Bile Acids and Gut Microbiome in the Pathogenesis of Inflammation in Cirrhosis

胆汁酸和肠道微生物组在肝硬化炎症发病机制中的作用

• 批准号: 8994662
• 负责人: Jasmohan S Bajaj
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994662
• 关键词: Abstinence; Affect; Age; Alcohol abuse; Alcoholic Liver Diseases; Alcohols; Animals; Bacteria; Bacterial Translocation; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Cause of Death; Cessation of life; Cirrhosis; Deoxycholic Acid; Development; Endotoxemia; Enterohepatic Circulation; Feces; Future; Gallbladder; Germ-Free; Health system; Hepatic; Human; Immunologic Markers; Individual; Infection; Inflammation; Inflammatory; Inflammatory disease of the intestine; Injury; Intervention; Intestinal Content; Intestines; Knowledge; Lead; Liver; Liver Cirrhosis; Liver diseases; Mediating; Medicine; Membrane; Microbe; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Organ failure; Pathogenesis; Patients; Prevention; Role; Serum; Severities; Systems Biology; Testing; Therapeutic; Transplantation; Underserved Population; Veterans; cost; cytokine; drinking; feeding; gut microbiome; gut microbiota; insight; liver transplantation; microbiome; microbiota; mortality; mouse model; non-alcoholic; non-alcoholic fatty liver; novel; prevent; problem drinker; programs; public health relevance; sobriety; stem; therapy design

DESCRIPTION (provided by applicant): Alcoholic liver disease and cirrhosis are one of the leading causes of morbidity and mortality in the US, as well as in the VA Health System. However, despite several programs to prevent and treat alcohol abuse, a significant proportion of affected Veterans continue to drink, even in the setting of cirrhosis. This can lead to a substantial burden that stems from an unchecked inflammatory milieu and endotoxemia due to bacterial translocation that precipitates infections, multi-organ failure and death. These patients are poor candidates for abstinence pharmacological therapy, are often non-adherent and cannot be offered liver transplant due to their continued drinking. Therefore prevention of this unchecked inflammation and bacterial translocation is critical; however, the exact mechanisms behind these are unclear, which is a major gap in our knowledge. Bile acids (BAs) and gut microbiota are key components of the intestinal milieu, whose interaction impacts bacterial translocation and inflammation. Our group has focused on delineating the role of microbiota, using culture- independent analyses, with inflammation and their modulation by BAs, especially the membrane-destabilizing secondary BAs in cirrhosis. We also discovered that actively drinking cirrhotics have a highly significant increase in fecal secondary BAs and intestinal inflammatory cytokine expression that may mediate intestinal injury and potentiate inflammation in these patients. Therefore, the study of the role of secondary BAs in the pathogenesis of intestinal and systemic inflammation in the context of altered gut microbiota or dysbiosis, in actively drinking cirrhotics compared to abstinent alcoholic cirrhotics and cirrhotics with non-alcoholic liver disease is critical in delineating the role of the intestinal milieu in the progression of liver disease. Our central hypothesis: Patients with cirrhosis, especially alcoholic cirrhotic patients who continue to drink, develop enhanced intestinal and systemic inflammation due to an increase in secondary bile acids associated with altered gut microbiota. This central hypothesis will be tested using these two specific aims: Specific aim 1: To define the effect of secondary bile acids on systemic and gut inflammation, gut microbiome and endotoxemia in cirrhotic patients with continued alcohol abuse compared to abstinent alcoholic cirrhotics and non-alcoholic cirrhotics using a systems biology approach. We will study the interaction of BAs with microbiome of the duodenal, ileal, colonic and fecal origin with systemic and intestinal wall inflammation in age- and cirrhosis-severity matched actively drinking cirrhotics compared to abstinent alcoholic cirrhotics, cirrhotic with NAFLD and healthy controls using a systems biology approach in 100 subjects. Specific Aim 2: To define the role of bile acids and gut microbiota in the pathogenesis of the increased intestinal and systemic inflammation, endotoxemia and bacterial translocation in a germ-free mouse model after colonization with stool from alcoholic cirrhotic patients. We will be utilizing germ-free mice to elucidate the individual contributions of bile acids and microbiota on endotoxemia, inflammation and bacterial translocation. Six groups of germ-free mice will be used: 1) without intervention 2) fed deoxycholic acid alone 3) colonized with healthy human stool 4) colonized with alcoholic cirrhotic stool. Each group will be evaluated for intestinal and systemic inflammation, endotoxemia, BA profile (serum, gallbladder, liver, fecal, intestinal contents) and microbiome changes (Groups 3-4) will be performed after colonization and compared between groups. The studies will provide a novel integrative platform to study the role of secondary bile acids and gut microbiota in the development of intestinal and systemic inflammation in all cirrhotic patients using cutting-edge translational and systems biology approaches. We expect the results of this proposal to increase our insight into the development of focused therapeutic approaches that benefit this underserved population of Veterans.

