Microbiome, Metabolites, and Alcohol in HIV to Reduce CVD (Supplement)

这项计划项目拨款(PPG)的主要主题是酒精相关的肠道生物失调和肠道 非生物代谢产物是HIV感染者心血管疾病(CVD)的危险因素 (PLWH)酗酒者。这项研究的目标是(1)确定定制的益生菌(即， 含有支持丁酸合成的细菌)可以缓解与酒精相关的肠道菌群失调和低水平 减少微生物移位、炎症，改善有害的非生物代谢产物(如三甲胺) 氮氧化物，TMAO)和(2)以确定这些代谢物是否与以下人群的心血管疾病事件和死亡有关 PLWH。我们假设，在PLWH中，益生菌与安慰剂相比可以减轻酒精相关的肠道症状。 微生物代谢失调和较低水平的微生物移位、炎症和改善代谢物谱(项目1 RCT，n=250)；这些代谢物的有害变化将与更高的事故风险相关 心血管疾病与死亡(项目2队列，n=2900)。项目1将于#年在巴甫洛夫国立医科大学进行。 俄罗斯圣彼得堡，与我们的肠道微生物组和代谢物研究(ACME HIV和TMAO)相同的地点 艾滋病毒)。项目2将利用退伍军人老龄化队列研究，这是一项对与 而且没有艾滋病病毒。这些项目将得到我们在范德比尔特大学医学院的行政核心的支持 路易斯维尔大学酒精中心与综合代谢组学和代谢组学核心 研究中心(ULARC)。后者是ACME HIV的核心，将产生元基因组学和 这个PPG的代谢组学。前者将协调所有研究项目/核心，并整合范德比尔特 学者在艾滋病毒和心、肺、血液和睡眠研究方面，将NIH K12培训计划纳入PPG。我们的 初步数据：(1)艾滋病毒感染是心血管疾病的危险因素；(2)炎症与 (3)在PLWH中，大量饮酒与心血管疾病风险增加相关 以丁酸产生菌的丧失为特征的肠道微生物失调；(4)肠道微生物失调 大量饮酒的PLWH与更高水平的炎症、TMAO和不良胆汁酸相关 (5)小鼠模型中的ULARC数据显示，大量饮酒会导致生物失调， 生物失调会导致炎症的生物标记物水平增加，而益生菌的靶向给药 酒精相关的肠道生物失调可减弱这些炎性生物标记物的升高，即使在存在 饮酒。跨项目验证：将使用项目1中的生物制品进行验证 项目2的重要发现。项目2中与酒精和心血管疾病显著相关的代谢物将是 在项目1中进行了探索，以了解益生菌是否有利于影响这些代谢物的水平。微生物组， 代谢物和HIV中的酒精可减少心血管疾病(Meta HIV CVD)PPG将告知益生菌作为标准的作用 辅助性治疗配合酒精干预在重度饮酒者中的应用 了解酒精与肠道生物失调及其代谢物如何导致心血管疾病和死亡。

The overarching theme for this program project grant (PPG) is that alcohol associated gut dysbiosis and gut dysbiotic metabolites are cardiovascular disease (CVD) risk factors among people living with HIV infection (PLWH) who are heavy drinkers. The goals of this research are (1) to determine if a tailored probiotic (i.e., contains bacteria supporting butyrate synthesis) can mitigate alcohol associated gut dysbiosis and lower levels of microbial translocation, inflammation, and improve harmful dysbiotic metabolite profiles (e.g. trimethylamine N oxide, TMAO) and (2) to determine if these metabolites are associated with incident CVD and death among PLWH. We hypothesize that, among PLWH, a probiotic vs. placebo can mitigate alcohol associated gut dysbiosis and lower levels of microbial translocation, inflammation, and improve metabolite profiles (Project 1 RCT, n=250); and that harmful alterations of these metabolites will be associated with higher risk of incident CVD and death (Project 2 Cohort, n=2,900). Project 1 will be conducted at Pavlov State Medical University in St. Petersburg, Russia, the same site as our gut microbiome and metabolite studies (ACME HIV and TMAO HIV). Project 2 will leverage the Veterans Aging Cohort Study, an observational cohort of veterans living with and without HIV. The Projects will be supported by our Administrative Core at Vanderbilt University Medical Center and the Integrated Metagenomics and Metabolomics Core at the University of Louisville's Alcohol Research Center (ULARC). The latter is the core for ACME HIV and will generate the metagenomics and metabolomics for this PPG. The former will coordinate all study projects/cores and integrate the Vanderbilt SCHolars in HIV and Heart, Lung, Blood, and Sleep ReSearch NIH K12 training program into the PPG. Our preliminary data: (1) HIV infection is a CVD risk factor; (2) inflammation is associated with increased risk of CVD among PLWH; (3) among PLWH, heavy drinking is associated with increased CVD risk and correlated with measures of gut dysbiosis, characterized by loss of butyrate producing bacteria; (4) gut dysbiosis among PLWH who are heavy drinkers is correlated with higher levels of inflammation, TMAO, and adverse bile acid metabolite profiles; and (5) ULARC data in murine models show heavy drinking causes dysbiosis, that dysbiosis leads to increased biomarker levels of inflammation, and that probiotic administration targeting alcohol-associated gut dysbiosis attenuates the rise in these inflammatory biomarkers even in the presence of alcohol consumption. Cross project validation: Biospecimens from Project 1 will be used to validate significant findings in Project 2. Metabolites significantly associated with alcohol and CVD in Project 2, will be explored in Project 1 to see if probiotics favorably impact the levels of those metabolites. The Microbiome, METabolites, and Alcohol in HIV to reduce CVD (META HIV CVD) PPG will inform probiotics' role as standard adjunctive therapy complementing alcohol interventions among PLWH who are heavy drinkers and advance the understanding of how alcohol associated gut dysbiosis and its metabolites contribute to CVD and death.