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

HIV 中的微生物组、代谢物和酒精可减少 CVD（补充）

• 批准号: 10846342
• 负责人: SHIRISH S BARVE
• 金额: $ 43.55万
• 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/10846342
• 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.

该计划项目赠款（PPG）的总体主题是与酒精相关的肠道疾病和肠道 艾滋病毒感染患者中的不植物代谢物是心血管疾病（CVD）危险因素 （plwh）饮酒者。这项研究的目标是（1）确定是否定制益生菌（即 含有支持丁酸酯合成的细菌）可以减轻与酒精相关的肠道疾病和较低的水平 微生物易位，炎症和改善有害的非生物代谢物谱（例如三甲胺 n氧化物，tmao）和（2）确定这些代谢物是否与出现CVD和死亡有关 plwh。我们假设在PLWH中，益生菌与安慰剂可以减轻与酒精相关的肠道 营养不良和较低水平的微生物易位，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较高的事件风险有关 CVD和死亡（项目2队列，n = 2,900）。项目1将在Pavlov州立医科大学的 俄罗斯圣彼得堡，与我们的肠道微生物组和代谢物研究相同的地点（Acme HIV和TMAO 艾滋病病毒）。项目2将利用退伍军人老化队列研究，这是一个与之相处的退伍军人的观察人群 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的行政核心的支持 中心以及路易斯维尔大学酒精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，将产生宏基因组学和 该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 艾滋病毒和心脏，肺，血液和睡眠研究NIH K12培训计划的学者进入PPG。我们的 初步数据：（1）HIV感染是CVD风险因素； （2）炎症与增加的风险有关 PLWH中的CVD； （3）在PLWH中，大量饮酒与CVD风险增加有关 具有肠道营养不良的措施，其特征是丁酸酯产生细菌； （4）肠道营养不良 饮酒者的PLWH与较高的炎症，TMAO和不良胆汁酸有关 代谢物谱； （5）鼠模型中的ularc数据显示大量饮酒会导致营养不良，这是 营养不良导致炎症的生物标志物水平升高，并且益生菌给予靶向 酒精相关的肠道营养不良也削弱了这些炎症生物标志物的上升 饮酒。跨项目验证：项目1的生物测量将用于验证 项目2中的重大发现。代谢物与项目2中的酒精和CVD显着相关，将是 在项目1中探索，以查看益生菌是否有利影响这些代谢产物的水平。微生物组， 代谢产物和艾滋病毒中的酒精以减少CVD（元HIV CVD）PPG将为益生菌作为标准的作用提供信息 辅助疗法补充饮酒者的PLWH中的酒精干预措施 对酒精相关的肠道营养不良及其代谢产物如何有助于CVD和死亡的理解。