Individuals vary widely in their drug responses, which can be dangerous and expensive due to significant treatment delays and adverse effects. Growing evidence implicates the gut microbiome in this variability, however the molecular mechanisms remain mostly unknown.
To systematically map the drug metabolizing capacity of the gut microbiota and assess its potential contribution to drug metabolism, the speaker measured the ability of 76 diverse human gut bacteria to metabolize each of 271 oral drugs. They found that two-thirds of these drugs are chemically modified by at least one of the tested microbes.
Through combination of high-throughput bacterial genetics with mass spectrometry-based metabolomics, the speaker systematically identified drug-metabolizing microbial enzymes. These proteins better explain the drug metabolizing capacity of bacterial strains than their phylogenetic classification.
The speaker further demonstrated that the abundance of homologs of these proteins predict the capacity of complete human gut communities to metabolize the targeted drugs. These causal links between microbiota gene content and metabolic activities connect inter-individual microbiome variability to interpersonal differences in drug metabolism, which has translatable potential on medical therapy and drug development across multiple disease indications.