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

Wenfan Ke, James A. Saba, Cong-Hui Yao, Michael A. Hilzendeger, Anna Drangowska-Way, Chintan Joshi, Vinod K. Mony, Shawna B. Benjamin, Sisi Zhang, Jason Locasale, Gary J. Patti, Nathan Lewis () and Eyleen J. O’Rourke ()
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Wenfan Ke: University of Virginia
James A. Saba: University of Virginia
Cong-Hui Yao: Washington University
Michael A. Hilzendeger: University of Virginia
Anna Drangowska-Way: University of Virginia
Chintan Joshi: University of California, San Diego
Vinod K. Mony: University of Virginia
Shawna B. Benjamin: University of Virginia
Sisi Zhang: Washington University
Jason Locasale: Duke University
Gary J. Patti: Washington University
Nathan Lewis: University of California, San Diego
Eyleen J. O’Rourke: University of Virginia

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16220-w

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