Estrogen-related receptor alpha mitigates radiation-induced bowel injury through gut enrichment of <i>Bacteroides vulgatus</i>

Radiation-induced gastrointestinal (GI) toxicity can be a major cause of morbidity in patients undergoing abdominal radiotherapy. There is an unmet need for treatments to ameliorate GI toxicity. Estrogen-related receptor alpha (ESRRA), a protein involved in the regulation of inflammation and autophagy, is widely expressed across human tissues. Our recent findings on ESRRA's significant contribution to intestinal homeostasis and inflammation control in inflammatory bowel disease inspired us to investigate its potential role in radiation-induced gastrointestinal injury. <i>esrra</i>^<i>-/-</i> mice showed distinct gut microbiota composition and increased susceptibility to abdominal irradiation with significant alteration of microbiota and increased intestinal inflammation. <i>B. vulgatus</i> reversed gut pathology in <i>esrra</i>^<i>-/-</i> mice by improving intestinal barrier function, reducing inflammation, and restoring the expression of <i>Tfeb</i> and its downstream genes. Additionally, in patients treated with abdominal radiotherapy, decreased ESRRA expression in rectal tissues correlated with increased IL-6 expression and radiation induced diarrhea. Our findings indicate that ESRRA contributes to intestinal homeostasis through gut enrichment of <i>B. vulgatus</i>.