Remodeling the Gut Microbiota Mitigates Radiation-Induced Intestinal Injury by Normalizing Sphingosine-1-Phosphate Signaling

Background Radiation-induced enteritis is a dose-limiting complication of radiotherapy, driven by mucosal inflammation and barrier breakdown. While the gut microbiota regulates host radiosensitivity, the precise metabolic mechanisms governing this interaction remain elusive. Specifically, whether antibiotic intervention acts merely by depleting bacteria or by actively remodeling the ecosystem to correct metabolic dysregulation requires clarification. Methods We established a murine model of radiation-induced intestinal injury and employed an antibiotic pre-treatment strategy to modulate the gut microbiota. We integrated metagenomic shotgun sequencing with untargeted metabolomics to dissect the structural and functional shifts in the microbiome and host metabolome. Results Radiation exposure (4 Gy) precipitated a dysbiotic state characterized by the depletion of core commensals and a maladaptive bloom of Bifidobacterium pseudolongum . This microbial shift coincided with a pathological surge of the bioactive lipid Sphingosine-1-Phosphate (S1P), indicative of metabolic inflammation. In contrast, antibiotic pre-treatment functioned as an "ecological filter," effectively suppressing the radiation-induced Bifidobacterium bloom. Instead, it established a resilient consortium enriched in Ileibacterium valens , Muribaculaceae , and specific Bacteroides species. Multi-omics correlation analysis revealed a functional dichotomy: while Bifidobacterium abundance positively correlated with the S1P surge, the remodeled microbiota was associated with the normalization of S1P levels and the suppression of pro-inflammatory arachidonic acid metabolites (e.g., 12(R)-HPETE). Conclusion Our findings demonstrate that antibiotic-mediated remodeling mitigates radiation toxicity not simply by bacterial depletion, but by establishing a distinct microbial guild that restores metabolic homeostasis. By preventing the pathological S1P surge and dampening lipid-driven inflammation, this "controlled remodeling" strategy offers a novel therapeutic avenue for enhancing the therapeutic window of radiotherapy.