Cellular and molecular gastroenterology and hepatology · 2026
Bacteroidesacidifaciens Attenuates Concanavalin A-Induced Liver Injury by Remodeling Bile Acids to Suppress CD95-Mediated Hepatocyte Apoptosis via the TGR5-FOSL1 Pathway.
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Zhang Xiang, Zhang Cheng, Zhou Yi, Han Yu, Wang Yawei, Wang Hesuiyuan, Yang Mengyan, Wu Qinhan, Bai Feng, Qu Fanfan, Ji Jianbin, Zhang Hongru, Wang Zhenglu, Wang Yuebing, Xu Haijin, Zhou Zhenghua, Qiao Mingqiang, Wu Zhenzhou
Аннотация
BACKGROUND & AIMS: Liver diseases have profound impacts on human physiological health. Gut microbiota and their metabolites exert significant regulatory roles in various hepatic disorders. Intestinal Bacteroides acidifaciens has been proven to be protective for hepatocyte apoptosis in some liver disease models, such as concanavalin A-induced hepatitis and acute/chronic alcoholic liver diseases. However, the specific metabolites from Bacidifaciens and their regulatory mechanisms need to be further elucidated.
METHODS: C57BL/6 mice were gavaged with Bacidifaciens, and liver bile acid profiles were analyzed using metabolomic analysis. Glycocholic acid was screened out according to death receptor CD95 expression, and its underlying mechanism was identified using inhibitor and CRISPR technology in the AML-12 cell line. In vivo protection of glycocholic acid was elucidated by drinking 0.2% glycocholic acid for 35 days.
RESULTS: Bacidifaciens administration significantly altered hepatic bile acid composition, such as glycocholic acid, β-muricholic acid, and hyocholic acid. Among differential bile acids, glycocholic acid reduced CD95 expression in transcription and membrane-binding protein levels in hepatic cells. Inhibition or deletion of membrane receptor Takeda G protein-coupled receptor 5 abolished the inhibition of glycocholic acid on CD95 expression. FOSL1 was identified as a downstream transcription regulator of Takeda G protein-coupled receptor 5. Mice administered with 0.2% glycocholic acid were less susceptible to concanavalin A-induced hepatitis with reduced CD95 expression and hepatocyte apoptosis.
CONCLUSIONS: Intestinal Bacidifaciens elevates hepatic glycocholic acid levels. Glycocholic acid binds to Takeda G protein-coupled receptor 5 and upregulates FOSL1. This subsequently downregulates CD95 transcription and inhibits CD95-mediated hepatocyte apoptosis, thereby alleviating concanavalin A-induced liver injury. This study elucidates the molecular mechanism by which Bacidifaciens modulates CD95-dependent hepatocyte apoptosis via glycocholic acid, providing a molecular foundation for exploring the protective role of Bacidifaciens in CD95-associated liver diseases.
METHODS: C57BL/6 mice were gavaged with Bacidifaciens, and liver bile acid profiles were analyzed using metabolomic analysis. Glycocholic acid was screened out according to death receptor CD95 expression, and its underlying mechanism was identified using inhibitor and CRISPR technology in the AML-12 cell line. In vivo protection of glycocholic acid was elucidated by drinking 0.2% glycocholic acid for 35 days.
RESULTS: Bacidifaciens administration significantly altered hepatic bile acid composition, such as glycocholic acid, β-muricholic acid, and hyocholic acid. Among differential bile acids, glycocholic acid reduced CD95 expression in transcription and membrane-binding protein levels in hepatic cells. Inhibition or deletion of membrane receptor Takeda G protein-coupled receptor 5 abolished the inhibition of glycocholic acid on CD95 expression. FOSL1 was identified as a downstream transcription regulator of Takeda G protein-coupled receptor 5. Mice administered with 0.2% glycocholic acid were less susceptible to concanavalin A-induced hepatitis with reduced CD95 expression and hepatocyte apoptosis.
CONCLUSIONS: Intestinal Bacidifaciens elevates hepatic glycocholic acid levels. Glycocholic acid binds to Takeda G protein-coupled receptor 5 and upregulates FOSL1. This subsequently downregulates CD95 transcription and inhibits CD95-mediated hepatocyte apoptosis, thereby alleviating concanavalin A-induced liver injury. This study elucidates the molecular mechanism by which Bacidifaciens modulates CD95-dependent hepatocyte apoptosis via glycocholic acid, providing a molecular foundation for exploring the protective role of Bacidifaciens in CD95-associated liver diseases.