Zimmermman, Johannes, Kaleta, Christoph, Chrysostomou, Despoina, Marchesi, Julian, W. Zatorska, Michalina, Barr, Alexis, Quintaneiro, Leonor, Cabreiro, Filipe, Martinez-Martinez, Daniel, Peres, Tanara, Kramer, Holger, Best, Lena, Marinos, Georgios, B. Mokochinski, Joao
[
International Worm Meeting,
2021]
Microbiota derived metabolites have been shown to influence cancer susceptibility, tumour progression and therapy outcome. Diet is a major environmental factor influencing gut microbiota composition, dictating the abundance of potential oncometabolites. The complex interactions between diet and the microbiota need to be clarified so that dietary intake may be shaped to influence disease outcome. Having previously demonstrated the impact of bacterial metabolism in 5-fluorouracil (5-FU) cancer drug efficacy, we set out to investigate the role of nutrition in host-microbe responses to this drug, an antimetabolite widely used for colorectal cancer (CRC) chemotherapy. Host-microbe-drug-nutrient interaction and its influence on drug efficacy were assessed using a high-throughput 4-way screening approach. To understand gene-nutrient interactions at the bacterial level that regulate the effect of a drug on host physiology, genetically modified E. coli from the Keio deletion library were used to probe the role of bacterial metabolic pathways in 5-FU effects in a nutrient-dependent manner. We found that glycolytic nutrients, including sugars, importantly antagonise the toxic effects of 5-FU action on the host. Sugars induce a shift in metabolic pathways that favour the production of nucleotides, specifically UMP and UTP derived from the activation of pyrimidine de novo biosynthesis pathway in bacteria, counteracting pro-drug activation through the salvage pathway. We also found that bacterial mutations in the TCA cycle and pyruvate metabolism decrease drug efficacy in amino acid-based media. A combination of bacterial genetic work and metabolomics has revealed the presence of a novel bacterial metabolite with the capacity to increase 5-FU drug efficacy in both C. elegans and human cancer cells. Importantly, flux balance analysis of the cancer associated microbiota predicts an increased production of this metabolite in several organs. In particular, investigations of the gut microbiome from four independent human CRC cohorts shows an increased production of this metabolite, compared to healthy patients, further implicating this metabolite in drug cancer therapy. These findings highlight the potential of manipulating gut microbiota through diet to improve cancer therapy outcome.