Abstract
SummaryFluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.
Highlights
Fluoropyrimidines are antimetabolite drugs primarily used to treat cancer
We compared 5-FU activity on worms fed five Escherichia coli laboratory strains commonly used in worm studies (Figure 1A) and observed up to 80-fold differences in 5-FU minimum inhibitory concentration (MIC) (HB101, MIC = 8 mM versus BL21G, MIC = 0.1 mM, p < 0.001)
We cultured nematodes on bacteria killed by heat or UV treatment. 5-FU efficacy was greatly decreased in nematodes fed dead BW25113 (128-fold, Figure 1C) or OP50 (Figure S1A)
Summary
Fluoropyrimidines are antimetabolite drugs primarily used to treat cancer. The archetype fluoropyrimidine, 5-fluorouracil (5-FU), is the principal therapy for colorectal cancer, the third most common cancer worldwide (Midgley and Kerr, 1999). Despite the widespread use of 5-FU-based chemotherapy, there is no universally accepted dose, and significant pharmacokinetic variations exist between individuals. Adverse effects are frequent (diarrhea, nausea) and response rates sub-optimal (10% as monotherapy, 50% with combination therapies) (Longley et al, 2003). The observed inter-patient variation in 5-FU efficacy/toxicity has been attributed to several factors, including genetic polymorphisms in TS, dihydropyrimidine dehydrogenase, methylene THF reductase, and cytidine deaminase (Offer and Diasio, 2016). Genetics alone does not explain differences in 5-FU tolerance between different continents suggesting environmental factors as key determinants in 5-FU action (O’Donnell and Dolan, 2009)
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