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)：丁酸在乙醇诱导的肝损伤的肠道-肝脏相互作用中的作用关键词：酒精，醋酸盐，肠，肝脏，丁酸盐最近发现肠道-肝脏的相互作用与酒精性肝病(ALD)的进展有关。有证据表明，酒精暴露会损害肠道完整性，导致细菌和/或内毒素移位到肝脏，并激活Toll样受体4，内毒素受体4与脂肪性肝炎和肝纤维化的进展有关。乙醇被代谢成乙醛，然后变成乙酸乙酯。喂食乙醇后，血液中的乙酸乙酯水平高于乙醛。在远端肠道的基侧膜上表达的单羧酸转运体可以将系统醋酸盐转运到结肠中。研究主要集中在乙醛是增加肠道对内毒素的通透性的罪魁祸首，以及ALD的进展，而对乙酸乙酯的作用研究较少。短链脂肪酸(醋酸酯、丙酸和丁酸)是在远端肠道中通过共生肠道微生物群发酵未消化的膳食纤维和淀粉而产生的。丁酸盐作为结肠细胞的主要能量来源，促进正常结肠上皮细胞的增殖而抑制肿瘤结肠上皮细胞的增殖，并通过其组蛋白脱乙酰酶抑制剂的作用调节基因表达，从而在维持肠道健康方面发挥重要作用。醋酸盐和丁酸的比例越高，结肠的病理程度越高。丁酸腔的缺失与粘膜萎缩、细胞凋亡和炎症有关，而丁酸滴注是可逆的。鉴于丁酸在维持肠道健康和完整性方面的重要作用，我们假设慢性酒精摄入降低了肠道中丁酸的比例，而非生理性升高的醋酸盐比例，以及维持SCFA的生理比例将防止和/或恢复受损的肠道完整性和ALD早期阶段的进展。为了验证我们的假设，我们将使用导致脂肪性肝炎的慢性重酒精喂养方案，以及慢性低剂量酒精和四氯化碳喂养方案，在该方案中，通过酒精喂养加强肝纤维化。我们将测试在这些模型中SCFA比率改变导致肠道通透性增加和ALD进展的预测，以及补充三丁酸甘油酯将预防和/或治疗这些影响。这项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。到目前为止，还没有简单的治疗方法。肝移植是酒精性肝损伤患者唯一可能的选择。我们拟议的工作将有助于我们更好地了解酒精性肝损伤的原因，以及确定预防和/或治疗酒精性肝损伤的新的治疗靶点。