期刊
JOURNAL OF AUTOIMMUNITY
卷 95, 期 -, 页码 47-57出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2018.09.010
关键词
Primary biliary cholangitis; Gut microbiota; Fecal bacterial analysis; Bacterial translocation; Gut-liver axis
类别
资金
- Program for Guangdong Introducing Innovative and Enterpreneurial Teams [2017ZT07S054]
- National Natural Science Foundation of China [81430034, 81401336, 91542123, 81671600, 81873877]
- National Key R&D Program of China [2017YFA0205600]
- National Institutes of Health grant, USA [DK090019]
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases Fund, China [SKL-HIDCA-2017-6]
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, dnTGF beta RII mice, and an additional unique construct, toll like receptor 2 (TLR2)-deficient dnTGF beta RII mice coined dnTGF beta RIITLR2(-/-) mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFPRII 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 dnTGF beta RII 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.
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