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

基本信息

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
项目类别：
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

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

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项目摘要

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。酒鬼肝炎是对慢性疾病的明显急性，具有明显的发病率和死亡率。患者酒精性肝炎表现出肠道营养不良和肠道通透性的增加。最近的证据表明与酒精相关的肝病是一种肠道营养不良的疾病。如何微生物群有助于与酒精相关的肝病，这在很大程度上尚不清楚。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。我们观察到粪便中的细胞溶酶素阳性肠球菌（E.粪便）酒精性肝炎患者的样本，加剧临床前酒精性肝病型号。慢性酒精的使用如何导致肠中的细胞溶糖蛋白阳性大肠杆菌的增加不是已知。该行政补充剂的应用将使用人奶寡糖（HMO）作为预防酒精相关肝病的饮食补充剂。我们假设更高酒精饮用障碍患者肠中肠道大肠杆菌的数量促进了酒精相关的肠上皮细胞糖囊肿的变化。我们预测肠道糖脂可以通过补充HMO来补偿。通过拟议的研究我们将表征HMO作为肠道肠球菌的重要抗性因子的作用殖民化。为了实现这一目标，我们将使用不同的HMO作为饮食补充剂来减少肠道。粪便中并预防小鼠乙醇诱导的肝病（特定目的）。我们的研究将获得新颖对肠道菌群对酒精相关肝病的贡献的见解，并会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的先例通常被认为是安全的（gras），并从多个不同的供应中获得大规模和低成本。