Junwei Shao1, Tiantian Ge1, Cuilan Tang2, Gang Wang1, Lantian Pang3, Zhi Chen4. 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. 2. Hepatobiliary and Pancreatic Surgery (Liver Disease Centre), The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310003, Zhejiang, China. 3. The Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310003, Zhejiang, China. 4. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China. zjuchenzhi@zju.edu.cn.
Abstract
BACKGROUND: Bile acids can regulate liver disease progression by affecting the functions of gut microbiota and immune cells. As the most potent natural agonist of G-protein coupled bile acid receptor 5 (TGR5) (expressed in macrophages, HSCs, and monocytes), lithocholic acid (LCA) has multiple functions, such as inhibiting inflammation and regulating metabolism. Therefore, this study aims to investigate the effects of LCA on immune cells and HSCs in liver fibrosis. METHODS: A liver fibrosis mouse model was induced by carbon tetrachloride followed by gavage of LCA, and the effects of LCA were evaluated by serum biochemical analysis, liver histology, and western bolt. Plasma cytokine levels and the number of immune cells were determined by cytometric bead array and flow cytometry, respectively. RESULTS: LCA could inhibit the activation of HSCs by inducing apoptosis and reducing the activation of transforming growth factor-β (TGF-β) Smad-dependent and Smad-independent pathways. Meanwhile, LCA inhibited glycolysis and promoted oxidative phosphorylation, leading to the differentiation of macrophages to M2 type and inhibiting their differentiation to M1 type. Furthermore, LCA increased the recruitment of NK cells and reduced the activation of NKT cells. However, these effects of LCA were attenuated after antibiotics reduced the diversity and abundance of the gut microbiota. CONCLUSIONS: Gut microbiota and LCA exerted synergistic anti-inflammatory effects on liver fibrosis. The combined intervention of gut microbiota and LCA will be a new strategy for treating liver fibrosis.
BACKGROUND: Bile acids can regulate liver disease progression by affecting the functions of gut microbiota and immune cells. As the most potent natural agonist of G-protein coupled bile acid receptor 5 (TGR5) (expressed in macrophages, HSCs, and monocytes), lithocholic acid (LCA) has multiple functions, such as inhibiting inflammation and regulating metabolism. Therefore, this study aims to investigate the effects of LCA on immune cells and HSCs in liver fibrosis. METHODS: A liver fibrosis mouse model was induced by carbon tetrachloride followed by gavage of LCA, and the effects of LCA were evaluated by serum biochemical analysis, liver histology, and western bolt. Plasma cytokine levels and the number of immune cells were determined by cytometric bead array and flow cytometry, respectively. RESULTS: LCA could inhibit the activation of HSCs by inducing apoptosis and reducing the activation of transforming growth factor-β (TGF-β) Smad-dependent and Smad-independent pathways. Meanwhile, LCA inhibited glycolysis and promoted oxidative phosphorylation, leading to the differentiation of macrophages to M2 type and inhibiting their differentiation to M1 type. Furthermore, LCA increased the recruitment of NK cells and reduced the activation of NKT cells. However, these effects of LCA were attenuated after antibiotics reduced the diversity and abundance of the gut microbiota. CONCLUSIONS: Gut microbiota and LCA exerted synergistic anti-inflammatory effects on liver fibrosis. The combined intervention of gut microbiota and LCA will be a new strategy for treating liver fibrosis.
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