BACKGROUND We have proved fecal microbiota transplantation (FMT) is an efficacious remedy to mitigate acute radiation syndrome (ARS); however, the mechanisms remain incompletely characterized. Here, we aimed to tease apart the gut microbiota-produced metabolites, underpin the therapeutic effects of FMT to radiation injuries, and elucidate the underlying molecular mechanisms. RESULTS FMT elevated the level of microbial-derived indole 3-propionic acid (IPA) in fecal pellets from irradiated mice. IPA replenishment via oral route attenuated hematopoietic system and gastrointestinal (GI) tract injuries intertwined with radiation exposure without precipitating tumor growth in male and female mice. Specifically, IPA-treated mice represented a lower system inflammatory level, recuperative hematogenic organs, catabatic myelosuppression, improved GI function, and epithelial integrity following irradiation. 16S rRNA gene sequencing and subsequent analyses showed that irradiated mice harbored a disordered enteric bacterial pattern, which was preserved after IPA administration. Notably, iTRAQ analysis presented that IPA replenishment retained radiation-reprogrammed protein expression profile in the small intestine. Importantly, shRNA interference and hydrodynamic-based gene delivery assays further validated that pregnane X receptor (PXR)/acyl-CoA-binding protein (ACBP) signaling played pivotal roles in IPA-favored radioprotection in vitro and in vivo. CONCLUSIONS These evidences highlight that IPA is a key intestinal microbiota metabolite corroborating the therapeutic effects of FMT to radiation toxicity. Owing to the potential pitfalls of FMT, IPA might be employed as a safe and effective succedaneum to fight against accidental or iatrogenic ionizing ARS in clinical settings. Our findings also provide a novel insight into microbiome-based remedies toward radioactive diseases. Video abstract.

中文翻译：

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肠道微生物群衍生的吲哚 3-丙酸通过保留酰基辅酶 A 结合蛋白来防止辐射毒性。


背景我们已经证明粪便微生物群移植（FMT）是缓解急性辐射综合征（ARS）的有效疗法；然而，这些机制的特征仍然不完全。在这里，我们的目的是梳理肠道微生物群产生的代谢物，支持 FMT 对辐射损伤的治疗作用，并阐明潜在的分子机制。结果 FMT 提高了受辐射小鼠粪便颗粒中微生物来源的吲哚 3-丙酸 (IPA) 的水平。通过口服途径补充 IPA 可减弱造血系统和与辐射暴露交织在一起的胃肠道损伤，但不会促进雄性和雌性小鼠的肿瘤生长。具体而言，IPA 治疗的小鼠在辐射后表现出较低的系统炎症水平、恢复性造血器官、缓解性骨髓抑制、改善的胃肠道功能和上皮完整性。 16S rRNA 基因测序和随后的分析表明，受辐射的小鼠肠道细菌模式紊乱，而这种模式在 IPA 给药后得以保留。值得注意的是，iTRAQ 分析表明，补充 IPA 保留了小肠中辐射重编程的蛋白质表达谱。重要的是，shRNA 干扰和基于流体动力学的基因传递测定进一步验证了孕烷 X 受体 (PXR)/酰基辅酶 A 结合蛋白 (ACBP) 信号在 IPA 有利的体外和体内辐射防护中发挥着关键作用。结论 这些证据强调，IPA 是一种关键的肠道微生物代谢物，证实了 FMT 对放射毒性的治疗作用。由于 FMT 的潜在缺陷，IPA 可以作为一种安全有效的替代品来对抗临床环境中意外或医源性电离 ARS。 我们的研究结果还为基于微生物组的放射性疾病疗法提供了新的见解。视频摘要。