Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

Publication date: 20 April 2017
Source:Cell, Volume 169, Issue 3
Author(s): Timothy A. Scott, Leonor M. Quintaneiro, Povilas Norvaisas, Prudence P. Lui, Matthew P. Wilson, Kit-Yi Leung, Lucia Herrera-Dominguez, Sonia Sudiwala, Alberto Pessia, Peter T. Clayton, Kevin Bryson, Vidya Velagapudi, Philippa B. Mills, Athanasios Typas, Nicholas D.E. Greene, Filipe Cabreiro
Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.

Graphical abstract

Teaser

A three-way high-throughput screen involving host-microbe-drug interactions reveals that the beneficial impact of some drugs can be due to effects of drug-dependent alterations by gut microbe composition rather than direct action of the therapeutic itself.


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