Human Milk Oligosaccharides for Prevention of Alcohol-Associated Liver Disease

母乳低聚糖用于预防酒精相关性肝病

• 批准号: 10266673
• 负责人: Derrick E Fouts
• 金额: $ 15.78万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266673
• 关键词: Acute; Administrative Supplement; Affect; Alcohol abuse; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Bacteriophages; Cessation of life; Chronic; Chronic Disease; Cytolysins; Data; Developed Countries; Development; Dietary Supplementation; Disease; Enteral; Enterococcus faecalis; Epithelial Cells; Ethanol; Etiology; Exotoxins; Experimental Models; Fucose; Galactose; Glycocalyx; Glycoproteins; Goals; Health; Hepatocyte; Human Milk; Infant formula; Intestinal Mucosa; Intestinal permeability; Intestines; Laboratories; Liver; Liver diseases; Mediating; Medical; Monitor; Morbidity - disease rate; Mus; Nature; Nutrient; Oligosaccharides; Patients; Polysaccharides; Pre-Clinical Model; Prevention strategy; Preventive; Publications; Publishing; Research; Role; Sampling; Secretor blood group alpha-2-fucosyltransferase; Severity of illness; Steatohepatitis; Surface; Systems Biology; Toxin; United States; alcohol prevention; alcohol use disorder; apical membrane; bacteriome; base; chronic alcohol ingestion; cost; design; dietary supplements; dysbiosis; gut colonization; gut dysbiosis; gut microbiome; gut microbiota; humanized mouse; improved; innovation; insight; intestinal epithelium; liver injury; microbiome research; microbiota; mortality; novel; pathobiont; prevent; resistance factors; transcriptome

Project Summary Alcohol associated health problems are a major medical burden in industrialized countries. Alcoholic hepatitis 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 alcohol-associated liver disease is a gut dysbiosis driven disease. The mechanism of how the microbiota contributes to alcohol-associated liver disease is largely unknown. Results from our laboratory suggest that alterations in the bacterial microbiome contribute to the development of alcoholic liver disease. We observed significantly greater numbers of cytolysin-positive Enterococcus faecalis (E. faecalis) in fecal samples from patients with alcoholic hepatitis, which exacerbates alcoholic liver disease in preclinical models. How chronic alcohol use results in increased cytolysin-positive E. faecalis in the intestine is not known. This Administrative Supplement application will use Human Milk Oligosaccharides (HMOs) as dietary supplement for prevention of alcohol-associated liver disease. We hypothesize that higher numbers of intestinal E. faecalis in the intestine of patients with alcohol use disorder are facilitated by alcohol-associated changes in the glycocalyx of intestinal epithelial cells. We predict that changes in the intestinal glycocalyx can be compensated by dietary supplementation with HMOs. Through the proposed study we will characterize the role of HMOs as important resistance factor for intestinal E. faecalis colonization. Towards this goal, we will use different HMOs as dietary supplements to reduce intestinal E. faecalis and prevent ethanol-induced liver disease in mice (Specific Aim). Our studies will gain novel insights into the contributions of the intestinal microbiota to alcohol-related liver disease, and will find innovative prevention strategies for these diseases. HMOs are ideal supplements, they are safe with a precedent for FDA generally recognized as safe (GRAS) and available from multiple different supplies at large scale and low costs.

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。酗酒者 肝炎是一种明显的急性慢性疾病，具有显着的发病率和死亡率。患者患有 酒精性肝炎表现为肠道菌群失调和肠道通透性增加。最近的证据 表明酒精相关的肝病是一种肠道菌群失调驱动的疾病。其机理是怎样的 微生物群对酒精相关性肝病的影响目前尚不清楚。我们实验室的结果 表明细菌微生物组的改变有助于酒精性肝病的发展。 我们观察到粪便中溶细胞素阳性粪肠球菌（E. faecalis）的数量显着增加 酒精性肝炎患者的样本，在临床前会加剧酒精性肝病 模型。长期饮酒如何导致肠道内溶细胞素阳性粪肠球菌增加，目前尚不清楚 已知。本行政补充申请将使用母乳低聚糖 (HMO) 作为 用于预防酒精相关肝病的膳食补充剂。我们假设更高 酒精使用障碍患者肠道内粪肠球菌的数量通过 酒精相关的肠上皮细胞糖萼变化。我们预测，变化 肠道糖萼可以通过膳食补充 HMO 来补偿。通过提议的 研究中我们将描述 HMO 作为肠道粪肠球菌重要抵抗因子的作用 殖民化。为了实现这一目标，我们将使用不同的 HMO 作为膳食补充剂来减少肠道大肠杆菌。 粪杆菌并预防乙醇引起的小鼠肝病（具体目标）。我们的研究将获得新颖 深入了解肠道微生物群对酒精相关性肝病的影响，并将发现 这些疾病的创新预防策略。 HMO 是理想的补充剂，它们是安全的 FDA 普遍认为安全（GRAS）的先例，并且可以从多个不同的供应商处获得 规模大、成本低。