Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans
Open accessAbstract
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 B 6 , B 9 , 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.
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Some bacterial species enhanced one drug's effect while reducing another's.
“Different bacterial species increased the response to 1 drug and decreased the effect of another.”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [191]
Bacterial ribonucleotide metabolism changed the cytotoxicity of 5-fluorouracil and 5-fluoro-20-deoxyuridine by shifting regulatory metabolites that synergized with drug-induced DNA damage.
“Bacterial ribonucleotide metabolism affected the cytotoxic effects 5-fluorouracil and 5-fluoro-20-deoxyuridine by altering production of regulatory metabolites had synergistic effects with drug-induced DNA damage.”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [191]
In C. elegans, bacterial metabolism changes the effectiveness of 5-fluorouracil, 5-fluoro-20-deoxyuridine, and camptothecin.
“Bacterial metabolism was found to affect the efficacy of the anti-pyrimidine drugs 5-fluorouracil and 5-fluoro-20-deoxyuridine and the topoisomerase I inhibitor camptothecin in Caenorhabditis elegans 191, 192.”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [191]
Bacterial uracil phosphoribosyltransferase can convert 5-FU to the RNA-damaging 5-fluorouridine monophosphate in a Caenorhabditis elegans model system.
“the widely present bacterial uracil phosphoribosyltransferase (Martinussen and Hammer, 1994) can convert 5-FU to the RNA-damaging 5-fluorouridine monophosphate using the nematode Caenorhabditis elegans as a model system (Garcia-Gonzalez et al., 2017;Scott et al., 2017).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Scott et al., 2017
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- Authors
- Scott, T. A., Quintaneiro, L. M., Norvaisas, P., Lui, P. P., Wilson, M. P., Leung, K.-Y., Herrera-Dominguez, L., Sudiwala, S., Pessia, A., Clayton, P. T., Bryson, K., Velagapudi, V., Mills, P. B., Typas, A., Greene, N. D. E., & Cabreiro, F.
- Affiliations
- Institute of Structural and Molecular Biology (GB)
- University College London (GB)
- University of Helsinki (FI)
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Cabreiro, Filipe
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 169
- Issue
- 3
- Pages
- 442-456.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5406385
- OpenAlex
- W2606663123
- Cited by
- 254
- References
- 36
- Citations by year
- 2026: 21 · 2025: 18 · 2024: 26 · 2023: 32 · 2022: 26 · 2021: 29 · 2020: 28 · 2019: 34 · 2018: 27 · 2017: 12 · 2016: 1
- FWCI
- 11.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BIROn (Birkbeck, University of London) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Medical Research Council Canada (MR/N003713/1)
- Medical Research Council
- Royal Society (Fellowship-102532/Z/12/Z)
- Great Ormond Street Hospital Charity
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- fluoropyrimidine, 5-fluorouracil, colorectal cancer, gut microbiota, ribonucleotide metabolism, autophagy, cell death, nucleoside diphosphate kinase, Caenorhabditis elegans, Escherichia coli, interindividual variability
- MeSH terms
- Gastrointestinal Microbiome, Animals, Antineoplastic Agents, Autophagy, Diet, Escherichia coli, Fluorouracil, Humans, Pentosyltransferases, Colorectal Neoplasms, Cell Death, Caenorhabditis elegans, Models, Animal
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