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）

基本信息

批准号：
10672807
负责人：
SHIRISH S BARVE
金额：
$ 21.58万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10672807
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

项目摘要

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.

该计划项目拨款 (PPG) 的首要主题是酒精相关的肠道菌群失调和肠道菌群失调。代谢失调是 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) 确定是否有定制的益生菌（即，含有支持丁酸合成的细菌）可以减轻酒精相关的肠道菌群失调并降低水平微生物易位、炎症，并改善有害的失调代谢物（例如三甲胺） N 氧化物、TMAO）和 (2) 以确定这些代谢物是否与心血管疾病和死亡相关感染者。我们假设，在感染者中，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较低水平的微生物易位、炎症，并改善代谢物谱（项目 1 随机对照试验，n=250)；这些代谢物的有害改变将与更高的事故风险相关 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 艾滋病病毒）。项目 2 将利用退伍军人老龄化队列研究，这是一个对患有以下疾病的退伍军人进行观察的队列并且没有艾滋病毒。这些项目将得到范德比尔特大学医学院行政核心的支持路易斯维尔大学酒精中心和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此 PPG 的代谢组学。前者将协调所有研究项目/核心并整合范德堡大学 HIV 和心脏、肺、血液和睡眠研究领域的学者将 NIH K12 培训计划纳入 PPG。我们的初步数据：（1）HIV感染是CVD危险因素； (2) 炎症与以下疾病的风险增加有关： PLWH 中的 CVD； (3) 在艾滋病病毒感染者中，酗酒与心血管疾病风险增加相关采取肠道菌群失调的措施，其特征是产生丁酸盐的细菌丧失； (4)肠道菌群失调酗酒的艾滋病感染者与较高水平的炎症、TMAO 和不良胆汁酸相关代谢物概况； (5) 小鼠模型中的 ULARC 数据显示，大量饮酒会导致菌群失调，即菌群失调会导致炎症生物标志物水平升高，而益生菌的给药目标是即使存在酒精相关的肠道菌群失调，也会减弱这些炎症生物标志物的上升饮酒量。跨项目验证：项目 1 的生物样本将用于验证项目 2 中的重大发现。项目 2 中与酒精和 CVD 显着相关的代谢物将被项目 1 中探讨了益生菌是否对这些代谢物的水平产生有利影响。微生物组， HIV 中的代谢物和酒精可减少 CVD (META HIV CVD) PPG 将告知益生菌的作用作为标准对重度饮酒者和晚期感染者进行酒精干预的辅助治疗了解酒精相关的肠道菌群失调及其代谢物如何导致心血管疾病和死亡。