TY - JOUR
T1 - Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion
AU - Ke, Wenfan
AU - Saba, James A.
AU - Yao, Cong Hui
AU - Hilzendeger, Michael A.
AU - Drangowska-Way, Anna
AU - Joshi, Chintan
AU - Mony, Vinod K.
AU - Benjamin, Shawna B.
AU - Zhang, Sisi
AU - Locasale, Jason
AU - Patti, Gary J.
AU - Lewis, Nathan
AU - O’Rourke, Eyleen J.
N1 - Funding Information:
We thank Vincent Galy for protocol to develop anti-LGG-1 antibodies, Malene Hansen for LGG-1 reporter strain, Dr. Sidney Kushner for generous help developing HB101 RNAi-competent derivative, and Xiaojing Liu and Juan Liu for optimizing and running fluorometabolite LC–MS analyses. We are very grateful to Filipe Cabreiro for sharing LC–MS protocol, E. coli strains, and general advice. We thank Bob Nakamoto and Yelena Peskova for training and use of their French Press. We thank Chenyu Yang, Noel Higgason, Alexandra Loperfito, Ahtesham Najeeb Chaudhry, and Meghna Shankar for help quantitating fertility images, and specially Nella Solodukhina, Leila Rayyan, and Mikayla Marraccini for help preparing reagents and conducting some of the experiments. We are grateful to the Keck Center for Cellular Imaging for the usage of the Leica SP5X microscopy system (PI: AP; NIH-RR025616). We acknowledge the C. elegans strains provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Some E. coli strains were provided by CGSC, which is funded by NSF/Biological Infrastructure/Living Collections Program (DBI-0742708). The HSP60 and 4A1(Tubulin) antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology. We thank Kevin Janes and Ariel Pani for revising this manuscript. We thank UVA DoubleHoo, College Council Minerva Research Grant, Ingrassia Family Research Award, and the Jefferson Foundation for support of trainees involved in this work. This work would not have been possible without the generous support of the W. M. Keck Foundation and PEW Charitable Trust.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085289879&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16220-w
DO - 10.1038/s41467-020-16220-w
M3 - Article
C2 - 32444616
AN - SCOPUS:85085289879
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2587
ER -