Human Milk Oligosaccharides for Prevention of Alcohol-Associated Liver Disease

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 肝炎是一种发病率和死亡率都很高的急慢性疾病。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 这表明酒精相关性肝病是一种由肠道生物失调引起的疾病。这个机制是如何 微生物区系对酒精相关性肝病的贡献在很大程度上是未知的。我们实验室的结果 提示细菌微生物群的改变有助于酒精性肝病的发展。 我们观察到粪便中细胞溶血素阳性的粪肠球菌数量显著增加。 临床前加重酒精性肝病的酒精性肝炎患者的样本 模特们。长期饮酒是如何导致肠道细胞溶素阳性粪肠球菌增加的 为人所知。此行政补充应用程序将使用人乳低聚糖(HMO)作为 预防酒精相关性肝病的膳食补充剂。我们假设更高的 酒精使用障碍患者肠道中粪肠球菌的数量通过以下方式促进 酒精引起的肠上皮细胞糖基化改变。我们预测，世界经济的变化 饮食中补充HMOS可以补偿肠道糖萼的损伤。通过建议的 我们将研究HMOS作为肠道粪肠球菌重要耐药因子的作用 殖民主义。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E。 粪便和预防小鼠酒精性肝病(特定目的)。我们的研究将会有新意 对肠道微生物区系对酒精相关肝病的贡献的洞察，并将发现 针对这些疾病的创新预防战略。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)，并可从多种不同的供应品中获得，网址为 规模大、成本低。

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.