Mechanisms of ethanol-induced dysregulation of gut homeostasis

乙醇引起的肠道稳态失调的机制

• 批准号: 9195509
• 负责人: Tasha Marie Barr
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195509
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Archaea; Bacteria; Biochemical Pathway; Blood flow; Cell Line; Cells; Chronic; Clinical; Colon; Colorectal Cancer; Communities; Complex; Development; Disease; Dose; Down-Regulation; Duodenum; Endotoxins; Environment; Epithelial; Epithelial Cells; Ethanol; Ethanol dependence; Formulation; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genes; Growth; Health; Heavy Drinking; Homeostasis; Host Defense; Human; Immune; Immune response; Immune system; In Vitro; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intervention; Intestines; Knowledge; Link; Liver; Maintenance; Malignant neoplasm of gastrointestinal tract; Mediating; Metabolic; Metabolic Pathway; Modeling; Mucous Membrane; Neoplasms; Organ; Outcome; Paraffin Embedding; Pathology; Pathway interactions; Peripheral; Permeability; Play; Prevalence; Probiotics; Process; Production; Proteins; Research; Resistance to infection; Role; Self Administration; Severities; Site; Small Interfering RNA; Specimen; Structure; Symbiosis; Testing; Tight Junctions; Tissues; Up-Regulation; Virus; alcohol use disorder; chronic alcohol ingestion; commensal microbes; fungus; gastrointestinal; gut microbiome; gut microbiota; ileum; improved; insight; intestinal homeostasis; jejunum; microbial; microbial community; microbiome; nonhuman primate; novel; pathogen; problem drinker; repaired; therapy design; transcriptome sequencing; tumor progression

Summary Chronic alcohol consumption leads to gut injury and increased incidence of gastrointestinal cancers. Studies have implicated quantitative and qualitative alterations of gut microbiota as well as dysregulation of tight junction proteins as key contributors to gut injury, leading to increased gut permeability. This in turn results in the translocation of bacteria and bacterial endotoxins into the portal blood flow that stimulate the production of pro-inflammatory mediators in the liver, culminating in alcoholic liver disease and other organ damage. However, our understanding of the mechanisms underlying these pathologies remains incomplete. Studies to date have not exhaustively identified ethanol-induced changes in gastrointestinal mucosal gene expression or specific microbial shifts that are responsible for tissue injury. The gut barrier is tightly regulated through interactions between epithelial cells, immune cells, and the microbiome. Deeper understanding of the interplay among these three components in the mucosa is necessary to identify processes of alcohol-induced gut injury. In this application, I will simultaneously define ethanol-mediated changes in the intestinal microbiome and mucosal gene expression within all major sections of the gut (duodenum, jejunum, ileum, and colon) using a translational nonhuman primate model of voluntary ethanol self-administration. This unique animal model provides us with an unprecedented opportunity to investigate region- and dose- dependent alterations in gut homeostasis under the influence of alcohol. Completion of these studies will provide us with the knowledge necessary to design interventions to repair mucosal injury and improve health outcomes in those with alcohol use disorders.

总结 长期饮酒会导致肠道损伤和胃肠道疾病的发生率增加 癌的研究表明，肠道微生物群的数量和质量发生了变化， 以及紧密连接蛋白的失调是肠道损伤的关键因素，导致 增加肠道通透性。这反过来又导致细菌和细菌的易位。 内毒素进入门静脉血流，刺激促炎介质的产生 最终导致酒精性肝病和其他器官损伤。但我们的 对这些病理的机制的理解仍然不完全。研究来 迄今尚未完全确定乙醇诱导的胃肠道粘膜基因变化 表达或特定微生物的变化，负责组织损伤。肠道屏障是 通过上皮细胞、免疫细胞和微生物组之间的相互作用进行严格调控。 对粘膜中这三种成分之间的相互作用有更深入的了解， 确定酒精诱导的肠道损伤过程所必需的。在这个应用程序中，我将 同时确定乙醇介导的肠道微生物组和粘膜基因的变化 使用免疫组织化学方法检测肠的所有主要部分（十二指肠、空肠、回肠和结肠）内的表达。 翻译非人灵长类动物自愿乙醇自我管理模型。这种独特 动物模型为我们提供了一个前所未有的机会，研究区域和剂量， 在酒精的影响下，肠道内稳态的依赖性改变。完成这些 研究将为我们提供必要的知识，设计干预措施， 伤害和改善酒精使用障碍患者的健康结果。