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.

Partial least squares-discriminant analysis We thank the Institute of Applied Electronics, China Academy of Engineering Physics, for providing the ultra-high dose rate electron beam irradiation platform. Dai Wu (Institute of Applied Electronics, China Academy of Engineering Physics) for offering technical support during the ultra-high dose rate electron beam irradiation process. This research was supported by the Youth Research Foundation of Shanxi Province (No. 20210302124283), the National Key R&D Program of China (2023YFA1800900 and 2018YFC0910502) and the National Science Foundation of China (Grant Nos. 32071465).

Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Center of AI Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, No. 1037 Luoyu Road, Wuhan, Hubei Province, China CNNC Key Laboratory for Radiation Protection Technology, Shanxi Key Laboratory for Radiation Safety and Protection, Department of Radiology and Environmental Medicine, China Institute for Radiation Protection, No. 102 Xuefu Street, Taiyuan, Shanxi Province, China Yayi Yuan, Lin Li, Chao Li, Juancong Dong, Jiao Cheng, Yufeng Guo & Xuhong Dang Correspondence to Xuhong Dang or Kang Ning. The authors declare no competing interests. All animal experiments were approved by the Institutional Animal Care and Use Committee of the China Institute for Radiation Protection (Approval No: CIRP-IACUC-R2021009).

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