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

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.

Gordian Knot: Gastrointestinal lesions caused by three highly pathogenic coronaviruses from SARS-CoV and MERS-CoV to SARS-CoV-2

“…It is worth mentioning application of nanotechnology targeting gut microbiota. However, it should still be warned that some drugs with therapeutic effects may become toxic after being metabolized by gut microbiota ( Ke et al, 2020 ; Javdan et al, 2020 ). Therefore, patients with gastrointestinal lesions should be requested to be treated with drugs that could both protect gastrointestinal functions.…”

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy

“…Indeed, cancer-associated microbiota’s ability to modulate antitumor immune activation and therapy response might involve the direct provision to tumor cells of nutrients derived from microbial sources not only at the primary tumor sites but also at metastatic localizations [ 194 , 195 , 196 , 197 ]. This scenario adds even more complexity to the systemic (e.g., insulin-lowering effects of the ketogenic diet) versus cell-autonomous effects (e.g., restriction of serine/glycine or methionine) of dietary interventions [ 198 ], especially when considering recent evidence showing that diet-microbe interactions can alter the host response to drugs without altering the drug or the host [ 199 ]. Nonetheless, the extent of inter-patient variability in normal metabolism further highlights the need for controlled studies with metabolic therapies and/or dietary interventions in varied populations before new developments in combination with ICIs could be carried out.…”

The role of the microbiome in drug resistance in gastrointestinal cancers

“…Another aspect of modulating gut microbiota is the change in metabolism by diet or probiotics [109,117,118]; this may not only modulate metabolism of normal metabolites, but also signaling, miRNA expression, and cross-talk between microbiota and mammalian cells (normal and tumor), subsequently altering the host response to the drug. It has also been demonstrated that crosstalk may be mediated by extracellular vesicles, which can carry not only proteins but also RNA and DNA, which may modulate genetic expression [119]…”