Absorption, Enterohepatic Circulation, and Fecal Excretion of Toxicants

Watkins, John B.; Klaassen, Curtis D.

doi:10.1016/b978-0-12-801238-3.02122-x

Cited by 1 publication

(1 citation statement)

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“…Furthermore, bacterial lysis, and the consequent release of cell content, is part of the normal mammalian gut dynamics 52 . The enterohepatic system permits exchange of metabolites, byproducts, and xenobiotics between the intraluminal intestine, the bloodstream, and animal tissues 53 . Indeed, microbiota-derived nucleosides and nucleotides can be found in blood and other host organs in mammals [54][55][56] including humans 57 , suggesting that microbial nucleotide metabolism could impact host nucleotide metabolism and hence the metabolism of chemotherapeutics beyond C. elegans.…”

Section: Discussionmentioning

confidence: 99%

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

Saba

Yao

et al. 2020

Nat Commun

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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.

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