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

在艾滋病毒携带者(PLWH)中，大量饮酒会增加心血管疾病(CVD)和 死亡。数据表明，与酒精相关的肠道生物失调在一定程度上推动了这种风险。干预措施是否 靶向酒精相关的肠道菌群失调改善PLWH，降低微生物水平 移位、炎症和有害代谢物(如三甲胺N-氧化物[TMAO])尚不清楚。我们的 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 肠道生物失调和较低水平的微生物移位、炎症和改善代谢物谱(项目 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记物方面拥有专业知识，已经进行了两项NIAAA研究 资助的试验、代谢物研究和对酗酒的俄罗斯PLWH进行的肠道微生物组研究。 这些研究的数据表明，在PLWH中：(1)大量饮酒与心血管疾病、死亡有关 和肠道生物失调(特征是丁酸产生菌减少)；和(2)这种肠道微生物失调是 与炎症、胆汁酸改变和高TMAO水平有关。根据飞行员提供的这些数据和报告 研究表明，益生菌是安全的，可以改善肠道菌群失调，减少PLWH的炎症， 我们建议在250名大量饮酒的PLWH中进行随机对照试验，这些人正在接受抗逆转录病毒治疗，并 让c4+计数≥350细胞/mm~3来比较一种为酒精相关的肠道定制的益生菌的效果 与安慰剂相比：(1)改善胃肠道生物失调；(2)降低血浆代谢物(如TMAO)和生物标志物 微生物移位和炎症水平；以及(3)降低心血管疾病和死亡风险。所有参与者将 接受以证据为基础的酒精使用咨询。我们的具体目标将比较 特制益生菌与安慰剂在6个月时的对比(目标1)生物失调(粪便Firmicents到类杆菌(F/B)) 比率，初步研究结果；粪便沙棘科-丁酸盐产生菌家族)和血浆代谢物 (血浆丁酸盐、脱氧胆酸/胆酸比率和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(酗酒百分比 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，相比于 安慰剂，益生菌手臂将有显著：(1)更高的F/B比和粪便沙棘螺旋菌水平， 血浆丁酸、脱氧胆酸/胆酸比值和TMAO水平降低；(2)血浆生物标志物降低 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)较低的% 在过去的一个月里，大量饮酒的日子和更高的CD4细胞计数。这项随机对照试验的发现，微生物组， 代谢物和减少心血管疾病的艾滋病毒中的酒精(Meta HIV CVD RCT)将告知益生菌作为标准的作用 在酗酒的PLWH患者中辅以酒精干预。

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.