIs on the GI system. This review utilized the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, PubMed Central (PMC), MEDLINE (Medical Literature Analysis and Retrieval System Online), MDPI (Multidisciplinary Digital Publishing Institute), and EBSCO (Elton B. Stephens Company) Library databases were searched for data published in the past 15 years, between 2010 and 2024, using Medical Subject Headings (MeSH) and keywords, and a total of 260 articles were identified. The PubMed search, which included articles from MEDLINE and PMC, yielded 216 results; the MeSH search included 11 articles. EBSCO and MDPI searches retrieved nine and 24 articles, respectively. After applying the eligibility criteria and performing qualitative synthesis, 50 articles were shortlisted. Quality assessment tools, such as the Assessment of Multiple Systematic Review (AMSTAR) for systematic reviews, the Cochrane bias assessment tool for randomized control trials, the scale for the assessment of narrative review articles (SANRA) checklist for narrative reviews, and the Newcastle-Ottawa Scale (NOS) for observational studies, and JBI critical appraisal checklist for case reports, were used. This review will help clinicians evaluate the risk-benefit factors of PPI use on a case-by-case basis, help mitigate unnecessary long-term prescription of PPI, and reduce the incidence of unwanted adverse events.