描述（由申请人提供）： 酒精性肝病和肝硬化是美国以及VA卫生系统中发病率和死亡率的主要原因之一。然而，尽管有几个预防和治疗酗酒的计划，但即使在肝硬化的情况下，也有很大一部分受影响的退伍军人继续喝酒。由于细菌易位，导致感染，多器官衰竭和死亡引起的细菌易位，这可能导致造成不受组织的炎症环境和内毒素血症的重大负担。这些患者是禁欲药物治疗的候选者，通常是不遵守的，由于肝脏的持续饮酒，无法提供肝移植。因此，预防这种不受组织的炎症和细菌易位至关重要。但是，这些背后的确切机制尚不清楚，这是我们所知的主要差距。胆汁酸（BAS）和肠道菌群是肠道环境的关键组成部分，其相互作用会影响细菌易位和炎症。我们的小组的重点是使用培养独立分析来描述微生物群的作用，并通过BAS进行炎症及其调节，尤其是在肝硬化中的膜降低的次级BAS。我们还发现，积极喝肝硬化的粪便继发性碱和肠道炎症细胞因子的表达急剧显着增加，这些表达可能介导这些患者的肠损伤和增强的炎症。因此，研究在肠道微生物群改变或营养不良的情况下，次级BAS在肠道和全身性炎症的发病机理中的作用在积极饮用cirrhotics中，与戒烟的葡萄球菌相比，与非葡萄肝疾病的戒烟相比，非酒精肝疾病的疾病在肠道中的作用至关重要。我们的中心假设：肝硬化患者，尤其是继续喝酒的酒精性肝硬化患者， 由于与肠道菌群改变有关的继发性胆汁酸的增加，导致肠道和全身性炎症增强。该中心假设将使用以下两个特定目的进行检验：具体目的1：与持有的酒精性肝硬化和非葡萄酒cirrocic Cirrhotics相比，持续酗酒的肝硬化患者对持续酗酒患者的次级胆汁酸对全身性和肠道炎症，肠道微生物组和内毒素血症的影响。我们将研究BAS与十二指肠，卵形，结肠和粪便起源的BAS与全身和肠道壁炎症的相互作用，与持有的酒精性ciRRHOTICS相比，年龄和肝硬化 - 严重性的cirrhotics与cirrhotics cirrhotics cirrhotics与Nafld和健康的对照组相比，使用系统的生物学方法进行了100个主题。具体目的2：定义胆汁酸和肠道菌群在肠道和全身性炎症增加的发病机理中的作用，在无菌小鼠模型中与酒精性肝硬化患者的粪便结肠化后，在无菌小鼠模型中的作用。我们将利用无菌小鼠阐明胆汁酸和微生物群对内毒素血症，炎症和细菌易位的个体贡献。将使用六组无菌小鼠：1）在不干预的情况下2）单独喂脱氧胆酸3）用健康的人粪便定居4）用酒精性肝硬化粪便定居。将评估每组的肠道和全身性炎症，内毒素血症，BA谱（血清，胆囊，肝脏，粪便，粪便，肠含量）和微生物组的变化（第3-4组）将在定植后进行并进行比较。这项研究将提供一个新型的综合平台，以研究所有持续转化和系统生物学方法中所有肝硬化患者中二级胆汁酸和肠道菌群在肠道和全身炎症发展中的作用。我们期望这项提案的结果能够提高对重点治疗方法发展的洞察力，从而使这一服务不足的退伍军人人口受益。