ABSTRACT

Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. Bacteroides thetaiotaomicron (Bt) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of Bt in the genesis of ethanol-induced liver steatosis. Bt DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living Bt, followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced Bt abundance, which was preserved by Bt oral supplementation. Bt-treated mice displayed lower hepatic steatosis and triglyceride content. Bt restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, Bt up-regulated Glucagon-like peptide-1 (GLP-1) expression and restored ethanol-induced Fibroblast growth factor 15 (FGF15) down-regulation. Lipid metabolism was consequently affected as Bt administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with Bt preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced Bt depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. Bt could serve as a novel probiotic to treat ALD in the future.

摘要

酒精相关性肝病 (ALD) 是肝病的主要原因，并且是全球负担，因为治疗选择稀缺。尽管 90% 的酒精滥用者会发展为酒精性脂肪性肝病 (AFLD)，但只有少数会发展为脂肪性肝炎和肝硬化。尽管最近出现了肠道屏障完整性和微生物群在 ALD 中的关键作用，但酒精会增加脂肪生成并抑制脂质氧化，这意味着脂肪变性。Bacteroides thetaiotaomicron ( Bt ) 是人和鼠肠道微生物群的重要成员，在新陈代谢、肠道免疫和黏膜屏障中发挥重要作用。我们旨在研究Bt在乙醇诱导的肝脂肪变性发生中的作用。BT在接受 Lieber-DeCarli 饮食并增加酒精浓度的野生型小鼠的粪便中测量 DNA。在第二步中，用活Bt口服处理乙醇喂养的小鼠，然后分析肠道内稳态以及肝脏的组织学和生化变化。酒精喂养降低了Bt丰度，而Bt口服补充剂保留了这一丰度。Bt治疗的小鼠表现出较低的肝脂肪变性和甘油三酯含量。Bt通过增强粘液厚度和 Mucin2 的产生来恢复粘膜屏障并减少 LPS 易位。此外，Bt上调胰高血糖素样肽 1(GLP-1) 表达和恢复乙醇诱导的成纤维细胞生长因子 15 (FGF15) 下调。脂质代谢因此受到影响，因为Bt给药减少了脂肪酸合成 (FA) 并改善了 FA 氧化和脂质输出。此外，用Bt治疗保留了酒精喂养小鼠的线粒体适应性和氧化还原状态。总之，通过口服补充剂恢复乙醇诱导的Bt消耗与恢复肠道稳态和改善实验性 ALD 相关。Bt可以作为一种新型益生菌在未来治疗 ALD。