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

Wenfan Ke,Gary J Patti,Eyleen J O’Rourke,Shawna B Benjamin,Sisi Zhang,Chintan Joshi,Michael A Hilzendeger,Vinod K Mony,Nathan Lewis,Anna Drangowska-Way,James A Saba,Cong-Hui Yao,Jason Locasale

doi:10.1038/s41467-020-16220-w

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.

Highlights

The gut microbiota metabolizes drugs and alters their efficacy and toxicity
fluorodeoxyuridine monophosphate (FdUMP) forms a stable complex with 5,10-mTHF and thymidylate synthase (TS), preventing the de novo synthesis of dTMP. 5,10-mTHF is essential for dTMP synthesis and for the FdUMP-mediated inhibition of TS5. 1C-loaded folates are not known to transfer across membranes; 5,10-mTHF must be locally generated5. 5,10-mTHF can be made from the amino acids serine and glycine
To define whether and how dietary nutrients alter the toxicity of fluoro 2′deoxyuridine (FUdR) in C. elegans, it is required first to identify the minimum dose leading to robust toxicity (i.e. 100% embryonic lethality) for further screens on dietary enhancers and inhibitors of the toxicity

Summary

Introduction

The metabolism of the microbiota, and the host. Whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. 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; autophagy promotes survival in this condition. Emerging evidence shows that diet can modulate drug efficacy and toxicity through modifying the composition or physiology of the microbiota, or the interaction between the microbiota and the host. The reaction that converts serine to glycine donates a 1C group to THF to form 5,10-mTHF, which is available to participate in the methyl transfer reaction that converts dUMP into dTMP. Serving as a substrate for the synthesis of 5,10-mTHF, the 1C-metabolite folinic acid is the most efficient fluoropyrimidine potentiator.

Methods

Results

Conclusion