Human microbiome signatures of differential colorectal cancer drug metabolism

Leah Guthrie,Johanna Daily,Libusha Kelly,Sanchit Gupta

doi:10.1038/s41522-017-0034-1

Leah Guthrie, Johanna Daily + Show 2 more

Open Access

https://doi.org/10.1038/s41522-017-0034-1

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Abstract

It is well appreciated that microbial metabolism of drugs can influence treatment efficacy. Microbial β-glucuronidases in the gut can reactivate the excreted, inactive metabolite of irinotecan, a first-line chemotherapeutic for metastatic colorectal cancer. Reactivation causes adverse drug responses, including severe diarrhea. However, a direct connection between irinotecan metabolism and the composition of an individual’s gut microbiota has not previously been made. Here, we report quantitative evidence of inter-individual variability in microbiome metabolism of the inactive metabolite of irinotecan 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 unreported microbial β-glucuronidases; inhibiting these enzymes may decrease irinotecan-dependent adverse drug responses in targeted subsets of patients. In total, this study reveals metagenomic mining of the microbiome, combined with metabolomics, as a non-invasive approach to develop biomarkers for colorectal cancer treatment outcomes.

Highlights

The microbiome shapes the metabolic[1] and immunological[2] landscape of individuals in health and disease
Glucuronidation is a common modification of xenobiotics as part of phase II drug metabolism
We find associations between the efficient microbiota-mediated turnover of SN-38G and specific microbial by microbial β-glucuronidases (BGs) from abundant gut species and we propose a putative transport mechanism for SN-38G entry into bacterial cells (Fig. 6)

Summary

Introduction

The microbiome shapes the metabolic[1] and immunological[2] landscape of individuals in health and disease. Its plasticity can be leveraged for therapeutic interventions[3] and to improve therapeutic outcomes.[4,5] Recent studies have implicated gut microbiome metabolism at the gene[5] and species[6] level in driving the variability in patient drug response and toxicity. Understanding the mechanisms of microbial mediated drug biotransformation and quantifying the microbial origins of variability in drug response may improve patient treatment outcomes. One of few therapeutic drugs for which we have a mechanistic understanding of how the gut microbiome influences drug metabolism is the colorectal cancer chemotherapeutic and prodrug irinotecan (CPT-11). CPT-11, in combination with fluorouracil and leucovorin, is one of three first-line treatments for metastatic colorectal cancer (CRC).[7,8] CPT-11 is administered to patients intravenously and converted to its active form (SN-38) by carboxylesterases in the liver.[5,9] It is inactivated by UDP-

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