RRC ID 66188
Author Ke W, Saba JA, Yao CH, Hilzendeger MA, Drangowska-Way A, Joshi C, Mony VK, Benjamin SB, Zhang S, Locasale J, Patti GJ, Lewis N, O'Rourke EJ.
Title Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion.
Journal Nat Commun
Abstract The gut microbiota metabolizes drugs and alters their efficacy and toxicity. Diet alters drugs, the metabolism of the microbiota, and the host. However, whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. Here we show that dietary thymidine and serine enhance 5-fluoro 2'deoxyuridine (FUdR) toxicity in C. elegans through different microbial mechanisms. Thymidine promotes microbial conversion of the prodrug FUdR into toxic 5-fluorouridine-5'-monophosphate (FUMP), leading to enhanced host death associated with mitochondrial RNA and DNA depletion, and lethal activation of autophagy. By contrast, serine does not alter FUdR metabolism. Instead, serine alters E. coli's 1C-metabolism, reduces the provision of nucleotides to the host, and exacerbates DNA toxicity and host death without mitochondrial RNA or DNA depletion; moreover, autophagy promotes survival in this condition. This work implies that diet-microbe interactions can alter the host response to drugs without altering the drug or the host.
Volume 11(1)
Pages 2587
Published 2020-5-22
DOI 10.1038/s41467-020-16220-w
PII 10.1038/s41467-020-16220-w
PMID 32444616
PMC PMC7244588
MeSH Animals Caenorhabditis elegans / drug effects* Caenorhabditis elegans / microbiology Caenorhabditis elegans / physiology Dietary Supplements Escherichia coli / drug effects Escherichia coli / metabolism Floxuridine / pharmacokinetics Floxuridine / toxicity* Folic Acid / metabolism Food-Drug Interactions* Gastrointestinal Microbiome / drug effects* Gastrointestinal Microbiome / physiology Serine / pharmacology* Thymidine / analogs & derivatives Thymidine / metabolism Thymidine / pharmacokinetics Thymidine / pharmacology Uracil Nucleotides / metabolism Uracil Nucleotides / pharmacokinetics
IF 12.121
Prokaryotes E. coli Keio collection