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 有缺陷的肠上皮紧密连接 (TJ) 屏障被认为是重要的致病因素 在多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，并且 肝脏疾病的发生需要肠道通透性。这笔赠款的总体目标 应用目的是： a) 研究介导饮酒相关的致病机制 肠道通透性增加，b) 描述肠道 TJ 屏障缺陷与 肝脏炎症的发展，以及 c) 研究益生菌乳酸菌的治疗作用 嗜酸菌 (LA) 靶向肠道 TJ 屏障，预防肝脏炎症。该项目的首要重点是 拨款提案将研究肠-肝轴相互作用或有缺陷的肠 TJ 屏障在 肝脏炎症和损伤的发病机制。根据我们令人信服的初步数据，我们提出了 肠道来源的细菌脂多糖（LPS）是一种病因的范式转换假说 导致与饮酒相关的肠道通透性增加以及随后的 肝脏疾病的发展。我们还假设肠道 TJ 屏障的治疗目标是 预防酒精性肝病的充分有效的策略。我们还提出了一个新的假设，即洛杉矶 抑制与酒精消耗相关的肠道通透性增加以及随后的症状 通过抑制（而非激活）肠上皮细胞的 TLR2 信号转导途径导致肝病发生 NF-KB p50/p65 和 MLCK 基因激活。提出两个具体目标来解决上述假设： 1) 确定肠道TJ屏障缺陷在肝病发展中的致病作用并 描述介导肠道 TJ 通透性增加的机制，并 2) 确定 益生菌靶向肠道 TJ 屏障预防或治疗肝病以及 描述所涉及的保护机制。拟议研究的成功完成将提供 关于肠肝轴在酒精性肝病病理生理学中所发挥的整体作用的重要新见解 损伤，还提供支持未来临床研究所需的关键临床前数据。