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

HIV 中的微生物组、代谢物和酒精可减少 CVD 的随机对照试验 (META HIV CVD RCT)

• 批准号: 10685513
• 负责人: MATTHEW S FREIBERG
• 金额: $ 85.26万
• 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/10685513
• 关键词: Acids; Aging; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Bacteria; Bile Acids; Biological Markers; Biometry; Blood specimen; Butyrates; CD4 Lymphocyte Count; Cardiovascular Diseases; Cells; Cessation of life; Cholic Acids; Circulation; Cohort Studies; Collaborations; Complement; Counseling; Data; Deoxycholic Acid; Disease; Disease Progression; Family; Fibrin fragment D; Firmicutes Bacteroidetes ratio; Funding; HIV; Heavy Drinking; Inflammation; Interleukin-6; Intervention; Leaky Gut; Measures; Medical; Metagenomics; Modeling; National Institute on Alcohol Abuse and Alcoholism; Outcome Study; Participant; Patient Self-Report; Persons; Pilot Projects; Placebos; Plasma; Probiotics; Process; Randomized, Controlled Trials; Reporting; Research; Risk; Risk Factors; Role; Russia; Site; Testing; United States National Institutes of Health; Universities; Veterans; Work; Zinc; alcohol effect; alcohol intervention; alcohol research; antiretroviral therapy; arm; bile acid metabolism; cardiovascular disorder epidemiology; cardiovascular disorder risk; cardiovascular risk factor; data management; disorder risk; dysbiosis; epidemiology study; evidence base; gut bacteria; gut dysbiosis; gut microbiome; heart disease risk; high risk; improved; indexing; lipopolysaccharide-binding protein; metabolomics; microbial; microbiome; microbiome research; mortality risk; nutrition; pill; recruit; trial design; trimethyloxamine

Among people living with HIV (PLWH), heavy drinking increases the risk of cardiovascular disease (CVD) and death. Data suggest that alcohol-associated gut dysbiosis partially drives this risk. Whether interventions targeting alcohol-associated gut dysbiosis among PLWH improve dysbiosis, lower levels of microbial translocation, inflammation, and harmful metabolites (e.g., trimethylamine N-oxide [TMAO)]) is unknown. Our hypothesis for this P01 application is that among PLWH, a probiotic can mitigate or reduce alcohol associated gut dysbiosis and lower levels of microbial translocation, inflammation, and improve metabolite profiles (Project 1); and that harmful levels of these metabolites will be associated with higher CVD and death risk (Project 2). Our team, with expertise in alcohol, HIV, gut microbiome, and biomarker research has conducted two NIAAA funded trials, a metabolite study, and a gut microbiome study among Russian PLWH who are heavy drinkers. Data from these studies show that among PLWH: (1) heavy drinking is associated with incident CVD, death and gut dysbiosis (characterized by a reduction in butyrate producing bacteria); and (2) this gut dysbiosis is associated with inflammation, altered bile acids, and high TMAO levels. Given these data and reports from pilot studies showing that probiotics are safe, may improve gut dysbiosis and reduce inflammation among PLWH, we propose an RCT among 250 PLWH with heavy alcohol consumption who are on antiretroviral therapy and have CD4+ counts≥350 cells/mm3 to compare the effects of a probiotic tailored to alcohol associated gut dysbiosis vs. placebo to: (1) improve GI dysbiosis; (2) reduce plasma metabolite (e.g., TMAO) and biomarker levels of microbial translocation and inflammation; and (3) lower CVD and mortality risk. All participants will receive evidenced-based counseling for alcohol use. Our specific aims will compare the effects of a tailored probiotic vs. placebo at 6 months on (Aim 1) dysbiosis (fecal Firmicutes to Bacteroidetes (F/B) ratio, primary study outcome; fecal Lachnospiraceae-family of butyrate producers) and plasma metabolites (plasma butyrate, deoxycholic acid:cholic acid ratio, and TMAO) (Aim 2) biomarkers of inflammation (plasma, IL-6, D-dimer, sCD14), microbial translocation [Lipopolysaccharide binding protein], (Aim 3) cardiovascular risk (Reynolds risk score), mortality risk (VACS index); (Aim 4 exploratory) alcohol consumption (% heavy drinking days in past month) and HIV disease progression (CD4 cell count). We hypothesize that as compared with placebo, the probiotic arm will have significantly: (1) higher F/B ratio and levels of fecal Lachnospiraceae, plasma butyrate, deoxycholic acid: cholic acid ratio and lower levels of TMAO; (2) lower plasma biomarker levels of microbial translocation and inflammation; (3) lower Reynolds risk score and VACS index; (4) lower % heavy drinking days in the past month and higher CD4 cell counts. The findings from this RCT, Microbiome, mETabolites, and Alcohol in HIV to reduce CVD (META HIV CVD RCT), will inform probiotics' role as standard adjunctive therapy complementing alcohol interventions among PLWH who are heavy drinkers.

