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    Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans

    Scott, T.A. and Quintaneiro, L.M. and Norvaisas, P. and Lui, P.P. and Wilson, M.P. and Leung, K.-Y. and Herrera-Dominguez, L. and Sudiwala, S. and Pessia, A. and Clayton, P.T. and Bryson, K. and Velagapudi, V. and Mills, P.B. and Typas, A. and Greene, N.D.E. and Cabreiro, Filipe (2017) Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans. Cell 169 (3), 442-456.e18. ISSN 0092-8674.

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    Abstract

    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.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): C. elegans, 5-FU, cancer, E. coli, Keio, chemical-genomics, autophagy, nucleotide metabolism, holobiont, co-metabolism
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 08 May 2017 14:57
    Last Modified: 08 May 2017 14:57
    URI: http://eprints.bbk.ac.uk/id/eprint/18676

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