Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite

The microbiota plays a major role in cancer. How the microbiota interacts with nutrients to produce regulatory metabolites is of significance for 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, we identified the metabolite 2-methylisocitrate to be produced and enriched in human tumor-associated microbiomes. 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. Drug-metabolite screening traced the chemotherapeutic signatures indicating synergy between 5-fluorouracil and 2-methylisocitrate, and multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, building on nature’s template, we altered the chemical structure of 2-methylisocitrate, 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.