The role of pathobionts in alcoholic liver disease

病原体在酒精性肝病中的作用

• 批准号: 10363227
• 负责人: Bernd G. Schnabl
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363227
• 关键词: Affect; Alcohol abuse; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholism; Alcohols; Bacteria; Bacteriophages; Cessation of life; Chronic; Clinical; Cytolysins; Data; Development; Disease; Disease model; Endotoxins; Enterococcus; Enterococcus faecalis; Escherichia; Escherichia coli; Etiology; Exotoxins; Experimental Models; Feces; Genes; Genome; Germ-Free; Gnotobiotic; Grant; Growth; Health; Hepatocyte; Intervention; Intestinal permeability; Intestines; Klebsiella; Kupffer Cells; Laboratories; Lipopolysaccharides; Liver Cirrhosis; Liver diseases; Mediating; Medical; Molecular; Morbidity - disease rate; Mus; Nature; Outcome; Patients; Persons; Phagocytosis; Play; Polysialic Acid; Pre-Clinical Model; Publications; Research; Role; Severity of illness; Shigella; Testing; Translating; United States; Veterans; Virulence; Virulence Factors; Yersinia; alcohol use disorder; capsule; dysbiosis; gut bacteria; gut metagenome; gut microbiota; humanized mouse; improved; in vivo; innovation; insight; liver inflammation; liver injury; metagenome; metagenomic sequencing; microbial products; microbiome; microbiome research; microbiota; mortality; non-alcoholic; novel; novel strategies; pathobiont; prevent; virulence gene

Alcohol use disorder and alcohol-related liver disease are a major cause of morbidity and mortality among Veterans. Chronic alcoholism is associated with changes in the intestinal microbiota, increased intestinal permeability, and elevated systemic levels of bacterial products. Results from our laboratory indicate that intestinal pathobionts contribute to alcohol-related liver disease. Using an unbiased approach by metagenomic sequencing we found significantly more virulence factors in fecal metagenomes from patients with alcoholic hepatitis than patients with alcohol use disorder or non-alcoholic controls. The presence of the virulence factor kpsM encoded in the genome of Escherichia coli (E. coli), is independently associated with mortality in patients with alcoholic hepatitis. E. coli kpsM is involved in the synthesis and expression of the polysialic acid capsule. Our preliminary data further shows that E. coli kpsM escapes phagocytosis by Kupffer cells. A subsequent increase in hepatic inflammation contributes to the development of ethanol-induced liver disease. This is supported by additional data demonstrating that colonization of gnotobiotic mice with feces from a patient with alcoholic hepatitis positive for E. coli kpsM exacerbates ethanol-induced liver disease. We hypothesize that pathobiontic kpsM-positive E. coli are an important etiological factor in the modulation of hepatic inflammation and the development of alcohol-related liver disease. Our experimental approach is to correlate specific virulence-related genes in the gut metagenomes with clinical outcomes of Veterans with alcohol-related liver disease (Aim 1). We will investigate the molecular mechanism of how kpsM-positive E. coli contribute to alcohol-related liver disease in vivo and in cultured liver cells (Aim 2). Using a precision-microbiome approach, we will test the hypothesis that targeted manipulation of alcohol-associated dysbiosis can ameliorate ethanol- induced liver disease (Aim 3). We believe these studies will provide novel insights into the contribution of the microbiota to alcohol-related liver disease. Innovative and novel strategies will be developed to prevent or ameliorate alcohol-related liver disease in Veterans.

酒精使用障碍和酒精相关性肝病是糖尿病患者发病和死亡的主要原因。 老兵慢性酒精中毒与肠道微生物群的变化有关， 渗透性和细菌产物的全身水平升高。我们实验室的结果表明， 肠道致病菌导致酒精相关的肝病。使用宏基因组的无偏方法 我们在酒精中毒患者的粪便宏基因组中发现了明显更多的毒力因子。 酒精使用障碍患者或非酒精对照组。毒力因子的存在 kpsM编码于大肠杆菌（Escherichia coli，E.大肠杆菌），与患者的死亡率独立相关 酒精性肝炎E. coli kpsM参与了聚唾液酸囊的合成和表达。 我们的初步数据进一步表明，E. coli kpsM逃避枯否细胞的吞噬作用。随后的 肝脏炎症的增加会导致乙醇诱导的肝脏疾病的发生。这是 得到了额外数据的支持，这些数据表明，用来自患有结肠癌的患者的粪便定殖非细菌性小鼠， 酒精性肝炎E.大肠杆菌kpsM可加重乙醇诱导的肝病。我们假设 致病性kpsM阳性E.大肠杆菌是肝脏炎症调节的重要致病因子 以及酒精相关肝病的发展。我们的实验方法是将特定的 肠道宏基因组中毒性相关基因与酒精相关性肝病退伍军人的临床结局 疾病（目标1）。我们将探讨kpsM阳性E.大肠杆菌有助于 酒精相关的肝脏疾病在体内和培养的肝细胞（目的2）。使用精确微生物组方法， 我们将检验这一假设，即有针对性地操纵酒精相关的生态失调可以改善乙醇- 肝脏疾病（Aim 3）。我们相信，这些研究将提供新的见解， 微生物群与酒精相关的肝病。将制定创新和新颖的战略，以防止或 改善退伍军人酒精相关的肝病。