Gut microbiota dysbiosis exacerbates radiation brain injury after FLASH whole-brain irradiation: insights from the microbiota-gut-brain axis

The microbiota–gut–brain axis (MGBA)plays a critical role in neurological injury and repair, but its involvement in FLASH radiotherapy, a modality that minimizes radiotoxicity to normal tissues, remains unexplored. We found that FLASH irradiation alone injured the brain (neuronal necrosis, elevated TNF-α and IL-1β, oxidative stress) and disturbed the gut (colon shortening, colonic inflammation); however, the microbiota was remodeled, with increased diversity and expansion of Akkermansia and Muribaculum , and the serum metabolome was barely affected. In contrast, Antibiotics alone collapsed microbial diversity and reduced differential serum metabolites, yet the brain remained normal by all pathological, cytokine, oxidative and metabolic measures. When dysbiosis preceded FLASH irradiation, however, radiation brain injury was amplified and sustained: neuronal necrosis and edema extended into day 9, ZO-1 remained reduced, cerebral IL-1β and colonic TNF-α remained elevated, and early oxidative stress was aggravated. The serum metabolome was remodeled, with microbiota-driven bile-acid and kynurenine changes. Taken together, these findings indicate that gut dysbiosis exacerbates radiation brain injury after FLASH irradiation mainly by altering the composition of the blood reaching the brain, making the MGBA a candidate target for improving radiotherapy outcomes.