Role of Butyrate in the Gut-Liver Interaction of Ethanol Induced Liver Injury

丁酸盐在乙醇引起的肝损伤的肠-肝相互作用中的作用

基本信息

批准号：
8329039
负责人：
Gail Ann Cresci
金额：
$ 5.22万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8329039
关键词：
Acetaldehyde Acetates Acute Affect Alcohol dehydrogenase Alcoholic Liver Diseases Alcoholic liver damage Alcoholism Alcohols Apoptosis Atrophic Blood Blood Circulation Butyrates CYP2E1 gene Carbon Tetrachloride Cell physiology Chronic Colon Complex Data Development Dietary Fiber Disease Progression Distal Dose Endotoxins Energy-Generating Resources Enterocytes Epithelium Ethanol Ethanol Metabolism Exposure to Extrahepatic Fatty Liver Fermentation Fibrosis Gastrointestinal tract structure Gene Expression Generations Goals Health Heavy Drinking Hepatic Stellate Cell Histone Deacetylase Inhibitor Human Inflammation Injury Intestines Knowledge Kupffer Cells Left Link Lipopolysaccharides Literature Liver Liver Fibrosis Mammals Mediating Modeling Mus Natural Immunity Neuraxis Oral Organ Pathology Pathway interactions Patients Permeability Physiological Plasma Play Prevention Process Propionates Protocols documentation Rattus Research Research Proposals Role Secondary to Staging Steatohepatitis Supplementation Testing Tissues Translating Volatile Fatty Acids Work alcohol effect alcohol exposure basolateral membrane chronic alcohol ingestion dietary starch drinking endotoxin receptor feeding gut microbiota liver transplantation mouse model neoplastic new therapeutic target novel novel therapeutics pre-clinical prevent response structured lipid toll-like receptor 4 tributyrin

项目摘要

Title: Role of Butyrate in the Gut-Liver Interaction of Ethanol Induced Liver Injury Key words: alcohol, acetate, intestine, liver, butyrate A gut-liver interaction has recently been linked with the progression of alcoholic liver disease (ALD). Evidence supports that alcohol exposure impairs gut integrity allowing for bacterial and/or endotoxin translocation to the liver and activation of toll-like receptor 4, the receptor for endotoxin which is associated with progression of steatohepatitis and liver fibrosis. Ethanol is metabolized to acetaldehyde and then to acetate. Following ethanol feeding, blood acetate levels are higher than acetaldehyde. Monocarboxylate transporters expressed in the basolateral membrane of the distal gut can transport systemic acetate into the colon. Research has focused primarily on acetaldehyde as the primary culprit in increasing gut permeability to endotoxin and progression of ALD leaving the role of acetate understudied. Short-chain fatty acids (acetate, propionate, and butyrate) are produced in the distal gut through the fermentation of undigested dietary fiber and starch by the commensal gut microbiota. Butyrate plays an important role in maintaining gut health by serving as the primary energy source for the colonocyte, increasing normal colonic epithelium proliferation but decreasing neoplastic colonocyte proliferation, and regulating gene expression through its role as an inhibitor of histone deacetylase. Higher acetate to butyrate ratios are associated with increased colonic pathology. Absence of luminal butyrate is associated with mucosal atrophy, as well as apoptosis and inflammation, which is reversible by butyrate instillation. Given the important role of butyrate in maintaining gut health and integrity, we hypothesize chronic ethanol consumption decreases butyrate ratios in the gut secondary to non-physiologic elevations in acetate ratios and that maintaining physiologic ratios of SCFA will prevent and/or restore impaired gut integrity and the progression of early stages of ALD. To test our hypothesis we will use a chronic heavy ethanol feeding protocol which induces steatohepatitis, and a chronic low-dose ethanol with carbon-tetrachloride feeding protocol in which liver fibrosis is enhanced with ethanol feeding. We will test the prediction that SCFA ratios are altered in these models leading to increased gut permeability and progression of ALD and that tributyrin supplementation will prevent and/or treat these effects. The proposed work will provide preclinical data to help determine new therapeutic management of alcoholic liver disease (ALD).

标题：丁酸酯在乙醇诱导肝损伤的肠道相互作用中的作用关键词：酒精，醋酸盐，肠道，肝脏，丁酸酯肠肝相互作用最近与酒精性肝病（ALD）的进展有关。证据支持酒精暴露会损害肠道完整性，允许细菌和/或内毒素转移到肝脏和收费受体4的激活，这是内毒素的受体，与脂肪性肝炎和肝纤维化的进展有关。将乙醇代谢为乙醛，然后代谢乙酸。乙醇进食后，乙酸血液水平高于乙醛。远端肠道基底外侧膜中表达的单羧酸盐转运蛋白可以将全身性乙酸酯转运到结肠中。研究主要集中于乙醛是增加肠道渗透性和ALD进展的主要罪魁祸首。短链脂肪酸（乙酸，丙酸酯和丁酸酯）是通过通过共生肠肠癌对未消化的饮食纤维和淀粉的发酵而在远端肠道中产生的。丁酸酯通过作为结肠细胞的主要能源来维持肠道健康，在维持肠道健康方面起着重要作用，增加了正常的结肠上皮增殖，但减少了肿瘤结肠细胞增殖，并通过其作为组蛋白脱乙酰基酶的抑制剂来调节基因表达。较高的乙酸酯与丁酸酯比与结肠病理增加有关。没有腔内丁酸氨基酯与粘膜萎缩以及细胞凋亡和炎症有关，这是通过丁酸滴注可逆的。鉴于丁酸酯在维持肠道健康和完整性中的重要作用，我们假设慢性乙醇消耗降低了继发于乙酸比的非生理学升高的肠道比率，并且维持SCFA的生理比率将预防和/或恢复不良的良好完整性的良好良好的良好型和进展。为了检验我们的假设，我们将使用一种慢性重乙醇喂养方案，该方案诱导脂肪性肝炎，以及具有慢性低剂量乙醇和碳四氯化物喂养方案，其中通过乙醇进食增强了肝纤维化。我们将测试以下预测：这些模型中SCFA的比率发生了变化，从而导致ALD的肠道渗透性和进展增加，而补充支流蛋白会预防和/或治疗这些作用。拟议的工作将提供临床前数据，以帮助确定酒精性肝病（ALD）的新治疗管理。