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

• 批准号: 8256351
• 负责人: Gail Ann Cresci
• 金额: $ 4.84万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/8256351
• 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

DESCRIPTION (provided by applicant): 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). Excessive alcohol consumption leads to liver damage. There is no straightforward treatment available to date. Liver transplantation is the only possible option for the patient suffering from alcohol-induced liver damage. Our proposed work will help us to better understand the cause of alcoholic liver damage as well as identify new therapeutic targets for prevention and/or treatment of alcoholic liver damage.

描述（由申请人提供）：丁酸盐在乙醇引起的肝损伤的肠-肝相互作用中的作用 关键词：酒精、醋酸盐、肠、肝脏、丁酸盐 最近，肠-肝相互作用与酒精性肝病的进展有关。酒精性LD）。有证据表明，酒精暴露会损害肠道完整性，导致细菌和/或内毒素易位至肝脏，并激活 Toll 样受体 4（内毒素受体，与脂肪性肝炎和肝纤维化的进展相关）。乙醇代谢为乙醛，然后代谢为乙酸。喂食乙醇后，血液中醋酸盐水平高于乙醛。远端肠道基底外侧膜中表达的单羧酸转运蛋白可以将全身乙酸盐转运到结肠中。研究主要集中在乙醛上，乙醛是增加肠道对内毒素的通透性和 ALD 进展的罪魁祸首，而醋酸盐的作用尚未得到充分研究。短链脂肪酸（乙酸盐、丙酸盐和丁酸盐）是通过共生肠道微生物群发酵未消化的膳食纤维和淀粉在远端肠道产生的。丁酸盐在维持肠道健康方面发挥着重要作用，它作为结肠细胞的主要能量来源，增加正常结肠上皮增殖但减少肿瘤性结肠细胞增殖，并通过其作为组蛋白脱乙酰酶抑制剂的作用来调节基因表达。较高的乙酸盐与丁酸盐的比率与结肠病理的增加相关。管腔丁酸盐的缺乏与粘膜萎缩以及细胞凋亡和炎症有关，而丁酸盐滴注可逆转这种情况。鉴于丁酸盐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会降低肠道中的丁酸盐比率，继发于乙酸盐比率的非生理性升高，并且维持 SCFA 的生理比率将预防和/或恢复受损的肠道完整性和ALD 早期阶段的进展。为了检验我们的假设，我们将使用诱发脂肪性肝炎的慢性重乙醇喂养方案，以及使用乙醇喂养增强肝纤维化的慢性低剂量乙醇和四氯化碳喂养方案。我们将测试以下预测：这些模型中 SCFA 比率的改变会导致肠道通透性增加和 ALD 进展，而补充三丁酸甘油酯将预防和/或治疗这些影响。拟议的工作将提供临床前数据，以帮助确定酒精性肝病（ALD）的新治疗方法。 过量饮酒会导致肝脏损伤。迄今为止还没有直接的治疗方法。对于酒精性肝损伤患者来说，肝移植是唯一可能的选择。我们提出的工作将帮助我们更好地了解酒精性肝损伤的原因，并确定预防和/或治疗酒精性肝损伤的新治疗靶点。