Mus musculus isolate:Liver Transcriptome or Gene expression. Mus musculus isolate:Liver

The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates intestinal bile acids. Targeted metabolomics confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower FXR activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (CYP7)-A1 protein expression and bile acid levels. Depletion of the commensal microbiota with non-absorbable antibiotics decreased hepatic CYP7A1 expression and reduced alcoholic liver disease in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal farnesoid x receptor (FXR) activity, we used a pharmacological intervention with the intestine-restricted FXR agonist Fexaramine, which protected mice from ethanol-induced liver injury. While bile acid metabolism was only minimally altered, Fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial lipid metabolic effect to FGF15, a non-tumorigenic FGF19 variant – a human FGF15 ortholog – was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions restore bile acid signaling and reduce ethanol-induced liver disease in mice.

本研究旨在明确肠道菌群变化如何介导酒精性肝病（alcoholic liver disease）发生的具体机制。对小鼠肠道内容物开展宏基因组测序结果显示，长期乙醇饲喂会伴随编码胆酰甘氨酸水解酶（choloylglycine hydrolase）的细菌基因组DNA丰度升高——该酶可解离肠道胆汁酸的结合态。靶向代谢组学验证表明，乙醇给药后小鼠小肠内游离胆汁酸的含量显著提升。受肠上皮细胞中法尼醇X受体（farnesoid X receptor, FXR）活性降低介导，成纤维细胞生长因子（fibroblast growth factor, FGF）-15的蛋白分泌量下降，这与肝脏细胞色素P450酶（cytochrome P450 enzyme, CYP）7-A1的蛋白表达上调以及胆汁酸水平升高密切相关。使用非吸收性抗生素清除共生菌群后，小鼠肝脏CYP7A1的表达量降低，酒精性肝病症状得以缓解，这提示胆汁酸合成增加依赖于肠道菌群。为恢复肠道法尼醇X受体（FXR）活性，我们采用肠道限制性FXR激动剂Fexaramine进行药理学干预，该药物可保护小鼠免受乙醇诱导的肝损伤。尽管该干预仅轻微改变了胆汁酸代谢，但Fexaramine治疗能够稳定肠道屏障，并显著调控肝脏内参与脂质代谢的基因表达。为将有益的脂质代谢效应与FGF15建立关联，我们通过腺相关病毒（adeno-associated viruses）在小鼠体内过表达一种非致瘤性FGF19变体——该变体是人类FGF15的同源物。FGF19治疗展现出相似的有益代谢效应，并改善了酒精性脂肪性肝炎。综上，与酒精相关的宏基因组变化会导致胆汁酸谱发生改变。靶向干预手段可恢复胆汁酸信号通路，并减轻小鼠体内乙醇诱导的肝病。