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一个主要医疗负担。慢性 酒精中毒与肠道微生物组的变化，肠道通透性的增加， 细菌产物的全身水平升高。我们已经证明了定量（过度增长）和定性 长期酒精给药小鼠模型中肠道微生物群的生态失调变化。一个强大 肠源性细菌产物与酒精性肝病进展之间存在关联， 动物模型，但促进肠道生态失调的发病因素是未知的。此外，如何 除了增加肠渗透性之外，生态失调对酒精性肝病的贡献也是未知的。 我们实验室的结果表明，抑制胃酸分泌和抑制肠 再生胰岛衍生的抗菌蛋白（Reg）-3b和Reg 3g有助于生态失调和肝脏疾病 在小鼠慢性乙醇喂养后。此外，生态失调导致肠道胆汁酸的解结合 在小肠近端解结合胆汁酸通过非离子扩散在 空肠，和少量的结合胆汁酸到达回肠末端，这破坏了 肠肝循环，导致肝胆汁酸合成增加。一个更大的胆汁酸池有助于 更多的肝细胞损伤和酒精性肝病。此应用程序的重点是表征因素 有助于微生物群的变化，并研究慢性肝病后生态失调如何影响肝病。 酒精管理我们假设胃酸抑制和酒精介导的抑制 抗微生物Reg 3凝集素调节肠道微生物群。生态失调反过来破坏了肝肠 胆汁酸的循环和增加总胆汁酸池，这增强了酒精引起的肝损伤。 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， 酸诱导肠道生态失调和肝脏疾病（目的1）。我们还将评估 抗微生物蛋白Reg 3b和Reg 3g与微生物群组成、细菌移位 酒精性肝病（Aim 2）然后我们将确定生态失调的微生物组变化的后果 通过关注胆汁酸代谢（目标3）。我们相信，这些研究将提供新的见解， 微生物群及其代谢产物对酒精性肝病的贡献。新的战略将演变为 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.