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

不健康的酒精使用在艾滋病毒感染者（PLWH）中很常见，并与心血管疾病有关。 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 组合物（即，肠道生态失调）和肠道生态失调可能导致CVD风险。肠道生态失调影响了 短链脂肪酸（SCFA例如，丁酸盐），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）。这些依赖微生物组的代谢物是否 与CVD事件和死亡相关，并导致重度PLWH中CVD的过度风险 饮酒者不详。这三种代谢途径（SCFA、胆汁酸和胆碱）中的每一种，如果相关 PLWH中的CVD，可以作为潜在的治疗靶点，以降低PLWH中的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）计划项目资助的是，在PLWH中，益生菌可以减轻酒精相关的 生态失调和减少微生物易位，炎症和有害的微生物组依赖性代谢产物 （项目1）; SCFA、胆汁酸和TMAO代谢的改变与CVD风险增加相关 死亡（2）。我们的初步数据支持不健康的酒精使用，肠道 生态失调和由此产生的代谢物改变有助于肠道通透性、免疫功能障碍、CVD， 死亡Meta HIV CVD队列（项目2）是一项前瞻性、观察性队列研究，由So-Armah博士领导。 （铅），弗赖贝格博士和巴夫博士。这项研究将使用现有的数据和生物标本， 老龄化队列研究（VACS）。待获得的新数据包括靶向代谢组学和更新的裁定 主要不良心脏事件（心肌梗死、缺血性卒中、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 来自这些途径的代谢物与酒精、CVD和HIV状态导致的死亡的关联。要求1 评估SCFA代谢途径，主要集中在丁酸盐，一种肠细胞必需的代谢物 健康目的2评估胆碱代谢途径，主要集中在三甲胺N-氧化物（TMAO）， 代谢物与CVD风险增加相关。目的3评估胆汁酸代谢途径，重点是 脱氧胆酸与胆酸的比例，这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、心血管疾病和/或死亡独立相关，并确定这些代谢物是否与饮酒、心血管疾病和/或死亡相关 艾滋病毒感染者与非艾滋病毒感染者之间的关联是独特的，或在感染者与非艾滋病毒感染者之间更为突出。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相关性 参与者（项目1）。影响：这项研究促进了对酒精相关肠道生态失调的理解 和依赖性代谢物导致CVD和死亡。如果我们的假设得到证实，这些结果可能 导致识别新的治疗目标，以减少重度饮酒者中的PLWH的CVD。

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.