Proton pump inhibitor-associated microbiomes shape systemic host responses

Proton pump inhibitors (PPIs) consistently alter the gut microbiome, but the contribution of these changes to systemic effects associated with PPI use remains unclear. Here, we show that PPI-associated microbiome remodelling induces systemic metabolic and transcriptional responses independently of direct drug exposure. Integrating human microbiome and metabolomics data with metabolic modelling, we identified consistent alterations in microbial metabolic functions and host-microbiome co-metabolism. Transfer of PPI-associated microbiota into germ-free mice reproduced key metabolic changes observed in humans, particularly in aromatic amino acid metabolism, and induced additional alterations in systemic lipid metabolism. These changes were accompanied by tissue-specific transcriptional responses in the colon, liver and brain, affecting metabolic and inflammatory pathways. Together, our findings identify transferable metabolic and transcriptional microbiome-mediated signatures that may contribute to the adverse systemic effects associated with PPI use.