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

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

Author information

1
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. Baokun.He@shgh.cn.
2
Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China. Baokun.He@shgh.cn.
3
Division of Gastroenterology, Department of Pediatrics, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA. Baokun.He@shgh.cn.
4
Division of Gastroenterology, Department of Pediatrics, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA.
5
Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
6
Department of Microbiology, Immunology & Parasitology, Louisiana State University School of Medicine, Children's Hospital, New Orleans, Louisiana, 70118, USA.
7
Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA.
8
Division of Gastroenterology, Department of Pediatrics, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA. J.Marc.Rhoads@uth.tmc.edu.

Abstract

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

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