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）

基本信息

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
项目类别：
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

项目摘要

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.

不健康饮酒在艾滋病毒感染者 (PLWH) 中很常见，并且与心血管疾病有关疾病（CVD）和死亡风险。先前的研究表明，大量饮酒会改变胃肠道微生物成分（即肠道菌群失调）和肠道菌群失调可能会增加 CVD 风险。肠道菌群失调会影响产生短链脂肪酸（SCFA，例如丁酸）、胆汁酸（例如脱氧胆酸）和胆碱代谢物（例如，三甲胺 N-氧化物，TMAO）。这些微生物组依赖性代谢物是否与 CVD 事件和死亡相关，并导致体重较重的 PLWH 的 CVD 风险过高饮酒者未知。这三种代谢途径（SCFA、胆汁酸和胆碱）中的每一种（如果相关）患有 CVD 的 PLWH 可以作为潜在的治疗目标，以降低 PLWH 的 CVD 风险。酗酒者。 HIV 中微生物组、代谢物和酒精减少 CVD 的中心假设 (META HIV CVD) 计划项目拨款表明，在 PLWH 中，益生菌可以减轻与酒精相关的症状生态失调并减少微生物易位、炎症和有害微生物组依赖性代谢物（项目1）； SCFA、胆汁酸和 TMAO 代谢的改变与 CVD 风险增加相关和死亡（项目 2）。我们的初步数据支持以下科学前提：不健康的饮酒、肠道菌群失调和由此产生的代谢物改变会导致肠道通透性、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（负责人）、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样本老龄化队列研究（VACS）。将获得的新数据包括目标代谢组学和更新的裁决主要不良心脏事件（心肌梗死、缺血性中风、冠状动脉血运重建、心脏衰竭、外周动脉疾病）。我们将评估 3 种微生物组依赖性代谢途径并确定这些途径的代谢物与酒精、CVD 和 HIV 状态导致的死亡之间的关系。目标1 评估 SCFA 代谢途径，主要关注丁酸盐，丁酸盐是肠细胞必需的代谢物健康。目标 2 评估胆碱代谢途径，主要关注三甲胺 N-氧化物 (TMAO)，一种与 CVD 风险增加相关的代谢物。目标 3 评估胆汁酸代谢途径，重点关注脱氧胆酸与胆酸的比例，可能与血脂异常有关。对于每个目标，我们将确定与饮酒、心血管疾病和/或死亡独立相关的代谢物，并确定这些是否与未感染艾滋病毒的人相比，艾滋病毒感染者和艾滋病病毒感染者之间的关联是独特的或更为突出。目标 4 将复制大量饮酒和这些代谢物与 META HIV CVD 临床试验基线数据的关联参与者（项目 1）。影响：这项研究增进了对酒精相关肠道菌群失调的理解依赖性代谢物会导致 CVD 和死亡。如果我们的假设得到证实，这些结果可能导致确定新的治疗靶点，以减少酗酒者的 PLWH 中的 CVD。