title: Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors.
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 A2Areceptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota-inosine-A2Areceptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction.
authors.affiliation: Pediatrics Gastroenterology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.|Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Baokun
authors.identifier: 0000-0002-8808-1997
authors.initials: B
authors.lastname: He
authors.affiliation: Pediatrics Gastroenterology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.|Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hoang
authors.affiliation: Pediatrics Gastroenterology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.|Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Ting
authors.identifier: 0000-0003-2222-5211
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine, New Orleans, LA 70118.
authors.forename: Michael
authors.identifier: 0000-0003-0473-7440
authors.initials: M
authors.lastname: Ferris
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine, New Orleans, LA 70118.
authors.forename: Christopher M
authors.identifier: 0000-0002-7983-5275
authors.initials: CM
authors.lastname: Taylor
authors.affiliation: The Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine, New Orleans, LA 70118.
authors.forename: Meng
authors.initials: M
authors.lastname: Luo
authors.affiliation: Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Dat Q
authors.identifier: 0000-0001-5310-8849
authors.initials: DQ
authors.lastname: Tran
authors.affiliation: Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Jain
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Nina
authors.initials: N
authors.lastname: Tatevian
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Fayong
authors.identifier: 0000-0001-8398-8197
authors.initials: F
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Molina
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: Center for Laboratory Animal Medicine and Care, The University of Texas Health Science Center at Houston, Houston, TX 77030.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gomez
authors.affiliation: Department of Microbiology, Uppsala BioCenter, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden.|BioGaia AB, 103 64 Stockholm, Sweden.
authors.forename: Stefan
authors.identifier: 0000-0002-1606-1794
authors.initials: S
authors.lastname: Roos
authors.affiliation: 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.|Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: J Marc
authors.identifier: 0000-0002-6252-9490
authors.initials: JM
authors.lastname: Rhoads
authors.affiliation: 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.|Pediatric Research Center, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030.
authors.forename: Yuying
authors.identifier: 0000-0003-3848-9254
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation; D005260:Female; D000069196:Gastrointestinal Microbiome; D007288:Inosine / Q000494:pharmacology; D052200:Limosilactobacillus reuteri; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology
chemical_list: D043705:Receptor, Adenosine A2A; D007288:Inosine