Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, VA, USA.
Department of Chemistry, Washington University, St. Louis, MO, USA.
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.
肠道微生物群代谢药物，并改变其疗效和毒性。饮食改变药物、微生物群的代谢以及宿主。然而，饮食引起的微生物群代谢变化是否能改变宿主对药物的反应在很大程度上还没有得到探索。在这里，我们表明，膳食胸苷和丝氨酸通过不同的微生物机制增强秀丽隐杆线虫中 5-氟 2'-脱氧尿苷 (FUdR) 的毒性。胸苷促进前药 FUdR 转化为有毒的 5-氟尿嘧啶-5'-单磷酸 (FUMP)，导致与线粒体 RNA 和 DNA 耗竭相关的宿主死亡增加，并导致自噬的致命激活。相比之下，丝氨酸不会改变 FUdR 的代谢。相反，丝氨酸改变大肠杆菌的 1C 代谢，减少核苷酸向宿主的供应，并在不耗尽线粒体 RNA 或 DNA 的情况下加剧 DNA 毒性和宿主死亡；此外，自噬在这种情况下促进了生存。这项工作表明，饮食-微生物相互作用可以改变宿主对药物的反应，而不改变药物或宿主。
