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Войти в исследования International immunopharmacology · 2025
Conjugated deoxycholic acid-microbiota interaction mitigate liver cirrhosis via inducing anti-inflammation response of macrophages.
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Lin Junlong, Qian Baifeng, Li Zhichao, Chen Jialin, Gao Kai, Li Qiao, Shen Jianming, Shen Rui, Guo Yu, Hua Yunpeng
Аннотация
BACKGROUND: Cirrhosis is a liver fibrosis disease caused by chronic liver disease, often accompanied by disorders of the gut microbiome and bile acid metabolism. The study aimed to probe the roles and mechanisms of the gut microbiota-bile acids (BAs) interaction in effecting the progression of liver cirrhosis.
METHODS: We analyzed gut microbiome composition and serum bile acid levels in cirrhotic patients, cirrhosis mouse models, vancomycin-treated mice, and BAs-treated mice. Key cirrhosis-related bacteria and BAs were identified, and their effects were tested in vivo and in vitro. Biochemical analysis and immunohistochemistry were used to assess liver cirrhosis, inflammation, and macrophage phenotypic changes.
RESULTS: In cirrhosis patients and mice, Actinobacteria levels were significantly lower, and Coriobacteriia and Coriobacteriales (subgroups of Actinobacteria) were notably reduced. Serum bile acids were elevated, with a decrease in conjugated secondary bile acids, especially conjugated deoxycholic bile acid (C-DCA), including glyco-deoxycholic acid (GDCA, predominant in humans) and tauro-deoxycholic acid (TDCA, predominant in mice). TDCA treatment inhibited cirrhosis and hepatocyte apoptosis, while promoting Coriobacteriia growth. Vancomycin inhibited Actinobacteria, Coriobacteriia, and Coriobacteriales, and reduced serum TDCA levels. TDCA suppressed macrophage aggregation in cirrhotic liver tissues. GO and KEGG analysis revealed GDCA inhibited inflammation-related genes in macrophages. GDCA upregulated anti-inflammatory genes (IL-4, IL-10, IL-13) and downregulated pro-inflammatory markers (P-STAT3, TLR2). Additionally, TGR5, a bile acid receptor, was upregulated in GDCA-treated macrophages.
CONCLUSIONS: This study reveals that the crosstalk of C-DCA and Coriobacteriales, originating from Actinobacteria, may be negatively associated with the progress of cirrhosis, and C-DCA may induce the transition of macrophages to an anti-inflammatory phenotype, thereby mitigating the inflammatory response.
METHODS: We analyzed gut microbiome composition and serum bile acid levels in cirrhotic patients, cirrhosis mouse models, vancomycin-treated mice, and BAs-treated mice. Key cirrhosis-related bacteria and BAs were identified, and their effects were tested in vivo and in vitro. Biochemical analysis and immunohistochemistry were used to assess liver cirrhosis, inflammation, and macrophage phenotypic changes.
RESULTS: In cirrhosis patients and mice, Actinobacteria levels were significantly lower, and Coriobacteriia and Coriobacteriales (subgroups of Actinobacteria) were notably reduced. Serum bile acids were elevated, with a decrease in conjugated secondary bile acids, especially conjugated deoxycholic bile acid (C-DCA), including glyco-deoxycholic acid (GDCA, predominant in humans) and tauro-deoxycholic acid (TDCA, predominant in mice). TDCA treatment inhibited cirrhosis and hepatocyte apoptosis, while promoting Coriobacteriia growth. Vancomycin inhibited Actinobacteria, Coriobacteriia, and Coriobacteriales, and reduced serum TDCA levels. TDCA suppressed macrophage aggregation in cirrhotic liver tissues. GO and KEGG analysis revealed GDCA inhibited inflammation-related genes in macrophages. GDCA upregulated anti-inflammatory genes (IL-4, IL-10, IL-13) and downregulated pro-inflammatory markers (P-STAT3, TLR2). Additionally, TGR5, a bile acid receptor, was upregulated in GDCA-treated macrophages.
CONCLUSIONS: This study reveals that the crosstalk of C-DCA and Coriobacteriales, originating from Actinobacteria, may be negatively associated with the progress of cirrhosis, and C-DCA may induce the transition of macrophages to an anti-inflammatory phenotype, thereby mitigating the inflammatory response.