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 the possibility of repurposing FDA-approved molecules as next-generation microbiome therapeutics. In the present study, we developed and validated an ex vivo high-throughput screening platform - the Mini Gut Model - to underpin the human gut microbiome response to molecular modulators. Ten FDA-approved compounds, selected on the basis of the maximum structural diversity described in terms of molecular fingerprint, 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, namely 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 pave the way for a new era of more precise gut microbiome modulation through drug repurposing, with the ultimate goal of targeting specific dysbiotic events.