Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion

Nat Commun. 2020 May 22;11(1):2587. doi: 10.1038/s41467-020-16220-w.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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


  • 2'-deoxythymidine-5'-monophosphate
  • Uracil Nucleotides
  • Floxuridine
  • Serine
  • Folic Acid
  • 5-fluorouridine 5'-phosphate
  • Thymidine