表观遗传机制在酒精引起的肝脏和肠道损伤中的作用

There is increasing evidence that demonstrates a critical pathogenic role for the “gut-liver axis” in the development of alcoholic liver disease (ALD). Alcohol consumption-mediated enteric dysbiosis and increased intestinal permeability and exacerbates the liver injury by gut-derived microbial products including endotoxin. The consequent hepatic steatosis and inflammation can in turn promote gut dysfunction. Epigenetic mechanisms play a significant role in the development of hepatic pathology. Alcohol consumption causes HDAC changes leading to modifications in histones and downstream gene expression of CPT1α expression, a key enzyme in free fatty acid β-oxidation. However, the investigation of epigenetic mechanisms affects ALD has been started just now, and it is still blank for the research of alcohol-induced HDAC changes in gut. Therefore, we hypothesis dysbiosis caused by alcohol exposure directly contributes to HDAC activity and modifications in the GI tract and liver, epigenetic mechanisms affecting “liver-gut axis” alterations and liver injury. The proposed studies will examines the effects of different way of alcohol exposure on the expression of HDAC and consequent histone modifications in liver and gut, and determine the therapeutic and preventive efficacy of LGG and tributyrin on alcohol-induced dysbiosis and HDAC changes in ALD.

大量研究表明，“肝-肠轴”在酒精性肝病（ALD）的生成和发展中起着重要作用。酒精摄入导致菌群紊乱，肠道通透性增加。肠道产生的内毒素进入肝脏加重酒精对肝脏的损伤。同时，肝脏脂肪堆积和炎症会进一步增加肠道的病变。表观遗传学机制在这个过程中起着重要作用。研究表明，酒精摄入影响去乙酰化酶（HDAC）的变化，引起组蛋白的修饰，从而调控与肝脏脂肪氧化相关的肉碱棕榈酰基转移酶-1α（CPT1α）的功能。但是表观遗传机制对酒精性肝病影响的研究才刚刚开始，而且酒精对肠道HDAC的调控研究还是空白。我们假设酒精引起的肠道生态紊乱直接影响肠道及肝脏的HDAC活性及组蛋白修饰，而这种表观遗传机制导致了“肝-肠轴”的变化及肝脏的损伤。本项目将主要研究不同酒精摄入方式对肝肠组织中HDAC和组蛋白修饰的影响，并研究以影响肠道菌群和HDAC活性为靶点的益生菌和三丁酸甘油酯对ALD的预防和治疗作用。

“肝-肠轴”在酒精性肝病（ALD）的生成和发展中起着重要作用。酒精摄入导致菌群紊乱，肠道产生的内毒素进入肝脏加重酒精对肝脏的损伤，肠道通透性增加；肝脏脂肪堆积和炎症会进一步增加肠道的病变。表观遗传学机制在上述过程中起到关键性作用。研究发现：急性酒精调控小鼠肝肠组织中不同亚型HDAC差异表达；肠上皮HIF-1α能维持肠道微生态平衡以及增加抗菌肽表达；肠上皮HIF-1α能够维持肠道屏障功能；LGG与BM-MSCs联合治疗能够显著改善酒精诱导的肝脏炎症和纤维化。本项目将主要研究不同酒精摄入方式对肝肠组织中HDAC和组蛋白修饰的影响，并研究以影响肠道菌群和HDAC活性为靶点的益生菌和三丁酸甘油酯对ALD的预防和治疗作用；并阐明肠上皮细胞中表达的HIF-1α介导酒精性肝病的分子机制，确证了HIF-1α可以作为缓解酒精性肝病的新靶点以及LGG与BM-MSCs联合治疗可以为缓解酒精性肝病提供新的治疗策略。