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: 10304049
• 负责人: MATTHEW S FREIBERG
• 金额: $ 58.7万
• 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/10304049
• 关键词: Aging; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Bacteria; Bile Acids; Biological Markers; Biometry; Blood Circulation; Blood specimen; Butyrates; CD4 Lymphocyte Count; Cardiovascular Diseases; Cells; Cessation of life; Cholic Acids; Cohort Studies; Complement; Counseling; Data; Data Reporting; Deoxycholic Acid; 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; 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; alcohol effect; alcohol intervention; alcohol research; antiretroviral therapy; arm; bile acid metabolism; cardiovascular disorder risk; cardiovascular risk factor; data management; 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.

在艾滋病毒感染者（PLWH）中，大量饮酒会增加心血管疾病（CVD）的风险， 死亡数据表明，酒精相关的肠道生态失调部分驱动了这种风险。干预措施是否 针对PLWH中酒精相关肠道生态失调改善生态失调，降低微生物水平 易位、炎症和有害代谢物（例如，N-氧化三甲胺（TMAO）]）。我们 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 肠道生态失调和微生物易位水平降低，炎症，并改善代谢产物谱（项目 1）;并且这些代谢物的有害水平将与更高的心血管疾病和死亡风险相关（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，已经进行了两次NIAAA 资助的试验，代谢物研究和俄罗斯PLWH中重度饮酒者的肠道微生物组研究。 这些研究的数据显示，在PLWH中：（1）大量饮酒与CVD事件、死亡相关， 和肠道生态失调（特征在于丁酸产生细菌的减少）;和（2）这种肠道生态失调是 与炎症、胆汁酸改变和高TMAO水平相关。根据这些数据和飞行员的报告 研究表明，益生菌是安全的，可以改善肠道生态失调，减少PLWH中的炎症， 我们建议在250名正在接受抗逆转录病毒治疗的重度饮酒的艾滋病毒携带者中进行随机对照试验， CD 4+计数≥350个细胞/mm 3，以比较针对酒精相关肠道定制的益生菌的效果 微生态失调与安慰剂相比：（1）改善GI微生态失调;（2）减少血浆代谢物（例如，TMAO）和生物标志物 微生物易位和炎症水平;和（3）降低CVD和死亡风险。所有参与者将 接受酒精使用的循证咨询。我们的具体目标将比较一个 定制益生菌与安慰剂在6个月时的（目标1）生态失调（粪便厚壁菌门到拟杆菌门（F/B）） 比值，主要研究结局;粪便毛螺菌科-丁酸生产者家族）和血浆代谢产物 （血浆丁酸盐、脱氧胆酸：胆酸比率和TMAO）（目的2）炎症的生物标志物（血浆， IL-6、D-二聚体、sCD 14）、微生物易位[脂多糖结合蛋白]、（目的3）心血管风险 （Reynolds风险评分），死亡风险（VACS指数）;（目标4探索性）酒精消费（%重度饮酒 过去一个月的天数）和HIV疾病进展（CD 4细胞计数）。我们假设， （1）更高的F/B比和粪便毛螺菌科的水平， 血浆丁酸盐、脱氧胆酸：胆酸比率和较低的TMAO水平;（2）较低的血浆生物标志物 微生物移位和炎症水平;（3）较低的Reynolds风险评分和VACS指数;（4）较低的% 在过去的一个月里酗酒和更高的CD 4细胞计数。这项随机对照试验的发现，微生物组， mETlets和酒精在HIV中减少CVD（Meta HIV CVD RCT）将告知益生菌的作用作为标准 在重度饮酒者中补充酒精干预的连续性治疗。