Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics
Open accessAbstract
The human microbiota greatly affects physiology and disease; however, the contribution of bacteria to the response to chemotherapeutic drugs remains poorly understood. Caenorhabditis elegans and its bacterial diet provide a powerful system to study host-bacteria interactions. Here, we use this system to study how bacteria affect the C. elegans response to chemotherapeutics. We find that different bacterial species can increase the response to one drug yet decrease the effect of another. We perform genetic screens in two bacterial species using three chemotherapeutic drugs: 5-fluorouracil (5-FU), 5-fluoro-2'-deoxyuridine (FUDR), and camptothecin (CPT). We find numerous bacterial nucleotide metabolism genes that affect drug efficacy in C. elegans. Surprisingly, we find that 5-FU and FUDR act through bacterial ribonucleotide metabolism to elicit their cytotoxic effects in C. elegans rather than by thymineless death or DNA damage. Our study provides a blueprint for characterizing the role of bacteria in the host response to chemotherapeutics.
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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 [192]
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 [192]
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 [192]
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 Garcia-Gonzalez et al., 2017
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Cites
THE GENETICS OF CAENORHABDITIS ELEGANS
Brenner, S. (1974) · Genetics · doi:10.1093/genetics/77.1.71 · Cited by 14,984 · see citing works
Construction of Escherichia coli K‐12 in‐frame, single‐gene knockout mutants: the Keio collection
Baba, T., Ara, T., Hasegawa, M., Takai, Y., Okumura, Y., Baba, M., Datsenko, K. A., Tomita, M., Wanner, B. L., & Mori, H. (2006) · Molecular Systems Biology · doi:10.1038/msb4100050 · Cited by 7,858 · see citing works
5-Fluorouracil: mechanisms of action and clinical strategies
Longley, D. B., Harkin, D. P., & Johnston, P. G. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1074 · Cited by 5,332 · see citing works
Commensal <i>Bifidobacterium</i> promotes antitumor immunity and facilitates anti–PD-L1 efficacy
Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-Michaels, K., Earley, Z. M., Benyamin, F. W., Man Lei, Y., Jabri, B., Alegre, M.-L., et al. (2015) · Science · doi:10.1126/science.aac4255 · Cited by 3,888 · see citing works
The gut microbiota--masters of host development and physiology
Sommer, F., & Bäckhed, F. (2013) · Nature Reviews Microbiology · doi:10.1038/nrmicro2974 · Cited by 3,681 · see citing works
Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota
Vétizou, M., Pitt, J. M., Daillère, R., Lepage, P., Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy, B., Roberti, M. P., Duong, C. P. M., et al. (2015) · Science · doi:10.1126/science.aad1329 · Cited by 3,488 · see citing works
Topoisomerase I inhibitors: camptothecins and beyond
Pommier, Y. G. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1977 · Cited by 2,294 · see citing works
The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide
Viaud, S., Saccheri, F., Mignot, G., Yamazaki, T., Daillère, R., Hannani, D., Enot, D. P., Pfirschke, C., Engblom, C., Pittet, M. J., et al. (2013) · Science · doi:10.1126/science.1240537 · Cited by 2,050 · see citing works
