Microbiome as therapeutic target in alcoholic hepatitis

微生物组作为酒精性肝炎的治疗靶点

• 批准号: 10427256
• 负责人: Derrick E Fouts
• 金额: $ 30.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427256
• 关键词: 16S ribosomal RNA sequencing; Acute; Address; Affect; Alcohol abuse; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Antifungal Agents; Attenuated; Bacteria; Bacteriophages; Benign; Binding; Blood Circulation; Candida albicans; Chronic; Chronic Disease; Cirrhosis; Clinical; Clinical Trials; Data; Developed Countries; Development; Disease; Disease Progression; Ecosystem; Enterococcus faecalis; Etiology; Experimental Models; Exposure to; Fatty Liver; Feces; Future; Goals; Health; Intervention; Intervention Studies; Intestinal permeability; Intestines; Kupffer Cells; Laboratories; Life; Liver; Liver diseases; Lytic; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Outcome; Patients; Pattern; Persons; Pharmacology; Population; Pre-Clinical Model; Probiotics; Publications; Research; Role; Saccharomyces; Sampling; Severities; Testing; Therapeutic Intervention; Transplantation; United States; Virus; bacteriome; base; beta-Glucans; design; dysbiosis; fecal microbiome; fecal transplantation; fungal microbiota; fungus; gut dysbiosis; gut microbiome; gut microbiota; improved; innovation; insight; intestinal barrier; liver inflammation; metagenomic sequencing; microbial; microbiome; microbiome research; microbiota; mortality; mycobiome; novel; novel therapeutics; pathogen; preventive intervention; probiotic supplementation; problem drinker; receptor; side effect; systemic inflammatory response; therapeutic target

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.

项目概要 酒精相关的健康问题是工业化国家的主要医疗负担。 肝炎（AH）是一种独特的急性慢性疾病，具有显着的发病率和死亡率。 酒精性肝炎显示肠道菌群失调和肠道通透性增加。 表明 AH 是一种肠道菌群失调驱动的疾病。微生物群如何导致 AH 的机制。 我们实验室的结果表明细菌微生物组的变化在很大程度上是未知的。 我们观察到，酒精性肝病的发病率显着增加。 AH 患者粪便样本中含有粪肠球菌，可加重酒精性肝病 尽管肠道微生物组由细菌、真菌、噬菌体和 病毒，酒精性肝病领域的研究几乎完全集中在相互作用上 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。 接触β-葡聚糖等真菌产品与肝硬化患者的死亡率相关 我们为这项拟议的合作研究提出了一个可检验的中心假设。 涉及肠道细菌、噬菌体和真菌干扰的应用同样重要 我们预测 AH 发生的病因是菌群失调和易位的程度。 微生物产物与全身炎症和肝脏炎症水平以及 AH 严重程度相关。 通过拟议的研究，我们将描述 AH 患者肠道噬菌体和细菌的特征。 为了实现这一目标，我们将使用裂解性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（目标 1）我们将描述患者肠道真菌组的特征。 使用抗真菌药物或补充益生菌减少肠道真菌过度生长。 布拉氏酵母菌将改善人源化 AH 模型中的肝脏疾病（目标 2）。 研究将为了解肠道微生物组对 AH 的贡献提供重要见解。 该方法将为酒精性肝炎患者带来新的治疗方法。

项目成果

The Level of Alcohol Consumption in the Prior Year Does Not Impact Clinical Outcomes in Patients With Alcohol-Associated Hepatitis.

前一年的饮酒水平不会影响酒精相关性肝炎患者的临床结果。

• 发表时间: 2021-10
• 作者: Musto, Jessica A;Eickhoff, Jens;Ventura;Abraldes, Juan G;Bosques;Verna, Elizabeth C;Brown Jr, Robert S;Vargas, Victor;Altamirano, Jose;Caballería, Juan;Shawcross, Debbie;Louvet, Alexandre;Mathurin, Philippe
• 通讯作者: Mathurin, Philippe