Healthy human fecal metagenomes variably reactivate Irinotecan active metabolite. feces metagenome

It is well appreciated that metabolism of irinotecan by the gut microbiota can influence efficacy and potentially produce patient-specific adverse drug responses. However, a direct connection between irinotecan metabollism and the composition of an individual’s gut microbiota has not previously been made. Here, we report the first quantitative evidence of inter-individual variability in microbiome metabolism of the inactive metabolite of irinotecan, a first-line chemotherapeutic for metastatic colorectal cancer, to its active form. We identify a high turnover microbiota metabotype with potentially elevated risk for irinotecan-dependent adverse drug responses. We link the high turnover metabotype to previously unreported microbial β-glucuronidases and suggest that inhibiting these enzymes therapeutically may decrease irinotecan-dependent adverse drug responses in targeted subsets of patients. In total, this study demonstrates that metagenomic mining of the microbiome, when combined with metabolomics, defines a non-invasive approach to develop biomarkers for colorectal cancer treatment outcomes.