Plasma and Fecal Metabolites Combined with Gut Microbiome Reveal Systemic Metabolic Shifts in 60Co Gamma-Irradiated Rats

<b>Background</b>: High-dose γ-ray exposure (≥7 Gy) in nuclear emergencies induces life-threatening acute radiation syndrome, characterized by rapid hematopoietic collapse (leukocytes <0.5 × 10⁹/L) and gastrointestinal barrier failure. While clinical biomarkers like leukocyte depletion guide current therapies targeting myelosuppression, the concomitant metabolic disturbances and gut microbiota dysbiosis-critical determinants of delayed mortality-remain insufficiently profiled across the 28-day injury-recovery continuum. <b>Methods</b>: This study investigates the effects of ⁶⁰Co γ-ray irradiation on metabolic characteristics and gut microbiota in Sprague Dawley rats using untargeted metabolomics and 16S rRNA sequencing. Meanwhile, body weight and complete blood counts were measured. <b>Results</b>: Body weight exhibited significant fluctuations, with the most pronounced deviation observed at 14 days. Blood counts revealed a rapid decline in white blood cells, red blood cells, and platelets post-irradiation, reaching nadirs at 7-14 days, followed by gradual recovery to near-normal levels by 28 days. Untargeted metabolomics identified 32 upregulated and 33 downregulated plasma metabolites at 14 days post-irradiation, while fecal metabolites showed 47 upregulated and 18 downregulated species at 3 days. Key metabolic pathways impacted included Glycerophospholipid metabolism, alpha-linolenic acid metabolism, and biosynthesis of unsaturated fatty acids. Gut microbiota analysis demonstrated no significant change in α-diversity but significant <i>β</i>-diversity shifts (<i>p</i> < 0.05), indicating a marked alteration in the compositional structure of the intestinal microbial community following radiation exposure. Principal coordinate analysis confirmed distinct clustering between control and irradiated groups, with increased abundance of <i>Bacteroidota</i> and decreased <i>Firmicutes</i> in irradiated rats. These findings highlight dynamic metabolic and microbial disruptions post-irradiation, with recovery patterns suggesting a 28-day restoration cycle. Spearman's rank correlation analysis explored associations between the top 20 fecal metabolites and 50 abundant bacterial taxa. <i>Norank_f_Muribaculaceae</i>, <i>Prevotellaceae_UCG-001</i>, and <i>Bacteroides</i> showed significant correlations with various radiation-altered metabolites, highlighting metabolite-microbiota relationships post-radiation. <b>Conclusions</b>: This study provides insights into potential biomarkers for radiation-induced physiological damage and underscores the interplay between systemic metabolism and gut microbiota in radiation response.