Gut microbiota and radiotherapy: towards enhancing radiotherapy efficacy and mitigating toxicities

Radiotherapy (RT) is a principal modality for cancer treatment; however, its clinical benefit is often limited by treatment-associated toxicities, particularly radiation enteritis (RE), which can reduce patients’ quality of life and treatment adherence. Increasing evidence indicates that the gut microbiota, an emerging pharmacological target and essential regulator of epithelial barrier integrity, metabolism, and immune homeostasis, plays an important role in both RT-induced intestinal injury and tumor radiosensitivity. RT disrupts microbial diversity and metabolic functions, leading to dysbiosis, impaired epithelial barrier repair, altered metabolite networks, and exaggerated inflammatory responses. Conversely, specific microbial taxa and their metabolites, especially short-chain fatty acids (SCFAs), can modulate antitumor immunity, DNA damage response and repair pathways, microbial metabolite signaling, and mucosal resilience, thereby influencing both tumor radiosensitivity and host susceptibility to intestinal injury. This review summarizes the bidirectional interactions between RT and the gut microbiota, with emphasis on mechanisms underlying radiation-induced microbial alterations and microbiota-mediated modulation of RT efficacy and toxicity. We further discuss microbiota-targeted therapeutic strategies, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), antibiotic modulation, dietary interventions, and traditional Chinese medicine (TCM)-derived compounds and formulae, as promising approaches to mitigate RE and improve therapeutic outcomes. Understanding these microbiota-RT interactions may support microbiota-guided precision radiotherapy and facilitate the development of microbiota-based drugs for enhancing RT efficacy and reducing toxicities.