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: 8319636
• 负责人: Jasmohan S Bajaj
• 金额: $ 35.29万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319636
• 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）是与酒精有关的死亡和残疾的主要原因。肝性脑病（HE）是ALD的严重并发症，其特征是多种神经认知功能障碍。 HE的发病机理是由肠道微生物衍生的因素，对这些因素的宿主反应，这些因素对肝功能的影响，潜在的肝病的严重程度和Portasystysic分类的。在ALD中，酒精对认知功能的直接影响及其对驱动HE的其他因素的直接影响增加了另一层复杂性。因此，肠道 - 脑轴代表一个复杂的系统，其在ALD中的扰动在ALD的Genesis中起着核心作用。不幸的是，在他和ALD中，大多数文献都集中在末端，而不是将它们视为复杂的生物系统。因此，尚未充分探索肠道菌群，肠，肝脏和大脑之间相互作用的影响。我们所知的差距阻碍了对HE的肠道肠道，肝脏和脑损伤机制的研究。在这项提议中，我们将通过测试中心假设来解决这种未满足的需求，即：酒精性肝硬化患者的肠道菌群种群和功能与炎性的环境和内毒素血症和内毒素血症和相关的脑功能和肝功能不全的人相关，与那些没有饮酒的人相比，我们的脑功能和肝疗法的变化是特定的。我们将在饮酒中进行特定的关系。与使用系统生物学方法相比，在肠道菌群功能和种群中，与非酒精性肝硬化的患者相比，酒精性肝硬化和肝脑病患者的认知影响相比。由于非酒精性脂肪肝病（NAFLD），将与患有ALD和肝硬化的受试者（有或没有HE）（有或没有HE）的受试者（有或没有HE）。将在每个患者中研究现象，微生物组，代谢组和元转录组。该现象的特征是使用酒精，肝硬化严重程度，HE的存在，认知功能（心理测试，脑MR光谱法（MRS）和扩散张量成像）以及全身性炎症状态（内毒素和内皮功能障碍）。肠道微生物组将使用粪便和结肠粘膜的长度异质性PCR和多标记的Pyrosequencing（MTP）分析。将使用尿液和血清MRS研究代谢组，并将使用深MTPS测定肠道菌群的荟萃转录组或功能能力。最终的系统生物学分析将证明他和ALD之间的关键联系将描述可能构成未来试验重点的特定目标。与NAFLD相比，它还将定义ALD中的HE发病机理的区别，而NAFLD将使在这些发散疾病中发育的机械差异。研究人员非常适合进行这些研究，因为他们的专业知识，受试者的可用性和环境。 公共卫生相关性：喝酒的患者会伤害他们的肝脏，大脑以及改变肠子中的细菌，所有这些都会在退出饮酒后很长时间会影响他们的生活质量和生存。该提案将研究肠道细菌的变化是否可以通过将曾经喝酒的患者与不喝酒的患者进行比较，以解释酒精对大脑以及整个身体的影响。结果将有助于我们找到新的治疗目标，以防止酒精对肠子，肝脏和大脑的有害影响

项目成果

TAB3 O-GlcNAcylation promotes metastasis of triple negative breast cancer.

TAB3 O-GlcNAc 酰化促进三阴性乳腺癌转移

• DOI: 10.18632/oncotarget.8182
• 发表时间: 2016-04-19
• 期刊: Oncotarget
• 作者: Tao T;He Z;Shao Z;Lu H
• 通讯作者: Lu H

Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: implications for the gut-liver-brain axis.

• DOI: 10.1007/s11011-014-9507-6
• 发表时间: 2014-12
• 期刊: METABOLIC BRAIN DISEASE
• 影响因子: 3.6
• 作者: Ahluwalia, Vishwadeep;Wade, James B.;Heuman, Douglas M.;Hammeke, Thomas A.;Sanyal, Arun J.;Sterling, Richard K.;Stravitz, R. Todd;Luketic, Velimir;Siddiqui, Mohammad S.;Puri, Puneet;Fuchs, Michael;Lennon, Micheal J.;Kraft, Kenneth A.;Gilles, HoChong;White, Melanie B.;Noble, Nicole A.;Bajaj, Jasmohan S.
• 通讯作者: Bajaj, Jasmohan S.

Effects of obstructive sleep apnea on sleep quality, cognition, and driving performance in patients with cirrhosis.

• DOI: 10.1016/j.cgh.2014.08.028
• 发表时间: 2015-02
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Bajaj JS;Thacker LR;Leszczyszyn D;Taylor SA;Heuman DM;Raman S;Sterling RK;Siddiqui MS;Stravitz RT;Sanyal AJ;Puri P;Luketic V;Matherly S;Fuchs M;White MB;Noble NA;Unser AB;Wade JB
• 通讯作者: Wade JB

Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.

• DOI: 10.1371/journal.pone.0060042
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bajaj JS;Heuman DM;Sanyal AJ;Hylemon PB;Sterling RK;Stravitz RT;Fuchs M;Ridlon JM;Daita K;Monteith P;Noble NA;White MB;Fisher A;Sikaroodi M;Rangwala H;Gillevet PM
• 通讯作者: Gillevet PM

Modified-orientation log to assess hepatic encephalopathy.

• DOI: 10.1111/j.1365-2036.2012.05038.x
• 发表时间: 2012-04
• 期刊: Alimentary pharmacology & therapeutics
• 影响因子: 7.6
• 作者: Salam M;Matherly S;Farooq IS;Stravitz RT;Sterling RK;Sanyal AJ;Gibson DP;Wade JB;Thacker LR;Heuman DM;Fuchs M;Puri P;Luketic V;Bickston SJ;Bajaj JS
• 通讯作者: Bajaj JS