Gastrointestinal microbiota alterations associated with pediatric gastroesophageal reflux disease and proton pump inhibitor exposure: a systematic review of microbiome changes, dysbiosis markers, and associated clinical outcomes.

INTRODUCTION: Gastroesophageal reflux disease (GERD) and proton pump inhibitor (PPI) therapy have both been associated with alterations of the developing gastrointestinal microbiome and potential downstream clinical consequences in children. However, available evidence is fragmented across disease-related, treatment-related, and mechanistic studies, making the overall biological relationship difficult to interpret. METHODS: PubMed, Web of Science, and Scopus databases were queried for the period January 2000 to May 2026 to synthesize evidence across the pathophysiological continuum linking pediatric GERD, microbiota alterations, inflammatory mechanisms, PPI exposure, and microbiota-associated clinical outcomes. RESULTS: The review included studies evaluating children with GERD as well as mechanistic studies involving pediatric upper gastrointestinal conditions requiring PPI therapy when microbiota-related outcomes were relevant to the review objective. Study selection was performed according to PRISMA guidelines, 31 of which were included in the final analysis. The data indicate that pediatric exposure to GERD and PPI is associated with changes in the gastrointestinal microbiota at multiple levels (oral, esophageal, gastric, and intestinal). These changes include reduced microbial diversity, changes in bacterial composition (particularly Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria), and increased similarity of microbiota between aerodigestive compartments, suggesting possible microbial transfer associated with reflux or aspiration. PPI exposure has been frequently associated with increased numbers of oropharyngeal bacteria in the gut, decreased beneficial taxa (e.g., Bifidobacterium), and increased numbers of potentially pathogenic genera (e.g., Streptococcus, Enterobacteriaceae). Several studies have reported an association between PPI and small intestinal bacterial overgrowth, but the results are inconsistent. PPI use has also been reported to be associated with an increased risk of infections, allergic diseases, and other systemic effects, coupled with the recognition of limited clinical benefit of PPI therapy in GERD in infants. CONCLUSION: Pediatric GERD and PPI exposure are associated with alterations in the gastrointestinal microbiome and possible systemic clinical effects. Most evidence is heterogeneous and influenced by confounding factors, which limits the establishment of a causal relationship. Prospective longitudinal and mechanistic studies using standardized microbiome methodologies are required to clarify causality and better define the respective contributions of GERD and PPI therapy to microbiota alterations and their clinical significance. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261405291, identifier CRD420261405291.