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退伍军人管理局卫生系统发病和死亡的主要原因之一。然而，尽管有多项预防和治疗酗酒的计划，但很大一部分受影响的退伍军人仍然饮酒，即使在肝硬化的情况下也是如此。这可能会导致巨大的负担，这种负担源于不受控制的炎症环境和细菌易位导致的内毒素血症，从而导致感染、多器官衰竭和死亡。这些患者不适合戒酒药物治疗，通常不依从治疗，并且由于持续饮酒而无法进行肝移植。因此，预防这种不受控制的炎症和细菌移位至关重要。然而，这些背后的确切机制尚不清楚，这是我们知识上的一个重大差距。胆汁酸 (BA) 和肠道微生物群是肠道环境的关键组成部分，它们的相互作用会影响细菌移位和炎症。我们的小组致力于利用独立于培养的分析、炎症及其 BA 的调节，特别是肝硬化中膜不稳定的继发性 BA 的调节，来描述微生物群的作用。我们还发现，主动饮酒的肝硬化患者粪便继发性 BA 和肠道炎症细胞因子的表达显着增加，可能介导肠道损伤并加剧这些患者的炎症。因此，在肠道菌群改变或菌群失调的背景下，研究继发性胆汁酸在肠道和全身炎症发病机制中的作用，在主动饮酒的肝硬化患者与戒酒性酒精性肝硬化患者和伴有非酒精性肝病的肝硬化患者中进行比较，对于描述肠道环境在肝病进展中的作用至关重要。我们的中心假设：肝硬化患者，尤其是持续饮酒的酒精性肝硬化患者， 由于与肠道微生物群改变相关的次级胆汁酸增加，导致肠道和全身炎症增强。这一中心假设将通过以下两个具体目标进行检验： 具体目标 1：使用系统生物学方法，与戒酒性酒精性肝硬化和非酒精性肝硬化患者相比，确定次级胆汁酸对持续酗酒的肝硬化患者的全身和肠道炎症、肠道微生物组和内毒素血症的影响。我们将在 100 名受试者中使用系统生物学方法，研究 BA 与十二指肠、回肠、结肠和粪便来源的微生物组与年龄和肝硬化严重程度匹配的主动饮酒肝硬化患者与戒酒性肝硬化患者、伴有 NAFLD 的肝硬化患者和健康对照者的全身和肠壁炎症的相互作用。具体目标 2：在酒精性肝硬化患者粪便定植后的无菌小鼠模型中，确定胆汁酸和肠道微生物群在肠道和全身炎症增加、内毒素血症和细菌易位发病机制中的作用。我们将利用无菌小鼠来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）不进行干预2）仅喂食脱氧胆酸3）用健康人粪便定植4）用酒精性肝硬化粪便定植。定植后将评估每组的肠道和全身炎症、内毒素血症、BA 谱（血清、胆囊、肝脏、粪便、肠道内容物）和微生物组变化（第 3-4 组）并进行组间比较。这些研究将提供一个新颖的综合平台，利用尖端的转化和系统生物学方法，研究次级胆汁酸和肠道微生物群在所有肝硬化患者肠道和全身炎症发展中的作用。我们期望该提案的结果能够增加我们对开发有针对性的治疗方法的洞察力，从而造福于服务不足的退伍军人群体。