Microbiome, metabolites, and alcohol in HIV to reduce CVD Cohort (META HIV CVD Cohort)

HIV 中的微生物组、代谢物和酒精可减少 CVD 队列（META HIV CVD 队列）

• 批准号: 10304050
• 负责人: Kaku So-Armah
• 金额: $ 41.84万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10304050
• 关键词: Aging; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Bacteria; Bile Acids; Biological Markers; Blood; Butyrates; Cardiac; Cardiovascular Diseases; Cells; Cessation of life; Cholic Acids; Choline; Cohort Studies; Coronary; Data; Deoxycholic Acid; Dyslipidemias; Echocardiography; Evaluation; Event; Functional disorder; Funding; Goals; HIV; HIV Infections; Health; Heart Diseases; Heart failure; Heavy Drinking; Immune System Diseases; Inflammation; Inflammatory; Insulin Resistance; Intervention; Intestinal permeability; Intestines; Ischemic Stroke; Justice; Kidney; Lead; Letters; Link; Lipids; Liver; Metabolic; Metabolic Pathway; Metabolism; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial dysfunction; Observational Study; Organ; Pathway interactions; Peripheral arterial disease; Probiotics; Production; Program Research Project Grants; Regulatory T-Lymphocyte; T-Lymphocyte Subsets; Testing; United States National Institutes of Health; Update; Veterans; Volatile Fatty Acids; Work; X-Ray Computed Tomography; adjudicate; adjudication; alcohol effect; alcohol misuse; cardiovascular disorder risk; clinical care; clinical trial participant; cohort; comorbidity; drinking; dysbiosis; epidemiology study; gastrointestinal; gut bacteria; gut dysbiosis; gut microbiome; heart disease risk; high risk; metabolomics; microbial; microbial composition; microbiome; mortality; mortality risk; new therapeutic target; primary outcome; prospective; response; therapeutic target; trimethyloxamine

Unhealthy alcohol use is common in people living with HIV (PLWH) and is associated with cardiovascular disease (CVD) and mortality risk. Prior work suggests that heavy drinking alters gastrointestinal microbial composition (i.e., gut dysbiosis) and gut dysbiosis may contribute to CVD risk. Gut dysbiosis impacts the production of short chain fatty acids (SCFAs e.g., butyrate), bile acids (e.g., deoxycholic acid), and choline metabolites (e.g., trimethylamine N-oxide, TMAO). Whether these microbiome-dependent metabolites are associated with incident CVD and death and contribute to the excess risk of CVD among PLWH who are heavy drinkers is unknown. Each of these three metabolic pathways (SCFA, bile acids, and choline), if associated with CVD in PLWH, could serve as a potential therapeutic target to reduce CVD risk among PLWH who are heavy drinkers. The central hypotheses in the Microbiome, Metabolites, and Alcohol in HIV to reduce CVD (META HIV CVD) program project grant are that among PLWH, a probiotic can mitigate alcohol-associated dysbiosis and reduce microbial translocation, inflammation and harmful microbiome-dependent metabolites (Project 1); and that altered SCFA, bile acid and TMAO metabolism are associated with increased risk of CVD and death (Project 2). Our preliminary data support the scientific premise that unhealthy alcohol use, gut dysbiosis and resulting metabolite alterations contribute to gut permeability, immune dysfunction, CVD, and death. META HIV CVD Cohort (Project 2), is a prospective, observational cohort study led by Dr. So-Armah (Lead), Dr. Freiberg, and Dr. Barve. The study will use existing data and biospecimens from the Veterans Aging Cohort Study (VACS). New data to be obtained include targeted metabolomics and updated adjudication of major adverse cardiac events (myocardial infarction, ischemic stroke, coronary revascularization, heart failure, peripheral artery disease). We will assess 3 microbiome-dependent metabolic pathways and determine the association of metabolites from these pathways with alcohol, CVD, and death by HIV status. Aim 1 assesses SCFA metabolic pathways focusing primarily on butyrate, a metabolite necessary for intestinal cell health. Aim 2 assesses choline metabolic pathways focusing primarily on trimethylamine N-oxide (TMAO), a metabolite associated with increased CVD risk. Aim 3 assesses bile acid metabolic pathways focusing on the deoxycholic acid to cholic acid ratio, which may be associated with dyslipidemia. For each aim, we will identify metabolites independently associated with alcohol use, CVD, and/or death and determine whether these associations are unique to or accentuated among PLWH vs. people without HIV. Aim 4 will replicate the associations of heavy drinking and these metabolites with baseline data from the META HIV CVD clinical trial participants (Project 1). IMPACT: This study advances understanding of how alcohol-associated gut dysbiosis and dependent metabolites contribute to CVD and death. If our hypotheses are confirmed, these results could lead to the identification of new therapeutic targets for reducing CVD among PLWH who are heavy drinkers.

