Format

Send to

Choose Destination
Cell. 2017 Apr 20;169(3):442-456.e18. doi: 10.1016/j.cell.2017.03.040.

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

Author information

1
Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK.
2
Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK; UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
3
Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK; Department of Computer Science, University College London, London WC1E 6BT, UK.
4
UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
5
European Molecular Biology Laboratory (EMBL) Heidelberg, Genome Biology, Meyerhofstraße 1, 69117 Heidelberg, Germany.
6
Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
7
Department of Computer Science, University College London, London WC1E 6BT, UK.
8
Institute of Structural and Molecular Biology, University College London and Birkbeck, London WC1E 6BT, UK. Electronic address: f.cabreiro@ucl.ac.uk.

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.

KEYWORDS:

5-FU; C. elegans; E. coli; Keio; autophagy; cancer; chemical-genomics; co-metabolism; holobiont; nucleotide metabolism

PMID:
28431245
PMCID:
PMC5406385
DOI:
10.1016/j.cell.2017.03.040
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center