Antibiotic-modulated microbiome suppresses lethal inflammation and prolongs lifespan in Treg-deficient mice

Baokun He,Yuying Liu,Xiangjun Tian,Dat Q Tran,Nina Tatevian,J Marc Rhoads,Thomas K Hoang,Christopher M Taylor,Meng Luo

doi:10.1186/s40168-019-0751-1

Abstract

BackgroundRegulatory 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.ResultsTo 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.ConclusionOur 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.

Highlights

Regulatory T cell (Treg) deficiency leads to Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a lethal autoimmune disease, in Human and mice
Antibiotic treatments reduce lethal inflammation induced by Treg deficiency Our previous studies have shown that gut microbiota plays an important role in the development of autoimmunity in Treg-deficient SF mice [12]
Antibiotic treatment prolonged lifespan, reduced inflammatory infiltrates in the liver and lungs, and decreased plasma level of pro-inflammatory cytokines which contributed to the development of lethal inflammation in SF mice

Summary

Introduction

Regulatory T cell (Treg) deficiency leads to IPEX syndrome, a lethal autoimmune disease, in Human and mice. Recent studies indicate that gut microbial dysbiosis is critically linked to the pathophysiology of autoimmune diseases, including inflammatory bowel disease, autoimmune arthritis, type I diabetes, and multiple sclerosis [10, 11]. Our previous studies have demonstrated the role of gut microbiota in the development of lethal inflammation induced by Treg-deficiency in SF mice [12]. Some previous studies have revealed that modulation of the gut microbiota by antibiotics may inhibit autoimmunity and reduce inflammation in autoimmune disease models [15, 16]. It remains unclear to what extent these microbial population changes and what mechanisms are involved in the immunosuppressive benefits in individuals with Treg dysfunction

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