Searching for new microbiome-targeted therapeutics through a drug repurposing approach

Commonly used non-antibiotic drugs have been associated with changes in gut microbiome composition, paving the way for repurposing FDA-approved molecules as next-generation microbiome therapeutics. Herein we developed and validated an ex vivo high-throughput screening platform - the Mini Gut Model - to underpin human gut microbiome response to molecular modulators. Ten FDA-approved compounds, selected based on the maximum molecular fingerprints' structural diversity, were screened against the gut microbiome of 5 healthy subjects, allowing us to characterize the ability of human-targeted drugs to specifically modulate the human gut microbiome network. Three compounds - THIP Hydrochloride, Methenamine, and Mesna - showed to be promising as novel gut microbiome therapeutics, in light of their capability of promoting health-associated features of the gut microbiome. Our findings provide a resource for future research on drug-microbiome interactions and lay the foundation for a new era of more precise gut microbiome modulation through drug repurposing, aimed at targeting specific dysbiotic events.