Raffinose-metabolizing bacteria impair radiation-associated hematopoietic recovery <i>via</i> the bile acid/FXR/NF-κB signaling pathway

Radiation-associated hematopoietic recovery (RAHR) is critical for mitigating lethal complications of acute radiation syndrome (ARS), yet therapeutic strategies remain limited. Through integrated multi-omics analysis of a total body irradiation (TBI) mouse model, we identify <i>Bacteroides acidifaciens</i>-dominated gut microbiota as key mediators of RAHR impairment. 16S ribosomal rRNA sequencing revealed TBI-induced dysbiosis characterized by <i>Bacteroidaceae</i> enrichment, while functional metagenomics identified raffinose metabolism as the most significantly perturbed pathway. Notably, raffinose supplementation (10% w/v) recapitulated radiation-induced microbiota shifts and delayed bone marrow recovery. Fecal microbiota transplantation (FMT) revealed a causative role for raffinose-metabolizing microbiota, particularly <i>Bacteroides acidifaciens</i>, in delaying RAHR progression. Mechanistically, <i>B. acidifaciens</i>-mediated bile acid deconjugation activated FXR, subsequently suppressing NF-κB-dependent hematopoietic recovery. Therapeutic FXR inhibition <i>via</i> ursodeoxycholic acid (UDCA) had been shown to be a viable method for rescuing RAHR. Our results delineated a microbiome-bile acid-FXR axis as a master regulator of post-irradiation hematopoiesis. Targeting <i>B. acidifaciens</i> or its metabolic derivatives could represent a translatable strategy to mitigate radiation-induced hematopoietic injury.