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

Microbiome. 2019 Nov 7;7(1):145. doi: 10.1186/s40168-019-0751-1.


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.

Keywords: Bile acid; Gut microbiota; IL-6; IPEX syndrome; Lethal inflammation; Treg deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Autoimmune Diseases* / immunology
  • Autoimmune Diseases* / microbiology
  • Chronic Disease
  • Diabetes Mellitus, Type 1 / congenital*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / microbiology
  • Diarrhea* / immunology
  • Diarrhea* / microbiology
  • Dysbiosis / microbiology*
  • Gastrointestinal Microbiome* / drug effects
  • Gastrointestinal Microbiome* / immunology
  • Genetic Diseases, X-Linked* / immunology
  • Genetic Diseases, X-Linked* / microbiology
  • Immune System Diseases / congenital*
  • Immune System Diseases / immunology
  • Immune System Diseases / microbiology
  • Inflammation* / immunology
  • Inflammation* / microbiology
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory / cytology


  • Anti-Bacterial Agents

Supplementary concepts

  • Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome