Bacterial Metabolism Alters the Efficacy of Chemotherapeutics Free

Chemotherapy is associated with a range of responses, toxicities, and pharmacokinetics in patients with colorectal cancer, but genetics is not sufficient to explain these differences. Two independent studies hypothesized that gut bacteria may influence response to chemotherapy and used C. elegans, which have a bacterial diet, as a model system to investigate host–microbiome–drug interactions. García-González and colleagues showed that chemotherapeutics 5-fluorouracil (5-FU), 5-fluoro-2′-deoxyuridine (FUDR), and camptothecin (CPT) impaired fecundity in C. elegans fed either E. coli or Comamonas. There was no difference in 5-FU efficacy between the two diets. FUDR caused nematodes to lay dead embryos when fed E. coli, but they fared better when fed Comamonas. Conversely, CPT promoted a mild increase in dead embryos laid by nematodes fed Comamonas compared with E. coli. Active metabolism of FUDR by E. coli enhanced the drug's efficacy, whereas Comamonas increased CPT efficacy through a passive mechanism. A genetic screen using mutant E. coli and Comamonas strains identified mutations that positively and negatively influence the efficacy of chemotherapeutics, including multiple nucleotide metabolism genes. In a related study, Scott and colleagues also found that C. elegans fed different human commensal bacteria strains exhibited differences in fluoropyrimidine (e.g. 5-FU, capecitabine, and FUDR) activity. A three-way high-throughput chemical-genomic screen revealed a complex network of host–microbe–drug interactions, and found that bacterial vitamins B₆ and B₉ were required for 5-FU efficacy in C. elegans. Vitamins B₆ and B₉ worked in concert with pyrimidine metabolism to regulate pro-drug bioconversion to active metabolites. Further, disrupting the bacterial pools of deoxynucleotides promoted 5-FU–induced autophagy and cell death of quickly dividing embryonic nematode cells. Together, these studies demonstrate that bacterial metabolism alters chemotherapeutic response in C. elegans, highlight that the host and microbe act together to metabolize and mediate the action of chemotherapeutics, and raise the possibility of the gut microbiome influencing chemotherapeutic efficacy in gastric cancer.

García-González AP, Ritter AD, Shrestha S, Andersen EC, Yilmaz LS, Walhout AJM. Bacterial metabolism affects the C. elegans response to cancer chemotherapeutics. Cell 2017;169:431–41.e8.

Scott TA, Quintaneiro LM, Norvaisas P, Lui PP, Wilson MP, Leung KY, et al. Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans. Cell 2017;169:442–56.e18.

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