Human microbiome signatures of differential colorectal cancer drug metabolism

NPJ Biofilms and Microbiomes
Leah GuthrieLibusha Kelly

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.

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Datasets Mentioned

BETA
PRJNA373879

Methods Mentioned

BETA
metabolomics assay
phosphotransferase

Software Mentioned

Prodigal
MUSCLE
MMNET R package
MetaPhlAn
USEARCH
clc
Cytoscape
STAMP
R
SPADES assembler

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