Hanyong Zhu, Hui Guo, Na Sun, Rui Xiao, Binbin Ji, Ruihan Jiang, Fuxing Dong, Chen Yao, Xuerong Wang, Rongqing Li, Jie Zhao, Xueqin Li, Shengzhe Gong, Yongqin Qin, Xin Chen, Yuchen Pan, Takayuki Ikezoe, Jing Yang
The gut microbiota is key to mitigating ionizing radiation (IR)-induced injuries; however, the specific species involved in and the molecular mechanisms remain elusive. Mitochondrial dynamics affect gut microbiota diversity. To identify the specific species involved in the radioprotective effect, we performed mitochondrial proteomic profiling of mouse intestinal epithelial cells and identified the accumulation of signal transducer and activator of transcription 3 (STAT3). Using mitochondrial STAT3 knock-in mice, we observed the abundance of the probiotic Faecalibaculum rodentium and its metabolite butyrate decreased in parallel with increased sensitivity to IR. Supplementation with Faecalibaculum rodentium or butyrate attenuated IR-induced intestinal barrier dysfunction, enhanced hematopoietic recovery, and prolonged survival. Butyrate is found to exert dual protective effects: It increases tight junction proteins, such as zonula occludens-1 (ZO-1) and occludin, and the defense factor levels to reinforce intestinal integrity. Furthermore, it sustains extracellular regulated protein kinases (ERK)-mediated pyruvate kinase isozyme type M2 (PKM2) nuclear localization, thereby attenuating p53-dependent apoptotic signaling in hematopoietic stem cells and ultimately prolonging mouse survival. These findings indicate that Faecalibaculum rodentium-derived butyrate confers radioprotection by maintaining the intestinal barrier and hematopoietic regeneration, suggesting a promising microbiota-directed therapeutic strategy against radiation-induced injury.