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

关键词：酒精、醋酸盐、肠、肝、丁酸盐肠-肝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/或内毒素转运到肝脏，并激活toll样受体4，这种内毒素受体与脂肪性肝炎和肝纤维化的进展有关。乙醇被代谢为乙醛，然后是乙酸。饲喂乙醇后，血液中乙酸水平高于乙醛水平。远端肠基底外膜表达的单羧酸转运蛋白可将全身醋酸盐转运到结肠。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，而乙酸的作用尚未得到充分研究。短链脂肪酸（醋酸酯、丙酸酯和丁酸酯）是在远端肠道中由共生肠道菌群通过未消化的膳食纤维和淀粉发酵产生的。丁酸盐作为结肠细胞的主要能量来源，增加正常结肠上皮细胞的增殖但减少肿瘤结肠细胞的增殖，并通过抑制组蛋白去乙酰化酶的作用调节基因表达，在维持肠道健康方面发挥重要作用。较高的乙酸与丁酸比率与结肠病理增加有关。腹腔内丁酸盐缺乏与粘膜萎缩、细胞凋亡和炎症有关，这可通过丁酸盐滴注逆转。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会降低肠道中丁酸盐的比例，继发于非生理性的醋酸盐比例升高，而维持生理性的SCFA比例将预防和/或恢复受损的肠道完整性和早期ALD的进展。为了验证我们的假设，我们将使用慢性重度乙醇喂养方案（会诱发脂肪性肝炎）和慢性低剂量乙醇与四氯化碳喂养方案（乙醇喂养会增强肝纤维化）。我们将测试SCFA比例在这些模型中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。

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.