Study on the Initiation Mechanisms of Primary Biliary Cholangitis by Xenobiotic Induced Mouse Model

• Main Authors: Yu-Wen Wang, 王禹文
• Other Authors: Ya-Hui Chuang
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/3q3qn6

碩士 === 國立臺灣大學 === 醫學檢驗暨生物技術學研究所 === 107 === Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease characterized by immune-mediated destruction of the intrahepatic bile ducts. PBC presents a female predominance with almost 10:1. Aside from the impact of sex chromosome and sex hormones, female tend to experience greater exposure to chemicals such as detergents, facial care products, and cosmetics, which are potential triggers of PBC. Diets, personal hygiene, and environmental xenobiotics affect the gut microbiota. Products of gut microbiota circulate through the gut-liver axis and provoke immune responses in the liver. In the study, we investigated the mechanisms of PBC by the xenobiotic induced PBC mouse model. To investigate the role of environmental xenobiotics in PBC, we exposed mice of both genders to equivalent 2-octynoic acid conjugated to ovalbumin (2-OA-OVA) to induce autoimmune cholangitis and monitored their immune responses. The results showed that both male and female mice immunized with 2-OA-OVA developed autoimmune cholangitis while female mice had higher lymphocytes infiltration and liver inflammation than males at 11 weeks post-immunization. Besides, apoptosis of cholangiocytes in 2-OA-OVA immunized mice were observed at 3 weeks post-immunization. Furthermore, we collected feces to analyze the gut microbiota of mice. We found the gut microbiota structure altered after immunization. Notably, naïve male mice maintained a protective gut microbiome. We then analyzed the expression levels of toll-like receptors (TLRs), which could recognize microbial components, and found expression levels of TLR7 and TLR9 in bile ducts were significantly upregulated after immunization. To research the impact of alternation of gut microbiota in the PBC pathogenesis, we disturbed the gut microbiota before 5 weeks 2-OA-OVA immunization by feeding mice with non-pathogenic E. coli (DH5α) and found that mice given exogenous bacteria had an increased cell infiltration and decreased protective TLR5 in the liver. Our results suggested that in xenobiotics exposure, dysbiosis of gut microbiota induce apoptosis of cholangiocytes, which led to the initiation of PBC.