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，大量饮酒会增加患心血管疾病（CVD）和 死亡。数据表明，与酒精相关的肠道菌群失调在一定程度上导致了这种风险。是否干预 针对 PLWH 中与酒精相关的肠道菌群失调，改善菌群失调，降低微生物水平 易位、炎症和有害代谢物（例如三甲胺 N-氧化物 [TMAO)]）尚不清楚。我们的 此 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 肠道菌群失调和微生物易位、炎症水平降低，并改善代谢物谱（项目 1）；这些代谢物的有害水平将与较高的 CVD 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拥有专业知识，已进行了两次 NIAAA 资助了针对俄罗斯酗酒者的艾滋病毒感染者的试验、代谢物研究和肠道微生物组研究。 这些研究的数据表明，在艾滋病感染者中：(1) 酗酒与心血管疾病、死亡的发生有关 和肠道菌群失调（其特征是产生丁酸的细菌减少）； (2) 这种肠道菌群失调是 与炎症、胆汁酸改变和高TMAO水平有关。鉴于这些数据和飞行员的报告 研究表明益生菌是安全的，可以改善肠道菌群失调并减少感染者的炎症， 我们建议对 250 名正在接受抗逆转录病毒治疗且酗酒的感染者进行随机对照试验 CD4+ 计数≥350 个细胞/mm3，以比较针对酒精相关肠道定制的益生菌的效果 菌群失调与安慰剂相比：(1) 改善胃肠道菌群失调； (2) 减少血浆代谢物（如TMAO）和生物标志物 微生物移位和炎症水平； (3) 降低心血管疾病和死亡风险。所有参与者将 接受基于证据的饮酒咨询。我们的具体目标将比较 6 个月时定制益生菌与安慰剂对比（目标 1）生态失调（粪便厚壁菌门到拟杆菌门 (F/B) 比率，主要研究结果；粪便毛螺菌科（丁酸盐生产者家族）和血浆代谢物 （血浆丁酸盐、脱氧胆酸：胆酸比和 TMAO）（目标 2）炎症生物标志物（血浆、 IL-6、D-二聚体、sCD14)、微生物易位[脂多糖结合蛋白]、（目标 3）心血管风险 （雷诺风险评分）、死亡风险（VACS指数）； （目标 4 探索性）饮酒量（重度饮酒百分比 上个月的天数）和 HIV 疾病进展（CD4 细胞计数）。我们假设与 安慰剂组中，益生菌组将显着：(1) 更高的 F/B 比和粪便 Lachnospiraceae 水平， 血浆丁酸盐、脱氧胆酸：胆酸比率和TMAO水平降低； (2)降低血浆生物标志物 微生物移位和炎症水平； (3)降低雷诺风险评分和VACS指数； (4) 降低% 过去一个月大量饮酒且 CD4 细胞计数较高。这项随机对照试验的结果，微生物组， HIV 中的代谢物和酒精可减少 CVD（META HIV CVD RCT），将告知益生菌作为标准的作用 对酗酒者的艾滋病患者进行酒精干预的辅助治疗。