Gut Microbiota-derived 3-hydroxybutyrate blocks GPR43-mediated IL6 signaling to ameliorate radiation proctopathy

Abstract Radiation proctopathy (RP) is a common complication of pelvic radiotherapy but lacking effective treatment. RP accompanies by microbial dysbiosis. However, how the gut microbiota affects the disease remains unclear. Here, we reveal that the fecal and serous concentrations of microbiota-derived 3-hydroxybutyrate (3HB) are significantly reduced in RP mice and radiotherapeutic patients. Moreover, the concentration of 3HB is negatively associated with the expression of proinflammatory IL6 that is increased along with the severity of radiation damage. 3HB treatment significantly downregulates IL6 expression and alleviates IL6-mediated radiation damage. Such a radioprotection of 3HB is mediated by GPR43. Akkermansia muciniphila, with a significant reduction in RP mice and patients, is associated with lower 3HB concentration. Treatment of A. muciniphila significantly increases 3HB concentration, downregulates GPR43 and IL6 expression, and ameliorates radiation damage in mice. Collectively, these results demonstrate that the gut microbiota, including A. muciniphila, induce higher concentrations of 3HB to block the GPR43-mediated IL6 signaling, thereby conferring radioprotection in RP mice. Our findings reveal a novel implication of the gut-immune axis in radiation pathophysiology, with potential therapeutic applications.