Gut microbiota metabolites: mechanistic insights and therapeutic strategies for radiation enteritis

Radiation enteritis (RE) is a frequent and debilitating complication in patients undergoing radiotherapy for pelvic or abdominal malignancies, significantly impairing both quality of life and adherence to treatment regimens. Accumulating evidence indicates that radiotherapy is associated with measurable gut-microbiota alterations in cancer patients, typically characterized by the depletion of potentially protective taxa, such as Bifidobacterium and Clostridium , and expansion of Enterobacteriaceae, while changes in Bacteroidetes vary across cohorts. These radiation-associated microbial shifts are accompanied by fluctuations in various metabolites, including short-chain fatty acids (SCFAs), bile acids (BAs), and tryptophan (Trp) derivatives. Recently, the role of the gut microbiota and its metabolic output in the pathogenesis and progression of RE has emerged as a focal point of gastrointestinal research. The collective metabolic capacity of the gut microbiota exceeds that of human cells, yielding bioactive products that may mediate host-microbe cross-talk. Gut microbiota metabolize dietary fibers, polyphenols, and other substrates to produce bioactive metabolites, such as SCFAs, urolithins, and indole derivatives. These metabolites not only contribute to maintaining intestinal barrier integrity and modulating immuno-inflammatory responses but also exert systemic physiological effects via various “gut-organ axes”. Despite this potential, clinical translation remains hindered by inter-individual metabolic variability, mechanistic controversies, and ethical considerations. Future research employing integrated multi-omics technologies and well-controlled clinical trials is needed to clarify causal pathways and test precision prevention and treatment strategies. This review summarizes the interplay between ionizing radiation (IR) and the gut microbiota, delineates primary microbial metabolic pathways, and evaluates radiation-induced metabolic shifts. We also highlight recent advances in the radioprotective properties of these metabolites and current therapeutic interventions targeting microbiota modulation, while providing a cautious theoretical framework for the development of novel radioprotective agents.