Microbiome as therapeutic target in alcoholic hepatitis

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。酗酒者 肝炎(AH)是一种发病率和死亡率均较高的急慢性疾病。患有疾病的患者 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 提示AH是一种由肠道生物失调引起的疾病。微生物区系对湿润烧伤的作用机制 在很大程度上是未知的。我们实验室的结果表明，细菌微生物群的变化 促进酒精性肝病的发展。我们观察到明显更多的 从AH患者的粪便样本中检出粪肠球菌，这加剧了 临床前模型。虽然肠道微生物群由细菌、真菌、噬菌体和 病毒，在酒精性肝病领域的研究几乎完全集中在相互作用上 在宿主和细菌之间。我们展示了与酒精相关的肠道真菌的成分变化 AH患者中真菌多样性降低和白色念珠菌过度生长的群体。的程度 接触β-葡聚糖等真菌产品与因以下原因而导致的肝硬变患者的死亡率相关 酗酒。我们已经为这项拟议的合作研究生成了一个可检验的中心假设 对肠道细菌、噬菌体和真菌具有重要干扰作用的应用 急性酒精性脑病发生的病因。我们预测生物失调和移位的程度 微生物产物与全身和肝脏炎症水平以及急性肝炎的严重程度相关。 通过这项拟议的研究，我们将确定急性肝炎患者的肠道噬菌体和细菌的特征。 为了实现这一目标，我们将使用裂解噬菌体减少肠道粪肠球菌，并改进 人源化急性肝炎模型中的肝病(目标1)。我们将描述患者肠道真菌菌群的特征。 和阿赫。使用抗真菌药物或添加益生菌减少肠道真菌过度生长 布氏酵母菌将在人源化的AH模型中改善肝脏疾病(目标2)。我们相信这些 研究将对肠道微生物群在急性胰腺炎中的作用提供重要的见解。最终这就是 该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.