不健康的饮酒在艾滋病毒（PLWH）的患者中很常见，并且与心血管有关 疾病（CVD）和死亡率风险。先前的工作表明，大量饮酒会改变胃肠道微生物 组成（即肠道营养不良）和肠道营养不良可能导致CVD风险。肠道营养不良影响 短链脂肪酸（例如丁酸酯），胆汁酸（例如脱氧胆酸）和胆碱的产生 代谢物（例如三甲胺N-氧化物，TMAO）。这些微生物组依赖性代谢产物是否是 与事件CVD和死亡有关，并促成了沉重的PLWH中CVD的过多风险 饮酒者是未知的。如果相关 使用PLWH中的CVD，可以作为降低PLWH中CVD风险的潜在治疗靶点 沉重的饮酒者。艾滋病毒中的微生物组，代谢产物和酒精中的中心假设以减少CVD （Meta HIV CVD）计划项目赠款是在PLWH中，益生菌可以减轻与酒精相关的 营养不良并减少微生物易位，炎症和有害微生物组依赖性代谢物 （项目1）;这种改变的SCFA，胆汁酸和TMAO代谢与CVD风险增加有关 和死亡（项目2）。我们的初步数据支持不健康的酒精使用的科学前提 营养不良和由此产生的代谢物改变导致肠道渗透性，免疫功能障碍，CVD和 死亡。 Meta HIV CVD队列（项目2）是一项由So-Armah博士领导的前瞻性观察队列研究 （LEAD），Freiberg博士和Barve博士。该研究将使用退伍军人的现有数据和生物测量 老化队列研究（VACS）。要获得的新数据包括针对性的代谢组学和更新的裁决 主要不良心脏事件（心肌梗塞，缺血性中风，冠状动脉血运重建，心脏 失败，周围动脉疾病）。我们将评估3个微生物组依赖性代谢途径，并确定 这些途径的代谢产物与酒精，CVD和艾滋病毒状况死亡的关联。目标1 评估主要集中在丁酸酯上的SCFA代谢途径，这是肠细胞所需的代谢物 健康。 AIM 2评估主要关注三甲胺N-氧化物（TMAO）的胆碱代谢途径，A 代谢物与CVD风险增加有关。 AIM 3评估胆汁酸代谢途径的关注 脱氧胆酸与胆酸比率，可能与血脂异常有关。对于每个目标，我们将确定 代谢物与饮酒，CVD和/或死亡独立相关，并确定这些是否是否 在PLWH与没有艾滋病毒的人之间，协会是独一无二的或突出的。 AIM 4将复制 大量饮酒和这些代谢产物的关联以及来自元HIV CVD临床试验的基线数据 参与者（项目1）。影响：这项研究进一步了解了与酒精相关的肠道疾病的理解 依赖的代谢产物有助于CVD和死亡。如果确认我们的假设，这些结果可能 导致确定新的治疗靶标，以减少饮酒者的PLWH中的CVD。