Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol‐associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over‐representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)‐15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)‐7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine‐restricted FXR agonist fexaramine, which protected mice from ethanol‐induced liver injury. Whereas 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 metabolic effect to FGF15, a nontumorigenic 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. Conclusion: Taken together, alcohol‐associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid–FXR–FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol‐induced liver disease in mice. (Hepatology 2018;67:2150‐2166).

中文翻译：

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调节肠道胆汁酸-FXR-FGF15 轴可改善小鼠酒精性肝病

酒精性肝病 (ALD) 与肠道微生物群的变化有关。酒精相关生态失调的功能后果在很大程度上是未知的。本研究的目的是确定肠道微生物群的变化如何导致 ALD 的机制。肠道内容物的宏基因组测序表明，小鼠长期摄入乙醇与编码胆酸甘氨酸水解酶的细菌基因组 DNA 的过度表达有关，胆酸水解酶可在肠道中分离胆汁酸。胆汁酸分析证实乙醇给药后小肠中未结合胆汁酸的量增加。由肠细胞中较低的法尼醇 X 受体 (FXR) 活性介导，较低的成纤维细胞生长因子 (FGF)-15 蛋白分泌与增加的肝细胞色素 P450 酶 (Cyp)-7a1 蛋白表达和循环胆汁酸水平有关。用不可吸收的抗生素消耗共生微生物群会减弱肝脏 Cyp7a1 的表达并降低小鼠的 ALD，这表明胆汁酸合成的增加依赖于肠道细菌。为了恢复肠道 FXR 活性，我们使用了肠道限制性 FXR 激动剂 fexaramine 的药理学干预，它可以保护小鼠免受乙醇引起的肝损伤。胆汁酸代谢仅发生很小的改变，而非沙明治疗稳定了肠道屏障并显着调节了参与脂质代谢的肝脏基因。将有益的代谢作用与 FGF15 联系起来，非致瘤性 FGF19 变体——人类 FGF15 直向同源物——在使用腺相关病毒的小鼠中过度表达。FGF19 治疗显示出类似的有益代谢作用和改善酒精性脂肪性肝炎。结论：总的来说，酒精相关的宏基因组变化会导致胆汁酸谱的改变。靶向干预通过调节肝脏 Cyp7a1 和脂质代谢改善胆汁酸-FXR-FGF15 信号传导，并减少乙醇诱导的小鼠肝脏疾病。（肝病学 2018 年；67：2150-2166）。靶向干预通过调节肝脏 Cyp7a1 和脂质代谢改善胆汁酸-FXR-FGF15 信号传导，并减少乙醇诱导的小鼠肝脏疾病。（肝病学 2018 年；67：2150-2166）。靶向干预通过调节肝脏 Cyp7a1 和脂质代谢改善胆汁酸-FXR-FGF15 信号传导，并减少乙醇诱导的小鼠肝脏疾病。（肝病学 2018 年；67：2150-2166）。