BACKGROUND Regulatory T cell (Treg) deficiency leads to IPEX syndrome, a lethal autoimmune disease, in Human and mice. Dysbiosis of the gut microbiota in Treg-deficient scurfy (SF) mice has been described, but to date, the role of the gut microbiota remains to be determined. RESULTS To examine how antibiotic-modified microbiota can inhibit Treg deficiency-induced lethal inflammation in SF mice, Treg-deficient SF mice were treated with three different antibiotics. Different antibiotics resulted in distinct microbiota and metabolome changes and led to varied efficacy in prolonging lifespan and reducing inflammation in the liver and lung. Moreover, antibiotics altered plasma levels of several cytokines, especially IL-6. By analyzing gut microbiota and metabolome, we determined the microbial and metabolomic signatures which were associated with the antibiotics. Remarkably, antibiotic treatments restored the levels of several primary and secondary bile acids, which significantly reduced IL-6 expression in RAW macrophages in vitro. IL-6 blockade prolonged lifespan and inhibited inflammation in the liver and lung. By using IL-6 knockout mice, we further identified that IL-6 deletion provided a significant portion of the protection against inflammation induced by Treg dysfunction. CONCLUSION Our results show that three antibiotics differentially prolong survival and inhibit lethal inflammation in association with a microbiota-IL-6 axis. This pathway presents a potential avenue for treating Treg deficiency-mediated autoimmune disorders.

中文翻译：

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抗生素调节的微生物组可抑制 Treg 缺陷小鼠的致命炎症并延长寿命。


背景技术调节性 T 细胞 (Treg) 缺陷会导致人类和小鼠出现 IPEX 综合征，这是一种致命的自身免疫性疾病。 Treg 缺陷型头皮屑 (SF) 小鼠的肠道微生物群失调已被描述，但迄今为止，肠道微生物群的作用仍有待确定。结果 为了研究抗生素修饰的微生物群如何抑制 SF 小鼠中 Treg 缺乏引起的致死性炎症，用三种不同的抗生素治疗 Treg 缺乏的 SF 小鼠。不同的抗生素会导致不同的微生物群和代谢组变化，并在延长寿命和减少肝脏和肺部炎症方面产生不同的功效。此外，抗生素改变了几种细胞因子的血浆水平，尤其是 IL-6。通过分析肠道微生物群和代谢组，我们确定了与抗生素相关的微生物和代谢组特征。值得注意的是，抗生素治疗恢复了几种初级和次级胆汁酸的水平，从而显着降低了体外 RAW 巨噬细胞中 IL-6 的表达。 IL-6 阻断可延长寿命并抑制肝脏和肺部的炎症。通过使用 IL-6 敲除小鼠，我们进一步发现 IL-6 缺失在很大程度上提供了针对 Treg 功能障碍引起的炎症的保护作用。结论 我们的结果表明，三种抗生素在延长生存期和抑制与微生物群-IL-6 轴相关的致命炎症方面存在差异。该途径为治疗 Treg 缺乏介导的自身免疫性疾病提供了潜在途径。