Microbiome and intestinal innate immune response in alcoholic liver disease

项目摘要 酗酒和与酒精有关的疾病是工业化国家的主要医疗负担。慢性 酒精中毒与肠道微生物群的改变、肠道通透性的增加以及 细菌产物的全身性水平升高。我们已经证明了数量(过度增长)和质量 慢性酒精摄入模型小鼠肠道微生物区系的非生理性变化。一个坚强的人 肠源性细菌产物与酒精性肝病的进展存在相关性 动物模型，然而促进肠道生物失调发生的因素尚不清楚。此外，如何 除了增加肠道通透性外，生物失调还导致酒精性肝病，这一点也尚不清楚。 我们实验室的结果表明，抑制胃酸分泌和抑制肠道 再生胰岛来源的抗菌蛋白(REG)-3b和Reg3g在生物失调和肝病中的作用 在小鼠长期喂食乙醇后。此外，生物失调导致肠道胆汁酸的去结合。 在近端的小肠中。去结合胆汁酸在体内通过非离子扩散迅速吸收 空肠，少量的结合胆汁酸到达末端回肠，这破坏了 肠-肝循环，导致肝脏胆汁酸合成增加。更大的胆汁酸池有助于 导致更多的肝细胞损伤和酒精性肝病。这个应用程序的重点是表征因素 促进微生物区系的变化，并调查慢性肝病后生物失调如何影响肝病 酒精管理。我们假设胃酸抑制和酒精介导的抑制 抗菌剂Reg3凝集素调节肠道微生物区系。生物失调反过来扰乱肠道和肝脏 促进胆汁酸循环，增加总胆汁酸池，从而加强酒精所致的肝损伤。 我们的实验方法是使用慢性酒精喂养的小鼠模型来研究胃的作用 酸在引起肠道生物失调和肝病中的作用(目标1)。我们还将评估以下项目的职能贡献 抗菌蛋白Reg3b和Reg3g对微生物区系组成变化、细菌易位的影响 和酒精性肝病(目标2)。然后我们将确定非生物微生物群变化的后果。 重点关注胆汁酸代谢(目标3)。我们相信，这些研究将为我们提供对 微生物区系及其代谢产物对酒精性肝病的贡献。新战略将演变为 预防或改善患者的酒精性肝病。

Project Summary Alcohol abuse and alcohol-related diseases are a major medical burden in industrialized countries. Chronic alcoholism is associated with changes in the intestinal microbiome, increases in intestinal permeability, and elevated systemic levels of bacterial products. We have demonstrated quantitative (overgrowth) and qualitative dysbiotic changes in the intestinal microbiota in mouse models of chronic alcohol administration. A strong association exists between gut-derived bacterial products and progression of alcoholic liver diseases in several animal models, yet factors facilitating the onset of intestinal dysbiosis are unknown. Furthermore, how dysbiosis contributes to alcoholic liver disease beyond increasing intestinal permeability is also not known. Results from our laboratory suggest that suppression of gastric acid secretion and inhibition of the intestinal antimicrobial proteins regenerating-islet derived (Reg)-3b and Reg3g contribute to dysbiosis and liver disease following chronic ethanol feeding in mice. Furthermore, dysbiosis leads to deconjugation of intestinal bile acids in the proximal small intestine. Deconjugated bile acids are rapidly absorbed by nonionic diffusion in the jejunum, and a smaller amount of conjugated bile acids reaches the terminal ileum, which disrupts the enterohepatic circulation and results in increased hepatic bile acid synthesis. A larger bile acid pool contributes to more hepatocyte damage and alcoholic liver disease. The focus of this application is to characterize factors contributing to changes in the microbiota and to investigate how dysbiosis affects liver disease after chronic alcohol administration. We hypothesize that gastric acid suppression and alcohol-mediated inhibition of the antimicrobial Reg3 lectins modulate the intestinal microbiota. Dysbiosis in turn disrupts enterohepatic circulation of bile acids and increases the total bile acid pool, which enhances alcohol-induced liver damage. Our experimental approach is to use mouse models of chronic alcohol feeding to investigate the role of gastric acid in inducing intestinal dysbiosis and liver disease (Aim 1). We will also assess the functional contribution of the antimicrobial proteins Reg3b and Reg3g to changes in the microbiota composition, bacterial translocation and alcoholic liver disease (Aim 2). We will then determine the consequences of dysbiotic microbiome changes by focusing on bile acid metabolism (Aim 3). We believe these studies will provide novel insights into the contribution of the microbiota and its metabolites to alcoholic liver disease. New strategies will evolve to prevent or ameliorate alcoholic liver disease in patients.