The Role of the Intestinal Mycobiome in Alcoholic Liver Disease

项目摘要 与酒精相关的健康问题是工业化国家的主要医疗负担。患有疾病的患者 酒精性肝病表现为肠道细菌代谢紊乱和肠道通透性增加。疾病 严重程度与全身移位的细菌产物水平相关。尽管有相当多的 了解宿主与肠道细菌的相互作用、肠道的作用的进展 真菌微生物群(又称霉菌群)在酒精性肝病中的作用尚未见报道。结果 来自Schnabl，Stärkel和Fouts实验室的国际合作表明，量化 肠道真菌菌群的变化和真菌产物的移位在小鼠模型中发生 酒精性肝病，而深层测序显示患者肠道真菌代谢异常 长期酗酒。使用抗真菌药物减少肠道真菌过度生长或恢复肠道屏障 使用益生菌布氏酵母改善实验性酒精性肝病。这个 这一提议的协作研究应用的中心假设暗示了干扰在 肠道真菌群在肝脏和全身调节中的重要致病因素 炎症和酒精性肝病的发展。我们预测长期饮酒会抑制 肠道免疫系统，促进肠道的质和量的变化 真菌菌群。真菌产物，如β-葡聚糖转移到门静脉循环和肝脏，并导致 酒精性肝病的进展。为了实现这一目标，我们将使用药物干预， 益生菌和转基因小鼠在酒精性肝损伤小鼠模型中的应用 疾病(目标1)。我们将描述酒精滥用患者肠道真菌菌群的特征，轻度和 进行性酒精性肝病。我们预测，移位的真菌产物与 全身和肝脏炎症，以及肝脏疾病的程度(目标2)。我们相信这些研究 将为酒精介导的肠道真菌生物群的变化提供重要的见解，这些变化导致 真菌易位。最终，这种方法可能会为慢性阻塞性肺疾病患者带来新的治疗靶点 酒精性肝病。

Project Summary Alcohol associated health problems are a major medical burden in industrialized countries. Patients with alcoholic liver disease show intestinal bacterial dysbiosis and increased intestinal permeability. Disease severity correlates with systemic levels of translocated bacterial products. Although there is considerable progress in understanding the interaction between the host and intestinal bacteria, the role of the intestinal fungal microbiome (also called mycobiome) in alcoholic liver disease has not been investigated. Results from an international collaboration by Schnabl, Stärkel and Fouts laboratories suggest that quantitative changes in the intestinal mycobiome and translocation of fungal products occur in a mouse model of alcoholic liver disease, while deep sequencing demonstrates intestinal fungal dysbiosis in patients with chronic alcohol abuse. Reducing intestinal fungal overgrowth with antifungals or restoring intestinal barrier function using probiotic Saccharomyces boulardii ameliorates experimental alcoholic liver disease. The central hypothesis of this proposed collaborative research application implicates disturbances in the intestinal mycobiome as an important etiological factor in the modulation of hepatic and systemic inflammation, and the development of alcoholic liver disease. We predict that chronic alcohol suppresses the intestinal immune system and facilitates qualitative and quantitative changes in the intestinal mycobiome. Fungal products such as β-glucan translocate to the portal circulation and liver, and cause progression of alcoholic liver disease. Towards this goal, we will use pharmacological interventions, supplementation of probiotics and genetically modified mice in preclinical mouse models of alcoholic liver disease (Aim 1). We will characterize the intestinal mycobiome in patients with alcohol abuse, mild and progressive alcoholic liver disease. We predict that translocated fungal products correlate with levels of systemic and hepatic inflammation, and with the degree of liver disease (Aim 2). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal mycobiome that result in fungal translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic liver disease.