Roseburia intestinalis sensitizes colorectal cancer to radiotherapy through the butyrate/OR51E1/RALB axis.

The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT) potentiates the tumoricidal effects of radiation and degrades the intertwined adverse events in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. FMT cumulates Roseburia intestinalis (R. intestinalis) in the gastrointestinal tract. Oral gavage of R. intestinalis assembles at the CRC site and synthetizes butyrate, sensitizing CRC to radiation and alleviating intestinal toxicity in primary and CRC hepatic metastasis mouse models. R. intestinalis-derived butyrate activates OR51E1, a G-protein-coupled receptor overexpressing in patients with rectal cancer, facilitating radiogenic autophagy in CRC cells. OR51E1 shows a positive correlation with RALB in clinical rectal cancer tissues and CRC mouse model. Blockage of OR51E1/RALB signaling restrains butyrate-elicited autophagy in irradiated CRC cells. Our findings highlight that the gut commensal bacteria R. intestinalis motivates radiation-induced autophagy to accelerate CRC cell death through the butyrate/OR51E1/RALB axis and provide a promising radiosensitizer for CRC in a pre-clinical setting.