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

不健康的饮酒在艾滋病毒携带者中很常见，并与心血管疾病有关 疾病(心血管疾病)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(即肠道生物失调)和肠道微生物失调可能会增加心血管疾病的风险。肠道生物失调影响 生产短链脂肪酸(如丁酸)、胆汁酸(如脱氧胆酸)和胆碱 代谢物(如三甲胺氮氧化物，TMAO)。这些依赖微生物组的代谢物是否 与心血管事件和死亡相关，并导致严重的PLWH患者发生心血管疾病的额外风险 饮酒者是未知的。这三个代谢途径中的每一个(SCFA、胆汁酸和胆碱)，如果相关的话 PLWH中存在心血管疾病，可作为潜在的治疗靶点，以降低PLWH患者的心血管风险 酗酒者。HIV中微生物组、代谢物和酒精降低心血管疾病的中心假说 (Meta HIV CVD)计划项目赠款是在PLWH中，一种益生菌可以减轻与酒精相关的 减少微生物移位、炎症和有害微生物组依赖的代谢物 (项目1)；SCFA、胆汁酸和TMAO代谢改变与心血管疾病风险增加相关 和死亡(项目2)。我们的初步数据支持不健康饮酒的科学前提，肠道 生态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、心血管疾病和 死亡。Meta HIV CVD Cohort(项目2)是由So-Armah博士领导的前瞻性观察性队列研究 (主要)，弗莱伯格博士和巴维博士。这项研究将使用现有的数据和退伍军人的生物标本 老年队列研究(VAS)。将获得的新数据包括靶向代谢组学和最新裁决 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条依赖微生物组的代谢途径，并确定 这些途径的代谢物与酒精、心血管疾病和因感染艾滋病毒而死亡的关系。目标1 评估主要集中在丁酸的SCFA代谢途径，丁酸是肠道细胞所必需的代谢物 健康。目的2评估胆碱代谢途径，主要集中在三甲胺氮氧化物(TMAO)，a 与心血管疾病风险增加相关的代谢物。目标3评估胆汁酸代谢途径，重点是 脱氧胆酸/胆酸比值，可能与血脂异常有关。对于每个目标，我们将确定 与酒精使用、心血管疾病和/或死亡独立相关的代谢物，并确定这些 PLWH与未感染HIV的人之间的联系是独一无二的，或者是突出的。AIM 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相关性 参与者(项目1)。影响：这项研究促进了人们对酒精相关的肠道生物失调的理解 依赖的代谢物会导致心血管疾病和死亡。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，以减少酗酒的PLWH患者的心血管疾病。

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.