A comprehensive genome-scale reconstruction of Escherichia coli metabolism—2011
Orth, J. D., Conrad, T. M., Na, J., Lerman, J. A., Nam, H., Feist, A. M., & Palsson, B. Ø. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.65 · Cited by 1,006 · see citing works
Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism
Cabreiro, F., Au, C., Leung, K.-Y., Vergara-Irigaray, N., Cochemé, H. M., Noori, T., Weinkove, D., Schuster, E., Greene, N. D. E., & Gems, D. (2013) · Cell · doi:10.1016/j.cell.2013.02.035 · Cited by 967 · see citing works
Gut Microbiota, Inflammation, and Colorectal Cancer
Brennan, C. A., & Garrett, W. S. (2016) · Annual Review of Microbiology · doi:10.1146/annurev-micro-102215-095513 · Cited by 572 · see citing works
The natural history of Caenorhabditis elegans
Félix, M., & Braendle, C. (2010) · Current Biology · doi:10.1016/j.cub.2010.09.050 · Cited by 493 · see citing works
The native microbiome of the nematode Caenorhabditis elegans: gateway to a new host-microbiome model
Dirksen, P., Marsh, S., Braker, I., Heitland, N., Wagner, S., Nakad, R., Mäder, S., Petersen, C., Kowallik, V., Rosenstiel, P. C., et al. (2016) · BMC Biology · doi:10.1186/s12915-016-0258-1 · Cited by 442 · see citing works
Félix, M., & Duveau, F. (2012) · BMC Biology · doi:10.1186/1741-7007-10-59 · Cited by 358 · see citing works
Assembly of the Caenorhabditis elegans gut microbiota from diverse soil microbial environments
Berg, M., Stenuit, B. A., Ho, J., Wang, A., Parke, C. D., Knight, M., Alvarez‐Cohen, L., & Shapira, M. (2016) · The ISME Journal · doi:10.1038/ismej.2015.253 · Cited by 345 · see citing works
Diet-Induced Developmental Acceleration Independent of TOR and Insulin in C. elegans
MacNeil, L. T., Watson, E. V., Arda, H. E., Zhu, L. J., & Walhout, A. J. M. (2013) · Cell · doi:10.1016/j.cell.2013.02.049 · Cited by 309 · see citing works
Self-citationWatson, E. V., MacNeil, L. T., Ritter, A. D., Yilmaz, L. S., Rosebrock, A. P., Caudy, A. A., & Walhout, A. J. M. (2014) · Cell · doi:10.1016/j.cell.2014.01.047 · Cited by 269 · see citing works
Self-citationHost-microbe co-metabolism dictates cancer drug efficacy in C. elegans
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., et al. (2017) · Cell · doi:10.1016/j.cell.2017.03.040 · Cited by 254 · see citing works
Bacterial Nitric Oxide Extends the Lifespan of C. elegans
Gusarov, I., Gautier, L., Смоленцева, О. А., Shamovsky, I., Eremina, S. Y., Mironov, A. S., & Nudler, E. (2013) · Cell · doi:10.1016/j.cell.2012.12.043 · Cited by 194 · see citing works
Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response
Watson, E., MacNeil, L. T., Arda, H. E., Zhu, L. J., & Walhout, A. J. M. (2013) · Cell · doi:10.1016/j.cell.2013.02.050 · Cited by 134 · see citing works
Self-citationMetabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans
Watson, E. V., Olín‐Sandoval, V., Hoy, M. J., Li, C., Louisse, T., Yao, V., Mori, A., Holdorf, A. D., Troyanskaya, O. G., Ralser, M., et al. (2016) · eLife · doi:10.7554/elife.17670 · Cited by 122 · see citing works
Self-citationWorms, bacteria, and micronutrients: an elegant model of our diet
Yilmaz, L. S., & Walhout, A. J. M. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.07.010 · Cited by 86 · see citing works
Self-citationIsolated remethylation disorders: do our treatments benefit patients?
