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导致人群发病和死亡的主要原因 退伍军人。慢性酒精中毒与肠道微生物群的变化、肠道菌群增加有关。 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 肠道病原体会导致酒精相关的肝病。使用宏基因组的公正方法 通过测序，我们发现酗酒患者粪便宏基因组中的毒力因子显着增加 与酒精使用障碍或非酒精对照患者相比，肝炎的发生率更高。毒力因子的存在 kpsM 编码于大肠杆菌 (E. coli) 基因组中，与患者死亡率独立相关 患有酒精性肝炎。大肠杆菌 kpsM 参与聚唾液酸胶囊的合成和表达。 我们的初步数据进一步表明大肠杆菌 kpsM 逃脱了库普弗细胞的吞噬作用。随后的 肝脏炎症的增加会导致乙醇诱发的肝病的发生。这是 另有数据支持，表明用来自患有患有该病的患者的粪便对无菌小鼠进行定植 大肠杆菌 kpsM 呈阳性的酒精性肝炎会加剧乙醇诱发的肝病。我们假设 致病性 kpsM 阳性大​​肠杆菌是调节肝脏炎症的重要病因 以及酒精相关肝病的发展。我们的实验方法是将特定的 肠道宏基因组中的毒力相关基因与患有酒精相关肝脏的退伍军人的临床结果 疾病（目标 1）。我们将研究 kpsM 阳性大​​肠杆菌如何促进的分子机制 体内和培养的肝细胞中与酒精相关的肝病（目标 2）。使用精密微生物组方法， 我们将检验这样一个假设：有针对性地操纵与酒精相关的生态失调可以改善乙醇- 诱发肝脏疾病（目标 3）。我们相信这些研究将为我们的贡献提供新的见解 微生物群与酒精相关的肝病。将制定创新和新颖的战略来预防或 改善退伍军人与酒精相关的肝病。