Gut microbiota translocation promotes autoimmune cholangitis. (December 2018)

• Record Type: Journal Article
• Authors: Ma, Hong-Di; Zhao, Zhi-Bin; Ma, Wen-Tao; Liu, Qing-Zhi; Gao, Cai-Yue; Li, Liang; Wang, Jinjun; Tsuneyama, Koichi; Liu, Bin; Zhang, Weici; Zhou, Yongjian; Gershwin, M. Eric; Lian, Zhe-Xiong
• Is Part Of: Journal of autoimmunity. Volume 95(2018)
• Page Start: 47
• Page End: 57
• Publication Date: 2018-12
• Subjects: Primary biliary cholangitis -- Gut microbiota -- Fecal bacterial analysis -- Bacterial translocation -- Gut–liver axis; PBC Primary biliary cholangitis -- dnTGFβRII, TG dominant negative transforming growth factor β receptor II -- WT wide type -- TLR2 Toll-like receptor 2 -- TGT2 dnTGFβRII TLR2−/− -- Tn naïve T cells -- Tcm central memory T cells -- Tem effector memory T cells -- ABx mixed antibiotics -- HMNCs hepatic mononuclear cells -- CFUs colony-forming units -- ZO-1 zonula occludens -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- DAPI 4ʹ, 6-diamidino-2-phenylindole -- PAMPs pathogen-associated molecular patterns -- PBMC peripheral blood mononuclear cell; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.09.010
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Gut microbiota and bacterial translocation have been implicated as significant contributors to mucosal immune responses and tolerance; alteration of microbial molecules, termed pathogen-associated molecular patterns (PAMP) and bacterial translocation are associated with immune pathology. However, the mechanisms by which dysregulated gut microbiota promotes autoimmunity is unclear. We have taken advantage of a well-characterized murine model of primary biliary cholangitis, dnTGFβRII mice, and an additional unique construct, toll-like receptor 2 (TLR2)-deficient dnTGFβRII mice coined dnTGFβRIITLR2 −/− mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFβRII mice manifest altered composition of gut microbiota and that alteration of this gut microbiota by administration of antibiotics significantly alleviates T-cell-mediated infiltration and bile duct damage. Second, toll-like receptor 2 (TLR2)-deficient dnTGFβRII mice demonstrate significant exacerbation of autoimmune cholangitis when their epithelial barrier integrity was disrupted. Further, TLR2-deficiency mediates downregulated expression of tight junction-associated protein ZO-1 leading to increased gut permeability and bacterial translocation from gut to liver; use of antibiotics reduces microbiota translocation to liver and also decreases biliary pathology. In conclusion, our data demonstrates the important role of gut microbiota and bacterial translocation in the pathogenesis of murine autoimmune cholangitis. Highlights: Dysbiosis of gut microbiota contributes to autoimmune cholangitis. Disrupted epithelial barrier aggravated cholangitis in dnTGFβRII mice. TLR2 deficiency aggravated colitis and colon injury in dnTGFβRII mice. Antibiotic treatment alleviated the exacerbated cholangitis and colitis. TLR2 deficiency increased gut permeability and promoted gut bacterial translocation.