Rethinking Long-Term PPI Therapy in GERD: A Narrative Review from a Microbial Ecology Perspective Beyond Acid Suppression

Gastroesophageal reflux disease (GERD) is a common chronic disorder of the upper gastrointestinal tract, traditionally explained by an acid-centric model in which gastric acid causes mucosal injury and symptoms. Proton pump inhibitors (PPIs) are the mainstay of therapy and effectively control symptoms in many patients. However, up to 50% of individuals remain symptomatic despite adequate acid suppression, suggesting that GERD is a multifactorial condition involving anti-reflux barrier dysfunction, impaired mucosal defense, immune activation, and alterations in the esophageal microbiota. This study is a narrative review aimed at evaluating current evidence on the interactions between acid suppression, esophageal microbial ecology, and host–microbe interactions in GERD, and at exploring the potential role of microbiota-targeted therapeutic strategies. The literature search was conducted using electronic databases (e.g., PubMed and Scopus), without formal time restrictions, prioritizing recent and clinically relevant studies. Evidence was qualitatively synthesized to provide an integrated overview. Recent studies suggest that the esophagus hosts a microbial ecosystem that may contribute to mucosal homeostasis. In GERD and Barrett’s esophagus, several studies report a shift toward Gram-negative anaerobic bacteria with potential pro-inflammatory activity. Long-term PPI therapy has been associated with increased gastric pH and changes in gastrointestinal microbiota composition, including a relative increase in taxa such as Streptococcus and Veillonella, and a reduction in short-chain fatty acid–producing bacteria. These alterations may be linked to dysbiosis and a possible increase in susceptibility to certain infections, although causality remains to be fully established. The main limitations of this review include its narrative design, the absence of systematic study selection, and the heterogeneity of the available evidence. Understanding the impact of acid suppression on microbial ecology may support the development of more integrated and personalized therapeutic strategies.