Gut microbiota and radiation-induced injury: mechanistic insights and microbial therapies

Radiotherapy represents a crucial therapeutic modality in cancer treatment, yet its efficacy is frequently limited by radiation-induced toxicity. Growing evidence indicates that gut microbiota and their metabolites serve as key regulators of both radioprotective and radiosensitizing effects. This review systematically examines three fundamental regulatory mechanisms through which gut microbiota and its metabolites mitigate radiation-induced injury: (1) modulation of intestinal epithelial cell regeneration and tumor cell apoptosis via Wnt/β-catenin and PI3K/AKT/mTOR pathways; (2) immunomodulation via Toll-like receptor activation and NF-κB signaling; (3) oxidative stress management via Nrf2 signaling. We also evaluate various microbiota-targeted interventions, ranging from probiotics and prebiotics to fecal microbiota transplantation and emerging engineered microbial therapies, highlighting their potential in clinical radiotherapy. Finally, we emphasize current limitations and future research directions, underscoring the need to overcome existing challenges in microbiome analysis and therapeutic durability to fully realize the potential of precision radio-microbiome medicine, which may provide valuable references for developing personalized radiotherapy strategies based on gut microbiota and their metabolites.