Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite (Targeted metabolomics - 2methylisocitrate)

Understanding how the microbiota produces regulatory metabolites is of significance for cancer and cancer therapy. Using a host-microbe-drug-nutrient 4-way screening approach, we evaluated the role of nutrition at the molecular level in the context of 5-fluorouracil toxicity. Notably, our screens identified the metabolite 2-methylisocitrate which was found to be produced and enriched in human tumor-associated microbiota. 2-methylisocitrate exhibits anti-proliferative properties across genetically- and tissue-diverse cancer cell lines, 3D spheroids and an in vivo Drosophila gut tumor model, where it reduced tumor dissemination and increased survival. Chemical landscape interaction screens identified drug-metabolite signatures and highlighted the synergy between 5-fluorouracil and 2-methylisocitrate. Multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, we converted 2-methylisocitrate into its trimethyl ester, thereby enhancing its potency. This work highlights the great impact of microbiome-derived metabolites on tumor proliferation, and their potential as promising co-adjuvants for cancer treatment.

Targeted metabolomics - 2methylisocitrate is reported in the current study MTBLS9994.
Targeted metabolomics - fluoronucleotides is reported in MTBLS9991.