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

描述（由申请人提供）：丁酸盐在乙醇诱导的肝损伤的肠-肝相互作用中的作用关键词：酒精，乙酸盐，肠，肝脏，丁酸盐肠-肝相互作用最近与酒精性肝病（ALD）的进展有关。证据支持酒精暴露损害肠道完整性，允许细菌和/或内毒素移位至肝脏并激活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，然后代谢为乙酸盐。乙醇喂养后，血液乙酸盐水平高于乙醛。在远端肠的基底外侧膜中表达的单羧酸转运蛋白可以将全身性乙酸盐转运到结肠中。研究主要集中在乙醛作为增加肠道对内毒素的渗透性和ALD进展的罪魁祸首，而乙酸盐的作用未得到充分研究。短链脂肪酸（乙酸酯、丙酸酯和丁酸酯）是通过肠道微生物群发酵未消化的膳食纤维和淀粉在远端肠道中产生的。丁酸盐通过充当结肠细胞的主要能量来源、增加正常结肠上皮细胞增殖但减少肿瘤性结肠细胞增殖以及通过其作为组蛋白脱乙酰酶抑制剂的作用调节基因表达而在维持肠道健康中起重要作用。较高的乙酸与丁酸的比率与结肠病理学的增加相关。管腔丁酸盐的缺乏与粘膜萎缩以及细胞凋亡和炎症相关，这通过丁酸盐滴注是可逆的。鉴于丁酸盐在维持肠道健康和完整性方面的重要作用，我们假设慢性乙醇消耗降低了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。为了验证我们的假设，我们将使用慢性重乙醇喂养协议，诱导脂肪性肝炎，和慢性低剂量乙醇与四氯化碳喂养协议，其中肝纤维化与乙醇喂养增强。我们将测试SCFA比率在这些模型中改变导致肠通透性增加和ALD进展以及三丁酸甘油酯补充剂将预防和/或治疗这些效应的预测。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。 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。肝移植是酒精性肝损伤患者唯一的选择。我们的工作将有助于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的治疗靶点。

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.