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

肠道屏障、益生菌和肠-肝轴

• 批准号: 10316171
• 负责人: THOMAS Y MA
• 金额: $ 47.17万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-18 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316171
• 关键词: Address; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Antigens; Applications Grants; Bacteria; Bacterial Genes; Bile Acid Biosynthesis Pathway; Biological Factors; Biological Process; Blood Circulation; Chronic; Clinical; Clinical Data; Clinical Research; Complex; Data; Defect; Development; Enterocytes; Ethanol; Etiology; Fibroblast Growth Factor; Functional disorder; Future; Gene Activation; Gene Expression; Genes; Goals; Health Care Costs; Hepatocyte; Inflammatory; Intestinal permeability; Intestines; Journals; Knowledge; Lactobacillus acidophilus; Leaky Gut; Link; Lipopolysaccharides; Liver; Liver diseases; Mediating; Medicine; Modeling; Molecular; Myosin Light Chain Kinase; NF-kappa B; National Institute on Alcohol Abuse and Alcoholism; New England; Pathogenesis; Pathogenicity; Penetration; Permeability; Pharmaceutical Preparations; Play; Prevention; Probiotics; Proteins; Publishing; Research; Role; Scientific Advances and Accomplishments; Serum; Signal Transduction Pathway; Small Intestines; Steroids; System; TLR2 gene; TLR4 gene; TNFRSF5 gene; Testing; Therapeutic; Tight Junctions; Treatment Efficacy; Virulence Factors; base; chronic alcohol ingestion; effective therapy; efficacious treatment; gut-liver axis; insight; intestinal barrier; intestinal epithelium; liver development; liver inflammation; liver injury; nonalcoholic steatohepatitis; novel; p65; pre-clinical; prevent; preventable death; receptor; therapeutic target

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.

抽象的 肠道上皮紧密连接（TJ）屏障已被假定发挥着重要的致病性 在各种炎症状况中的作用，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的增加，并增加 肝病的发展需要肠道通透性。这笔赠款的总体目标 应用是：a）研究介导酒精消耗的致病机制 - 相关 肠道通透性的增加，b）描述有缺陷的肠道TJ屏障与 肝脏炎症的发展，c）研究益生菌乳酸杆菌的治疗作用 嗜酸菌（LA）靶向肠道TJ屏障以防止肝脏炎症。主要重点 赠款提案将在肠道轴相互作用或肠道中有缺陷的TJ屏障的作用上 肝脏炎症和损伤的发病机理。基于我们引人注目的初步数据，我们推进了 肠道衍生的细菌脂多糖（LPS）是一个病因学因子，范式转移假设 负责与饮酒相关的肠道通透性的增加和随后的 肝病的发展。我们还假设肠道TJ屏障的治疗性靶向都是 足够有效的策略来预防酒精性肝病。我们也推进了一个新的假设 抑制酒精消耗 - 相关的肠道通透性和随后的增加 通过TLR2信号转导途径抑制肝脏疾病的发展（非激活） NF-KB p50/p65和MLCK基因激活。提出了两个具体目标来解决上述假设： 1）确定有缺陷的肠道TJ障碍在肝病发展和TO中的致病作用 描述介导肠道TJ渗透率增加的机制，并确定2） 肠道TJ屏障的益生菌细菌靶向预防或治疗肝病的治疗功效 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生理学中发挥不可或缺的作用的重要新见解 伤害，还提供了支持未来临床研究所需的至关重要的临床前数据。