The gut microbiota encodes 150-fold more genes than the human genome, representing a rich reservoir of enzymes with the potential to metabolize therapeutic drugs. In this systematic screening approach, Andrew Goodman and colleagues measure the capacity of 76 representatives of the gut microbiota to metabolize 271 oral drugs, and report that many of these drugs are indeed chemically modified by microbes. They also identify the microbiome-encoded enzymes responsible for these activities, and show in mice that they can directly impact intestinal and systemic drug metabolism. Finally, the authors used gene enrichment analysis to establish that the presence of homologues of newly identified microbial metabolic enzymes, but not the abundance of bacterial strains that express these enzymes, best explains the drug metabolizing capacity of individual gut isolates and of human gut microbial communities. This framework may pave the way towards identifying causal relationships between the microbiota and drug metabolism, with implications for therapeutic interventions.
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