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J Exp Med. 2017 Jan;214(1):107-123. doi: 10.1084/jem.20160961. Epub 2016 Dec 19.

Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors.

Author information

1
Pediatrics Gastroenterology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
2
Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
3
Department of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine, New Orleans, LA 70118.
4
The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
5
Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
6
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
7
Center for Laboratory Animal Medicine and Care, The University of Texas Health Science Center at Houston, Houston, TX 77030.
8
Department of Microbiology, Uppsala BioCenter, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden.
9
BioGaia AB, 103 64 Stockholm, Sweden.
10
Pediatrics Gastroenterology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030 Yuying.Liu@uth.tmc.edu J.Marc.Rhoads@uth.tmc.edu.

Abstract

Regulatory T (T reg) cell deficiency causes lethal, CD4+ T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency-mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3+ T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota-inosine-A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction.

PMID:
27994068
PMCID:
PMC5206500
DOI:
10.1084/jem.20160961
[Indexed for MEDLINE]
Free PMC Article

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