Intestinal Barrier, Probiotic Bacteria, and the Gut-Liver Axis

摘要 肠上皮细胞紧密连接（TJ）屏障的缺陷被认为是肠上皮细胞损伤的重要致病因素。 在各种炎症性疾病中发挥作用，包括酒精性肝病。我们的初步研究 表明长期饮酒会导致肠道通透性增加， 肝脏疾病的发展需要肠通透性。这项补助金的首要目标是 应用是：a）调查介导酒精消耗相关的致病机制 肠通透性增加，B）描述了肠TJ屏障缺陷和 肝脏炎症的发展，和c）研究益生菌乳杆菌的治疗作用 嗜酸乳杆菌（LA）靶向肠道TJ屏障，以防止肝脏炎症。的主要重点 拨款提案将是关于肠-肝轴相互作用或缺陷性肠TJ屏障在 肝脏炎症和损伤的发病机制。基于我们令人信服的初步数据，我们提出了一个 肠源性细菌脂多糖（LPS）是致病因素的范式转变假说 负责酒精消费相关的肠道通透性增加和随后的 肝病的发展。我们还假设，肠TJ屏障的治疗靶点是 充分和有效的策略来预防酒精性肝病。我们还提出了一个新的假设， 抑制酒精消耗相关的肠道通透性增加， 通过TLR 2信号转导途径抑制（而非激活）肠上皮细胞而发展肝病 NF-κ B p50/p65和MLCK基因活化。为解决上述假设，提出了两个具体目标： 1)确定肠道TJ屏障缺陷在肝脏疾病发展中的致病作用， 阐明介导肠TJ渗透性增加的机制，2）确定 靶向肠TJ屏障的益生菌预防或治疗肝脏疾病的治疗功效， 描述所涉及的保护机制。拟议研究的成功完成将提供 对肠-肝轴在酒精诱导的肝脏病理生理学中的整体作用的重要新见解 损伤，并提供支持未来临床研究所需的关键临床前数据。

Abstract Defective intestinal epithelial tight junction (TJ) barrier has been postulated to play an important pathogenic role in a wide variety of inflammatory conditions, including alcoholic liver disease. Our preliminary studies suggest that chronic alcohol consumption causes an increase in intestinal permeability and that the increase in intestinal permeability is required for the development of liver disease. The overarching goals of this grant application are to: a) investigate the pathogenic mechanisms that mediate alcohol consumption - associated increase in intestinal permeability, b) delineate the causal linkage between defective intestinal TJ barrier and development of liver inflammation, and c) investigate the therapeutic role of probiotic bacteria Lactobacillus acidophilus (LA) in targeting the intestinal TJ barrier to prevent liver inflammation. The primary focus of the grant proposal will be on the gut-liver axis interaction or on the role of defective intestinal TJ barrier in the pathogenesis of liver inflammation and injury. Based on our compelling preliminary data, we advance a paradigm-shifting hypothesis that gut-derived bacterial lipopolysaccharide (LPS) is an etiologic factor responsible for the alcohol consumption-associated increase in intestinal permeability and the subsequent development of liver disease. We also hypothesize that therapeutic targeting of intestinal TJ barrier is both sufficient and effective strategy to prevent alcoholic liver disease. We also advance a novel hypothesis that LA inhibits the alcohol consumption - associated increase in intestinal permeability and the subsequent development of liver disease via a TLR2 signal transduction pathway suppression (not activation) of enterocyte NF-KB p50/p65 and MLCK gene activation. Two specific aims are proposed to address the above hypotheses: 1) to determine the pathogenic role of defective intestinal TJ barrier in the development of liver disease and to delineate the mechanisms that mediate the increase in intestinal TJ permeability and 2) to determine the therapeutic efficacy of probiotic bacterial targeting of intestinal TJ barrier to prevent or treat liver disease and to delineate the protective mechanisms involved. The successful completion of the proposed studies will provide important new insight into the integral role gut-liver axis plays in the pathophysiology of alcohol-induced liver injury and also provide crucial pre-clinical data needed to support future clinical studies.