在艾滋病毒（PLWH）的人中，大量饮酒会增加心血管疾病（CVD）和 死亡。数据表明，与酒精相关的肠道营养不良部分驱动了这种风险。是否干预 PLWH中靶向与酒精相关的肠道营养不良，改善了营养不良，微生物水平较低 易位，炎症和有害代谢产物（例如三甲胺N-氧化物[TMAO）]）是未知的。我们的 该P01应用的假设是，在PLWH中，益生菌可以减轻或减少与酒精相关的酒精 肠道营养不良和较低水平的微生物易位，注射和改善代谢物谱（项目 1）;这些代谢物的有害水平将与CVD和死亡风险更高有关（项目2）。 我们的团队在酒精，艾滋病毒，肠道微生物组和生物标志物研究方面具有专业知识，进行了两项NIAAA 资助试验，一项代谢物研究以及俄罗斯PLWH的肠道微生物组研究，他们是饮酒者。 这些研究的数据表明，在PLWH中：（1）大量饮酒与事件CVD，死亡有关 和肠道营养不良（以丁酸盐产生细菌的降低为特征）； （2）这种肠道营养不良是 与炎症，胆汁酸改变和高tmao水平相关。鉴于这些数据和飞行员的报告 研究表明，益生菌是安全的，可以改善肠道营养不良并减少PLWH中的注射， 我们在250 plwh中提议使用抗逆转录病毒疗法的大量饮酒和大量饮酒和 具有CD4+计数≥350细胞/mm3，以比较针对酒精相关肠的益生菌的作用 营养不良与安慰剂至：（1）改善胃肠道疾病障碍； （2）减少血浆代谢物（例如TMAO）和生物标志物 微生物易位和注射水平； （3）降低CVD和死亡率风险。所有参与者都会 接受基于证据的饮酒咨询。我们的具体目标将比较 在（AIM 1）营养不良的6个月时量身定制的益生菌与安慰剂（粪便1） 比率，主要研究结果；粪便生产者和血浆代谢产物的粪便lachnospileceae。 （血浆丁酸，脱氧胆酸：胆酸比和tmao）（AIM 2）炎症的生物标志物（血浆，等离子体， IL-6，D-二聚体，SCD14），微生物易位[脂多糖结合蛋白]（AIM 3）心血管风险 （雷诺风险评分），死亡风险（VACS指数）； （AIM 4探索性）饮酒（饮酒％％ 过去一个月的天数）和艾滋病毒疾病进展（CD4细胞计数）。我们假设这与 安慰剂，益生菌将有显着的：（1）较高的f/b比和粪便水平的水平， 血浆丁酸血浆，脱氧胆酸：胆酸比率和较低的TMAO水平； （2）下等离子体生物标志物 微生物易位和炎症水平； （3）较低的雷诺风险评分和VACS指数； （4）较低％ 过去一个月的大量饮酒日和CD4细胞计数较高。来自此RCT的Microbiome的发现， 代谢物和艾滋病毒中的酒精以减少CVD（元HIV CVD RCT），将为益生菌作为标准的作用提供依据 饮酒者的辅助疗法完成了饮酒者的酒精干预措施。