The Role of the Intestinal Mycobiome in Alcoholic Liver Disease

肠道菌群在酒精性肝病中的作用

• 批准号: 9900694
• 负责人: Bernd G. Schnabl
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900694
• 关键词: Affect; Alcohol abuse; Alcohol dependence; Alcoholic Liver Diseases; Alcoholism; Alcohols; Animal Model; Antifungal Agents; Bacteria; Belgium; Blood Circulation; California; Candida albicans; Chronic; Collaborations; Data; Developed Countries; Development; Disease; Disease model; Endotoxins; Etiology; Experimental Animal Model; Functional disorder; Germ-Free; Goals; Health; Hepatic; Human; Immune system; Inflammation; Inflammatory; Infrastructure; Institutes; Interleukin-1 beta; International; Intervention; Intestinal permeability; Intestines; Kupffer Cells; Laboratories; Lead; Leaky Gut; Ligation; Lipopolysaccharides; Liver; Liver diseases; Mediating; Medical; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Pathogenesis; Patients; Pharmacology; Population; Pre-Clinical Model; Preventive Intervention; Principal Investigator; Probiotics; Publications; Research; Research Personnel; Role; Saccharomyces; Severity of illness; Supplementation; Testing; Therapeutic Intervention; United States; Universities; University Hospitals; Virulence Factors; Virus; bacteriome; base; beta-Glucans; cohort; cytokine; dectin 1; deep sequencing; design; dysbiosis; early onset; feeding; fungus; gut microbiome; gut-liver axis; innovation; insight; intestinal barrier; liver inflammation; microbial; microbiome research; microbiota; mortality; mouse model; mycobiome; new therapeutic target; novel; pre-clinical; prevent; probiotic supplementation; receptor

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.

项目概要 与酒精相关的健康问题是工业化国家的主要医疗负担。患者患有 酒精性肝病表现出肠道细菌失调和肠道通透性增加。疾病 严重程度与易位细菌产物的全身水平相关。虽然有相当大的 在理解宿主和肠道细菌之间的相互作用、肠道的作用方面取得了进展 酒精性肝病中的真菌微生物组（也称为真菌组）尚未得到研究。结果 Schnabl、Stärkel 和 Fouts 实验室的一项国际合作表明，定量 肠道真菌组的变化和真菌产物的易位发生在小鼠模型中 酒精性肝病，而深度测序表明患有酒精性肝病的患者存在肠道真菌失调 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 使用益生菌布拉氏酵母菌的功能可改善实验性酒精性肝病。这 这项拟议的合作研究应用的中心假设涉及干扰 肠道真菌组作为肝脏和全身调节的重要病因 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，促进肠道质和量的变化 真菌组。真菌产物如β-葡聚糖易位至门静脉循环和肝脏，并引起 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措施， 在酒精肝临床前小鼠模型中补充益生菌和转基因小鼠 疾病（目标 1）。我们将描述酒精滥用、轻度和酒精滥用患者的肠道真菌组特征。 进行性酒精性肝病。我们预测易位的真菌产物与 全身性和肝脏炎症，与肝脏疾病的程度有关（目标2）。我们相信这些研究 将为酒精介导的肠道菌群变化提供重要的见解，从而导致 真菌易位。最终，这种方法可能会为患有此病的患者带来新的治疗靶点 酒精性肝病。