High-throughput transcriptomics of bacteria-xenobiotic interactions reveal mechanism of statin-driven gut microbiota perturbation

Many oral drugs perturb the gut microbiome, potentially leading to negative health conse-quences. Unfortunately, mechanisms of most microbe-xenobiotic responses have not been elu-cidated at the genetic level. To bridge this knowledge gap, we characterized the gene expression profiles of prevalent gut bacteria exposed to top-prescribed oral pharmaceuticals using high-throughput bacterial transcriptomics. Across 380 drug-microbe pairs, significant and reproduci-ble transcriptional responses were observed. KEGG analysis revealed conserved pathways af-fected by oral drugs, especially those involved in multi-drug resistance and transport. We identi-fied several responses with potential clinical impact, including modulation of tartrate metabolism and riboflavin biosynthesis. Importantly, we discovered that statin-mediated overexpression of the AcrAB-TolC efflux pump enhances toxicity of vitamin A and secondary bile acids. We further found that gut bacteria carrying AcrAB-TolC genes are depleted in individuals taking simvastatin. This work demonstrates the value of high-throughput transcriptomics for dissecting mechanisms of drug-mediated microbiota shifts towards better informed clinical interventions.