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

摘要 肠上皮紧密连接(TJ)屏障缺陷被认为是一种重要的致病因素 在各种炎症条件下发挥作用，包括酒精性肝病。我们的初步研究 提示长期饮酒会导致肠道通透性增加，而 肝脏疾病的发展需要肠道通透性。这笔赠款的首要目标是 应用于：a)研究与酒精消费相关的致病机制 肠道通透性增加，b)描绘了肠道TJ屏障缺陷和 肝脏炎症的发展，以及c)研究益生菌乳杆菌的治疗作用 嗜酸菌(LA)靶向肠道TJ屏障以防止肝脏炎症。的主要关注点 GRANT建议将关于肠道-肝轴的相互作用或肠道TJ屏障缺陷在 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 肠源性细菌脂多糖是致病因素的范式转换假说 与饮酒相关的肠道通透性增加以及随后的 肝病的发展。我们还假设，肠道TJ屏障的治疗靶点既有 预防酒精性肝病的充分和有效的策略。我们还提出了一个新的假设，即LA 抑制与饮酒相关的肠道通透性增加和随后的 通过抑制(而不是激活)肠细胞TLR2信号转导通路发展为肝病 核因子-kB p50/p65和MLCK基因激活。针对上述假设，本文提出了两个具体目标： 1)确定肠道TJ屏障缺陷在肝病发生发展中的致病作用 描述介导肠道TJ通透性增加的机制和2)确定 益生菌靶向肠道TJ屏障防治肝病的疗效观察 描述所涉及的保护机制。成功完成拟议的研究将提供 肠肝轴在酒精性肝病病理生理中的重要作用 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.