Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
Department of Integrated Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio.
Cell Mol Gastroenterol Hepatol. 2024;18(1):71-87. doi: 10.1016/j.jcmgh.2024.02.015. Epub 2024 Feb 28.
BACKGROUND & AIMS: Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding.
After injection of adeno-associated virus-green fluorescent protein or AAV-FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge.
Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfβ, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens.
Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.
过量饮酒可导致酒精相关性肝病，其范围从脂肪变性到纤维化和肝硬化。胆汁酸通过与细胞和核受体结合来调节代谢途径，它们还与肠道微生物群相互作用以控制微生物过度生长。成纤维细胞生长因子 19（FGF-19）是一种回肠衍生的激素，在胆汁酸激活核受体法尼醇 X 受体时被诱导和释放。FGF-19 信号转导在乙醇消耗时失调，并在酒精性肝炎患者中增加。在这里，我们在慢性+ binge 乙醇喂养的小鼠模型中检查了 FGF-19 的作用。
在注射腺相关病毒-绿色荧光蛋白或 AAV-FGF-19 后，雌性 C57BL/6J 小鼠接受 Lieber DeCarli 液体饮食（5%v/v）或对照饮食 10 天，并接受 5%乙醇或麦芽糖对照的单次胃管灌胃以代表 binge 饮酒事件。 binge 后 9 小时收集组织进行分析。
无论 FGF-19 表达如何，慢性+ binge 乙醇喂养都会诱导脂肪变性。有趣的是，与单独使用乙醇相比，FGF-19 和乙醇导致肝炎症明显增加，如 Il6、Tgfβ 和 Tnfα 所测量的那样。乙醇和 FGF-19 均降低胆汁酸合成，FGF-19 显著降低次级胆汁酸，导致特定病原体细菌的过度生长，包括粪肠球菌、大肠杆菌和产气荚膜梭菌。
在饮酒期间 FGF-19 的失调以及胆汁酸合成和组成的变化可能是酒精性肝病和菌群失调的一个促成因素。
