Gut microbiota and microbiota-derived metabolites in radiation-induced injury: mechanisms and therapeutic opportunities.

Radiation-induced injury is a complex pathological process involving DNA damage, oxidative stress, inflammatory amplification, epithelial barrier disruption, immune dysregulation, metabolic remodeling, and impaired tissue repair. Accumulating evidence indicates that the gut microbiota is not merely altered by irradiation but may also modify host radiation responses and tissue recovery; however, direct causal support remains confined to selected microbes, metabolites, and pathways, predominantly in preclinical models. Irradiation is frequently associated with reduced microbial diversity, depletion of selected commensals, expansion of opportunistic pathobionts, and altered microbial metabolic output; selected experimental studies further indicate that these changes can modify intestinal injury and host recovery. Conversely, defined microbes and metabolites have improved radiation outcomes in preclinical intervention models by supporting epithelial, immune, and metabolic homeostasis. In this review, we summarize current advances in understanding the gut microbiota-metabolite axis in radiation-induced injury. We first discuss radiation-induced gut dysbiosis and the major microbial metabolites involved, including short-chain fatty acids, tryptophan-derived metabolites, bile acids, lipid metabolites, polyamines, and other bioactive molecules. We then highlight the key mechanisms by which gut microbiota and microbial metabolites mitigate radiation injury, including suppression of oxidative stress, inhibition of inflammatory signaling, restoration of epithelial barrier integrity, promotion of intestinal stem cell-mediated regeneration, regulation of immune homeostasis, and modulation of lipid peroxidation-associated ferroptosis. Finally, we evaluate microbiota-targeted intervention strategies, including probiotics, prebiotics, postbiotics, fecal microbiota transplantation, antibiotic modulation, natural products, engineered probiotics, and nanomedicine-assisted delivery systems. Overall, the gut microbiota-metabolite axis represents a biologically plausible and increasingly testable target for radioprotection and mitigation, although its clinical utility remains to be established. Future studies should move beyond descriptive microbiome profiling toward causal, function-oriented, and multi-omics-driven investigations, with particular emphasis on the microbiota-lipid metabolism-ferroptosis axis and precision microbiome therapeutics. Carefully validated microbiota-targeted approaches may provide future opportunities to reduce normal-tissue toxicity and improve recovery without compromising tumor control.