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，其特征是一系列神经认知功能障碍。 HE 的发病机制是由肠道菌群衍生因素、宿主对这些因素的反应、这些因素对肝功能的影响、潜在肝病的严重程度和门体分流驱动的。对于 ALD，酒精对认知功能的直接影响及其对导致 HE 的其他因素的间接影响又增加了一层复杂性。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，大多数文献都关注终末器官，而不是将其视为复杂的生物系统。因此，肠道菌群、肠道、肝脏和大脑之间的相互作用对 ALD 中 HE 发生的影响尚未得到充分探索。我们知识上的这一差距阻碍了对 HE 背景下酒精引起的肠道、肝脏和脑损伤机制的研究。在本提案中，我们将通过测试以下中心假设来解决这一未满足的需求：酒精性肝硬化患者的肠道菌群和功能发生了特定的改变，这与促炎环境和内毒素血症以及相关的脑功能和肝功能受损有关。与那些没有酒精性肝硬化的人相比，脑病的发生率更高。我们将通过以下具体目标来检验这一假设：确定肠道菌群功能和人口变化之间的关联及其对健康的相关影响。使用系统生物学方法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的认知能力。将患有 ALD 和肝硬化（伴或不伴 HE）的受试者与由于非酒精性脂肪肝病（NAFLD）而患有肝硬化（伴或不伴 HE）的受试者进行比较。将研究每位患者的表型组、微生物组、代谢组和宏转录组。该现象的特征是饮酒、肝硬化严重程度、HE的存在、认知功能（心理测试、脑部磁共振波谱（MRS）和扩散张量成像）和全身炎症状态（内毒素和内皮功能障碍）。将使用粪便和结肠粘膜的长度异质性 PCR 和多标记焦磷酸测序 (MTPS) 来分析肠道微生物组。将使用尿液和血清 MRS 研究代谢组，并使用深度 MTPS 分析肠道菌群的宏转录组或功能能力。最终的系统生物学分析将证明 HE 和 ALD 之间的关键联系，从而描绘出可能成为未来试验重点的具体目标。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、受试者的可用性和环境，他们非常适合进行这些研究。 公共卫生相关性：饮酒的患者会损害他们的肝脏、大脑，并改变肠道内的细菌，所有这些都会影响他们戒酒后很长一段时间的生活质量和生存率。该提案将通过比较曾经饮酒的患者和不饮酒的患者，研究肠道细菌的变化是否可以解释酒精对大脑和整个身体的这些影响。研究结果将帮助我们找到新的治疗目标，以防止酒精对肠道、肝脏和大脑的这些有害影响

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

LecT-Hepa facilitates estimating treatment outcome during interferon therapy in chronic hepatitis C patients.

LecT-Hepa 有助于评估慢性丙型肝炎患者干扰素治疗期间的治疗结果。

• DOI: 10.1186/1559-0275-11-44
• 发表时间: 2014
• 期刊: Clinical proteomics
• 影响因子: 3.8
• 作者: Zou,Xia;Chi,Xiumei;Pan,Yu;Du,Dongning;Sun,Haibo;Matsuda,Atsushi;Li,Wei;Kuno,Atsushi;Zhang,Xinxin;Narimatsu,Hisashi;Niu,Junqi;Zhang,Yan
• 通讯作者: Zhang,Yan

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