Microbiome and intestinal innate immune response in alcoholic liver disease

描述(申请人提供)：酒精相关的健康问题是工业化国家的主要医疗负担。酒精性肝病以脂肪变性为特征，可发展为酒精性肝炎、纤维化或肝硬变。酒精性肝病患者表现为肠道细菌过度生长和生物失调。他们还表现出肠道通透性的增加，疾病的严重程度与全身细菌产品的水平有关。虽然实验性酒精性肝病依赖于肠道细菌产物，但酒精如何破坏粘膜屏障并调节肠道微生物群的变化尚不清楚。我们实验室的结果表明，肠道微生物组的质和量变化是通过抑制粘膜固有免疫系统，特别是抑制抗菌分子，如再生胰岛衍生的3-伽马(Reg3g)来促进的。抗菌分子表达的减少打开了一个空间利基，使某些具有致病活性的细菌能够生长，增强了细菌的易位。这一应用的重点是进一步表征酒精、肠道固有免疫系统和肠道微生物区系变化之间的关系。我们的实验方法是使用小鼠灌胃酒精的模型来研究抗菌蛋白对与肝病相关的肠道生物失调和细菌过度生长的贡献(目标1)。然后我们将评估微生物组变化的后果及其对细菌易位的贡献。重点将放在酒精喂养后诱导的细菌物种Akkermansia visiniPhila上。我们将测试新的概念，即粘液阿克曼氏菌通过降解肠道粘液层促进细菌易位(目标2)。然后，我们将通过使用益生元改变肠道营养的可利用性来控制酒精引起的微生物失调。将使用系统生物学方法以及新的和强大的焦磷酸测序方法来监测服用益生元后宿主转录组和肠道微生物组的变化(目标3)。我们相信，这些研究将为酒精介导的肠道固有免疫系统的变化提供重要的见解，这些变化导致肠道微生物群和细菌易位的变化。最终，这种方法可能会为酒精性肝病患者带来新的治疗目标。

DESCRIPTION (provided by applicant): Alcohol associated health problems are a major medical burden in industrialized countries. Alcoholic liver disease is characterized by steatosis and may progress to alcoholic hepatitis, fibrosis, or cirrhosis. Patients with alcoholic liver disease show intestinal bacterial overgrowth and dysbiosis. They also demonstrate increased intestinal permeability, and disease severity correlates with systemic levels of bacterial products. Although experimental alcoholic liver disease is dependent on gut derived bacterial products, yet it is unknown how alcohol disrupts the mucosal barrier and mediates changes in the enteric microbiome. Results from our laboratory suggest that qualitative and quantitative changes in the intestinal microbiome are facilitated by suppression of the mucosal innate immune system and in particular of antimicrobial molecules such as regenerating-islet derived 3-gamma (Reg3g). Reduced expression of antimicrobial molecules opens up a spatial niche that enables the growth of certain bacterial strains with pathogenic activity enhancing bacterial translocation. The focus of this application is to further characterize the relationship between alcohol, the intestinal innate immune system and changes in the intestinal microflora. Our experimental approach is to use a mouse model of intragastric alcohol feeding to investigate the contribution of antimicrobial proteins to intestinal dysbiosis and bacterial overgrowth associated with liver disease (Aim 1). We will then assess the consequences of microbiome changes and their contribution to bacterial translocation. The focus will be on the bacterial species Akkermansia muciniphila that is induced following alcohol feeding. We will test the new concept that Akkermansia muciniphila facilitates bacterial translocation by degrading the intestinal mucus layer (Aim 2). We will then manipulate alcohol-induced dysbiosis by altering enteral nutrient availability using prebiotics. A system biology approach with new and powerful methods for pyrosequencing will be used for monitoring changes in the host transcriptome and the enteric microbiome, following administration of prebiotics (Aim 3). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal innate immune system that result in changes in the intestinal microbiome and bacterial translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic liver disease.