Schiff, M., Benoist, J., Tilea, B., et al. (2010) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-010-9120-8 · Cited by 83 · see citing works
The development of the BSAC standardized method of disc diffusion testing
Andrews, J. M. (2001) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/48.suppl_1.29 · Cited by 83 · see citing works
Ison, G., Beaver, J. A., McGuinn, W. D., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0638 · Cited by 81 · see citing works
Watson, E. V., Yilmaz, L. S., & Walhout, A. J. M. (2015) · Annual Review of Genetics · doi:10.1146/annurev-genet-112414-055257 · Cited by 53 · see citing works
Self-citationCaenorhabditis elegans metabolic gene regulatory networks govern the cellular economy
Watson, E. V., & Walhout, A. J. M. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.03.004 · Cited by 28 · see citing works
Self-citationBoettcher, B. R., & Meister, A. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)69114-3 · Cited by 27 · see citing works
Allosteric Dominance in Carbamoyl Phosphate Synthetase
Braxton, B. L., Mullins, L. S., Raushel, F. M., et al. (1999) · Biochemistry · doi:10.1021/bi982097w · Cited by 19 · see citing works
Tawornsamretkit, I., Thanasomboon, R., Thaiprasit, J., Waraho‐Zhmayev, D., Cheevadhanarak, S., & Meechai, A. (2012) · Procedia Computer Science · doi:10.1016/j.procs.2012.09.004 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Comprehensive review of targeted therapy for colorectal cancer
Xie, Y.-H., Chen, Y.-X., & Fang, J.-Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0116-z · Cited by 1,687 · see citing works
The Human Gut Microbiome: From Association to Modulation
Schmidt, T. S. B., Raes, J., & Bork, P. (2018) · Cell · doi:10.1016/j.cell.2018.02.044 · Cited by 845 · see citing works
Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer
Song, M., Chan, A. T., & Sun, J. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.06.048 · Cited by 752 · see citing works
Gut reactions: Breaking down xenobiotic–microbiome interactions
Clarke, G., Sandhu, K. V., Griffin, B. T., Dinan, T. G., Cryan, J. F., & Hyland, N. P. (2019) · Pharmacological Reviews · doi:10.1124/pr.118.015768 · Cited by 319 · see citing works
Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy
Pryor, R., Norvaisas, P., Marinos, G., Best, L., Thingholm, L. B., Quintaneiro, L. M., De Haes, W., Esser, D., Waschina, S., Lujan, C., et al. (2019) · Cell · doi:10.1016/j.cell.2019.08.003 · Cited by 274 · see citing works
Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans
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., et al. (2017) · Cell · doi:10.1016/j.cell.2017.03.040 · Cited by 254 · see citing works
Gut Microbiota and Type 1 Diabetes
Han, H., Li, Y., Fang, J., Liu, G., Yin, J., Li, T., & Yin, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19040995 · Cited by 206 · see citing works
Qi, B., & Han, M. (2018) · Cell · doi:10.1016/j.cell.2018.07.032 · Cited by 164 · see citing works
Zhang, J., Li, X., Olmedo, M., Holdorf, A. D., Shang, Y., Artal-Sanz, M., Yilmaz, L. S., & Walhout, A. J. M. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.07.010 · Cited by 77 · see citing works
Computational methods and challenges in analyzing intratumoral microbiome data
Wang, Q., Liu, Z., Ma, A., Li, Z., Liu, B., & Ma, Q. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.01.011 · Cited by 37 · see citing works
- Authors
- García-González, A. P., Ritter, A. D., Shrestha, S., Andersen, E. C., Yilmaz, L. S., & Walhout, A. J. M.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Northwestern University (US)
- Corresponding author
- Walhout, Albertha J.M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 169
- Issue
- 3
- Pages
- 431-441.e8
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5484065
- OpenAlex
- W2605441431
- Cited by
- 243
- References
- 30
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 21 · 2023: 34 · 2022: 35 · 2021: 26 · 2020: 25 · 2019: 32 · 2018: 26 · 2017: 13
- FWCI
- 17.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- NIH (DK068429, GM082971, GM107227, AI121836, GM122393)
- NIH Office of Research Infrastructure Programs (P40 OD010440)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- Caenorhabditis elegans, bacterial metabolism, cancer chemotherapeutic agents, host-bacteria interactions, 5-fluorouracil, 5-fluorodeoxyuridine, camptothecin, ribonucleotide metabolism, drug response, bacterial diet, genetic screen
- MeSH terms
- Gastrointestinal Microbiome, Animals, Antineoplastic Agents, Camptothecin, Deoxyuridine, Diet, Escherichia coli, Fluorouracil, Humans, Pyrimidine Nucleosides, Colorectal Neoplasms, Caenorhabditis elegans, Comamonas, Models, Animal
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