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

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

• 批准号: 10685506
• 负责人: SHIRISH S BARVE
• 金额: $ 173.7万
• 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/10685506
• 关键词: Academic Medical Centers; Acids; Advisory Committees; Aging; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Area; Attenuated; Bacteria; Bile Acids; Biological Markers; Biological Specimen Banks; Biometry; Blood; Butyrates; CD4 Lymphocyte Count; Cardiovascular Diseases; Cells; Cessation of life; Cholic Acids; Choline; Clinical Trials Data Monitoring Committees; Cohort Studies; Complement; Data; Deoxycholic Acid; Disease Progression; Echocardiography; Event; Family; Fibrin fragment D; Firmicutes Bacteroidetes ratio; Funding; Future; Goals; Grant; HIV; HIV Infections; Heart; Heart Diseases; Heavy Drinking; Inflammation; Inflammatory; Interleukin-6; Intestinal permeability; Justice; Lead; Lipids; Lung; Measures; Medical; Mentored Clinical Scientist Development Program; Mentorship; Metabolic Pathway; Metagenomics; Monitor; Myocardial Infarction; Persons; Placebos; Plasma; Policies; Preparation; Probiotics; Procedures; Program Research Project Grants; Progress Reports; Publications; Regulatory T-Lymphocyte; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Role; Russia; Sampling; Serum; Services; Site; Sleep; Specimen; Training; Training Programs; United States National Institutes of Health; Universities; Validation; Veterans; Volatile Fatty Acids; Work; alcohol intervention; alcohol research; cardiovascular disorder risk; cardiovascular risk factor; cohort; data exchange; data repository; dysbiosis; follow-up; gut bacteria; gut dysbiosis; gut microbiome; high risk; improved; indexing; interest; lipopolysaccharide-binding protein; meetings; metabolomics; microbial; microbiome; mortality risk; mouse model; primary outcome; probiotic supplementation; program dissemination; programs; recruit; synergism; trimethyloxamine

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.

这项计划项目资助（PPG）的首要主题是酒精相关的肠道生态失调和肠道 在HIV感染者中，代谢物是心血管疾病（CVD）的危险因素 他们是豪饮者。本研究的目标是（1）确定定制的益生菌（即， 含有支持丁酸合成的细菌）可以减轻酒精相关的肠道生态失调， 微生物易位，炎症，并改善有害的微生态代谢物谱（如三甲胺 N氧化物，TMAO）和（2），以确定这些代谢物是否与事件CVD和死亡之间 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 生态失调和微生物易位，炎症水平较低，并改善代谢产物谱（项目1 RCT，n=250）;这些代谢物的有害改变将与更高的事件风险相关 CVD和死亡（项目2队列，n= 2，900）。项目1将在巴甫洛夫国立医科大学进行， 圣俄罗斯彼得堡，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 HIV）。项目2将利用退伍军人老龄化队列研究，这是一个观察性的退伍军人队列， 没有艾滋病毒。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 中心和路易斯维尔酒精大学的综合宏基因组学和代谢组学核心 研究中心（ULARC）。后者是ACME HIV的核心，将产生宏基因组学， 代谢组学研究前者将协调所有研究项目/核心，并整合范德比尔特 HIV和心脏，肺，血液和睡眠研究NIH K12培训计划的SCHolars进入PPG。我们 初步数据：（1）HIV感染是心血管疾病的危险因素;（2）炎症与心血管疾病风险增加有关。 PLWH中的CVD;（3）在PLWH中，大量饮酒与CVD风险增加相关， 肠道生态失调的措施，其特征在于丁酸生产细菌的损失;（4）肠道生态失调， 重度饮酒者的PLWH与更高水平的炎症，TMAO和不良胆汁酸相关 代谢物谱;和（5）鼠模型中的ULARC数据显示大量饮酒导致生态失调， 生态失调导致炎症的生物标志物水平增加，并且益生菌施用靶向 酒精相关的肠道生态失调减弱了这些炎症生物标志物的上升， 酒精消费。交叉项目确认：将使用项目1的生物标本进行确认 项目2的重大发现。在项目2中，代谢物与酒精和CVD显著相关， 在项目1中探索，看看益生菌是否有利地影响这些代谢物的水平。微生物组， METablets和HIV中的酒精减少CVD（Meta HIV CVD）PPG将告知益生菌作为标准的作用 在重度饮酒者和进展的PLWH中补充酒精干预的连续性治疗 了解酒精相关的肠道生态失调及其代谢产物如何导致CVD和死亡。