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

Scott, TA; Quintaneiro, LM; Norvaisas, P; Lui, PP; Wilson, MP; Leung, K-Y; Herrera-Dominguez, L; ... Cabreiro, F; + view all (2017) Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans. Cell , 169 (3) 442-456.e18. 10.1016/j.cell.2017.03.040. Green open access

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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.

Type: Article
Title: Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cell.2017.03.040
Publisher version: http://doi.org/10.1016/j.cell.2017.03.040
Language: English
Additional information: © 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, ONE-CARBON METABOLISM, ESCHERICHIA-COLI, CAENORHABDITIS-ELEGANS, DNTP POOLS, 5-FLUOROURACIL, AUTOPHAGY, DEFECTS, THERAPY, GLYCINE, CELLS, C. elegans; 5-FU; cancer; E. coli; Keio; chemical-genomics; autophagy; nucleotide metabolism; holobiont; co-metabolism
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: https://discovery.ucl.ac.uk/id/eprint/1554588
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