Microbiome as therapeutic target in alcoholic hepatitis

项目摘要 酒精相关的健康问题是工业化国家的主要医疗负担。酒精 肝炎（AH）是一种独特急性慢性疾病，具有显著的发病率和死亡率。患者 酒精性肝炎表现为肠道生态失调和肠道通透性增加。最近的证据 表明AH是肠道生态失调驱动的疾病。微生物群如何促进AH的机制 基本上是未知的。我们实验室的结果表明， 导致酒精性肝病的发展。我们观察到， 来自AH患者的粪便样本中的粪肠球菌，其加重了 临床前模型。虽然肠道微生物组由细菌、真菌、噬菌体和 尽管酒精性肝病的研究主要集中在病毒与酒精性肝病的相互作用上， 宿主和细菌之间的联系我们证明了肠道真菌中与酒精相关的成分变化， AH患者中真菌多样性降低和白色念珠菌过度生长的人群。程度 暴露于真菌产物如β-葡聚糖与肝硬化患者的死亡率相关， 酗酒我们已经产生了一个可测试的中心假设，这一拟议的合作研究 应用，涉及肠道细菌，噬菌体和真菌的干扰作为重要的 AH发生的病因学因素。我们预测，生态失调和易位的程度 微生物产物与全身和肝脏炎症水平以及AH严重程度相关。 通过拟议的研究，我们将表征AH患者的肠道噬菌体和细菌。 为了实现这一目标，我们将使用裂解噬菌体来减少肠道粪肠球菌并改善 人源化AH模型中的肝脏疾病（目的1）。我们将描述患者的肠道菌群 与AH。用抗真菌药或补充益生菌减少肠道真菌过度生长 布拉酵母菌将在人源化AH模型中改善肝脏疾病（目的2）。我们相信这些 研究将为肠道微生物组对AH的贡献提供重要见解。最终这 这种方法将为酒精性肝炎患者带来新的治疗方法。

Project Summary Alcohol associated health problems are a major medical burden in industrialized countries. Alcoholic hepatitis (AH) is a distinct acute on chronic disease with significant morbidity and mortality. Patients with alcoholic hepatitis show intestinal dysbiosis and increased intestinal permeability. Recent evidence suggests that AH is a gut dysbiosis driven disease. The mechanism of how the microbiota contributes to AH is largely unknown. Results from our laboratories suggest that alterations in the bacterial microbiome contribute to the development of alcoholic liver disease. We observed significantly greater numbers of Enterococcus faecalis in fecal samples from AH patients, which exacerbates alcoholic liver disease in preclinical models. Although the intestinal microbiome consists of bacteria, fungi, bacteriophages and viruses, research in the field of alcoholic liver disease has almost exclusively focused on the interaction between the host and bacteria. We demonstrate alcohol-associated compositional changes in gut fungal populations with reduced fungal diversity and overgrowth of Candida albicans in AH patients. The degree of exposure to fungal products such as β-glucan correlates with mortality in patients with cirrhosis due to alcohol abuse. We have generated a testable central hypothesis of this proposed collaborative research application that implicates disturbances in intestinal bacteria, bacteriophages and fungi as important etiological factors for the development of AH. We predict that the degree of dysbiosis and translocated microbial products correlate with levels of systemic and hepatic inflammation, and with AH severity. Through the proposed study we will characterize gut bacteriophages and bacteria in patients with AH. Towards this goal, we will use lytic bacteriophages to reduce intestinal Enterococcus faecalis and improve liver disease in a humanized AH model (Aim 1). We will characterize the intestinal mycobiome in patients with AH. Reducing intestinal fungal overgrowth with antifungals or supplementation with probiotic Saccharomyces boulardii will ameliorate liver disease in a humanized AH model (Aim 2). We believe these studies will provide important insights into the contribution of the intestinal microbiome to AH. Eventually this approach will lead to new therapeutics for patients with alcoholic hepatitis.