Abstract

Despite the precise targeting of radiation therapy, collateral damage to adjacent healthy tissues remains an inevitable consequence. Currently, no effective clinical intervention exists to prevent or alleviate these adverse effects. To address this issue, our study established a whole-abdominal irradiation (WAI) model using C57BL/6J mice to investigate the systemic effects of ionizing radiation (IR) on the gut and other organs. Results confirmed that IR not only causes significant intestinal damage but also induces cardiac injury and cognitive dysfunction through remote effects. Ergothioneine (EGT), a naturally occurring dietary sulfur compound, has garnered significant attention in recent years for its unique functions in antioxidant, anti-inflammatory, and metabolic regulation. Our findings reveal that EGT significantly mitigates IR-induced structural damage to the intestine, preserves crypt-villus architecture, restores goblet cell numbers, and reduces systemic inflammation. Furthermore, EGT modified post-IR gut microbiota composition by decreasing the relative abundance of Candidatus_Soleaferrea and downregulating calcium voltage-gated channel subunit alpha1 C (Cacna1c) expression. EGT alleviated WAI-induced cardiac and cognitive dysfunction through the gut-heart and gut-brain axes. EGT also ameliorated dextran sulfate sodium (DSS)-induced colitis and enhanced intestinal barrier function. Our findings identify EGT as a novel multi-organ radioprotective agent that acts through microbiota modulation and Cacna1c regulation, providing a viable strategy for improving radiotherapy safety and efficacy.