Microbiota-derived indole-3-propionic acid enhances 5-fluorouracil efficacy in colorectal cancer through increasing the cytotoxicity of T lymphocytes

Individual variability in 5-fluorouracil (5-FU) response among colorectal cancer (CRC) patients involves complex mechanisms including gut microbiota interactions. Metabolomic analysis of 59 CRC patients identified indole-3-propionic acid (IPA) as a key metabolite correlating with 5-FU treatment success. Validation in mouse models showed that IPA supplementation significantly enhances 5-FU efficacy. Mechanistically, single-cell RNA sequencing and knockout models (Rag1-/ - and Ahr-/- mice) revealed that IPA activates the Aryl Hydrocarbon Receptor (AHR) in CD8+ T cells. This signaling triggers elevated IFN-Gamma production, subsequently activating the STING pathway to increase tumor sensitivity to chemotherapy. The study confirmed that the gut bacterium Clostridium sporogenes is a primary producer of IPA. Furthermore, administering engineered E. coli Nissle 1917 successfully modulated this axis. These findings establish a gut microbiome-metabolite-immune axis, suggesting that targeting IPA-producing bacteria or AHR signaling can overcome 5-FU resistance and improve clinical outcomes in CRC patients.