Hepatic Encephalopathy in Alcoholic Cirrhosis: A Systems Biology Approach

酒精性肝硬化中的肝性脑病：系统生物学方法

• 批准号: 8150413
• 负责人: Jasmohan S Bajaj
• 金额: $ 34.38万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150413
• 关键词: Activities of Daily Living; Address; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Ammonia; Bacteria; Biological Assay; Brain; Brain Injuries; Cirrhosis; Cognition; Cognitive; Cognitive deficits; Coma; Complex; Complication; Cross-Sectional Studies; Data; Development; Diffusion Magnetic Resonance Imaging; Discrimination; Disease; Endotoxemia; Endotoxins; Environment; Evaluation; Feces; Functional disorder; Future; Gene Expression Profile; Goals; Hepatic; Hepatic Encephalopathy; Heterogeneity; Hospitalization; Immune; Immune response; Impaired cognition; Impairment; Infection; Inflammatory; Intestines; Investigation; Knowledge; Length; Light; Link; Literature; Liver; Liver Cirrhosis; Liver diseases; Magnetic Resonance Spectroscopy; Malnutrition; Mucous Membrane; Organ; Pathogenesis; Patients; Performance; Play; Population; Psychometrics; Quality of life; Research; Research Personnel; Role; Serum; Severities; Signal Transduction; System; Systems Biology; Testing; Toxin; Urine; alcohol effect; alcohol-related death; cognitive function; disability; drinking; gut microflora; microbiome; mortality; non-alcoholic; non-alcoholic fatty liver; phenome; phenomics; prevent; problem drinker; public health relevance

DESCRIPTION (provided by applicant): Alcoholic liver disease and cirrhosis (ALD) is a leading cause of alcohol-related death and disability. Hepatic encephalopathy (HE) is a serious complication of ALD and is characterized by a spectrum of neuro-cognitive dysfunction. The pathogenesis of HE is driven by intestinal microflora-derived factors, the host response to these factors, the impact of these factors on hepatic function, the severity of the underlying liver disease and portasystemic shunting. In ALD, another layer of complexity is added by the direct effects of alcohol on cognitive function and its indirect effects on the other factors that drive HE. Thus, the gut-liver-brain axis represents a complex system and its perturbation in ALD plays a central role in the genesis of HE in ALD. Unfortunately, in both HE and ALD, most of the literature has focused on end-organs rather than consider them a complex biologic system. The impact of the interactions between the intestinal microflora, intestine, liver and the brain in the genesis of HE in ALD has therefore not been fully explored. This gap in our knowledge has hindered the investigation of the mechanisms of alcohol-induced gut, liver and brain injury in the context of HE. In this proposal, we will address this unmet need by testing the central hypothesis that: patients with alcoholic cirrhosis have a specific alteration in their gut flora population and function that is linked with a pro- inflammatory milieu and endotoxemia and associated impaired brain function and hepatic encephalopathy, compared to those who do not have alcoholic cirrhosis.. We will test this hypothesis by the following specific aim: To determine the association between changes in gut microflora function and population and their associated effects on cognition in patients with alcoholic cirrhosis and hepatic encephalopathy compared to those with non-alcoholic cirrhosis using a systems biology approach. Subjects with ALD and cirrhosis (with or without HE) will be compared to those with cirrhosis (with or without HE) due to non- alcoholic fatty liver disease (NAFLD). The phenome, the microbiome, the metabolome and the meta- transcriptome will be studied in each patient. The phenome will be characterized by alcohol use, cirrhosis severity, presence of HE, cognitive function (psychometric tests, brain MR spectroscopy (MRS) and diffusion tensor imaging) and systemic inflammatory state (endotoxin and endothelial dysfunction). The gut microbiome will be analyzed using Length-heterogeneity PCR and Multi-tagged pyrosequencing (MTPS) of stool and colonic mucosa. The metabolome will be studied using urine and serum MRS, and the meta-transcriptome or functional capacity of the gut microflora will be assayed using deep MTPS. The final Systems Biology analysis will demonstrate key linkages between HE and ALD that will delineate specific targets that could form the focus of future trials. It will also define distinctions in the HE pathogenesis in ALD compared to NAFLD that would shed light into the mechanistic differences of HE development in these divergent diseases. The investigators are well suited to perform these studies because of their expertise, availability of subjects and the environment. PUBLIC HEALTH RELEVANCE: Patients who drink alcohol can hurt their liver, brain as well as change the bacteria in their bowels, all of which can affect their quality of life and survival long after they quit drinking. This proposal will study whether change in the bowel bacteria can explain these effects of alcohol on the brain as well as the entire body by comparing patients who used to drink to those who do not drink. The results will help us find newer targets for treatments to prevent these injurious effects of alcohol on the bowels, liver and brain

描述（由申请人提供）：酒精性肝病和肝硬化（ALD）是酒精相关死亡和残疾的主要原因。肝性脑病（HE）是ALD的严重并发症，以一系列神经认知功能障碍为特征。HE的发病机制受肠道微生物源性因素、宿主对这些因素的反应、这些因素对肝功能的影响、潜在肝脏疾病的严重程度和门脉系统分流等因素驱动。在ALD中，酒精对认知功能的直接影响及其对其他驱动HE因素的间接影响增加了另一层复杂性。因此，肠-肝-脑轴代表了一个复杂的系统，其在ALD中的扰动在ALD中HE的发生中起着核心作用。不幸的是，在HE和ALD中，大多数文献都集中在终末器官上，而不是将其视为一个复杂的生物系统。因此，肠道菌群、肠道、肝脏和大脑之间的相互作用在ALD中HE发生中的影响尚未得到充分探讨。这一知识缺口阻碍了我们在HE背景下对酒精诱导的肠道、肝脏和脑损伤机制的研究。在本提案中，我们将通过验证中心假设来解决这一未满足的需求：与没有酒精性肝硬化的患者相比，酒精性肝硬化患者的肠道菌群和功能有特定的改变，这与促炎环境和内毒素血症以及相关的脑功能受损和肝性脑病有关。我们将通过以下具体目的来验证这一假设：使用系统生物学方法，确定与非酒精性肝硬化患者相比，酒精性肝硬化和肝性脑病患者肠道微生物群功能和种群变化之间的关系，以及它们对认知的相关影响。ALD合并肝硬化（伴或不伴HE）的受试者将与由非酒精性脂肪性肝病（NAFLD）引起的肝硬化（伴或不伴HE）受试者进行比较。将对每位患者的表型组、微生物组、代谢组和元转录组进行研究。该表型的特征包括酒精使用、肝硬化严重程度、HE的存在、认知功能（心理测试、脑磁共振波谱（MRS）和弥散张量成像）和全身炎症状态（内毒素和内皮功能障碍）。肠道微生物组将使用长度异质性PCR和粪便和结肠粘膜的多标记焦磷酸测序（MTPS）进行分析。代谢组将通过尿液和血清MRS进行研究，肠道微生物群的meta转录组或功能能力将通过深层MTPS进行分析。最后的系统生物学分析将展示HE和ALD之间的关键联系，这将描绘出可能形成未来试验重点的特定靶点。它还将定义ALD与NAFLD中HE发病机制的区别，从而揭示这些不同疾病中HE发展的机制差异。由于研究人员的专业知识、研究对象的可用性和环境，他们非常适合进行这些研究。