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Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing evidence implicates the gut microbiome in this variability, the molecular mechanisms involved remain largely unknown. Here we show, by measuring the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs, that many drugs are chemically modified by microorganisms. We combined high-throughput genetic analyses with mass spectrometry to systematically identify microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents. These causal links between the gene content and metabolic activities of the microbiota connect interpersonal variability in microbiomes to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.
Following administration, drug molecules typically undergo chemical modification(s); the resulting metabolites can have functional and toxicological properties that are distinct from those of their parent drug1. Most drugs are delivered orally and can encounter commensal microorganisms in the small and large intestine. These microorganisms collectively encode 150-fold-more genes than the human genome; this genetic diversity encompasses a rich enzyme repository with drugmetabolizing potential. Anecdotal examples of interactions between the gut microbiome and drugs or drug metabolites, with intestinal and systemic pharmacological effects, have previously been reported. Such compound modifications by gut microorganisms can lead either to their activation (for example, sulfasalazine2), inactivation (for example, digoxin3) or toxification (for example, sorivudine and brivudine4,5, and irinotecan6). For a few drugs, microbial biotransformation has been assigned to specific bacterial strains and gene products3,5,7. However, these examples are the exception, as there is little systematic understanding of the scope, specificity or microbial and/or chemical determinants of microbiome-drug interactions8.
We set out to systematically assay interactions between drugs and microorganisms by measuring the ability of representative human gut bacteria to metabolize structurally diverse drugs, and by identifying drug-metabolizing microbial gene products. We establish that these drug-metabolizing microbial proteins can contribute to the in vivo drug metabolism of gnotobiotic mice, and provide evidence that metagenomics and genomics sequence data can explain the capacity of...