1/2 Alcohol Associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV)

HIV感染者（HIV+）酗酒者通过无数途径有患心血管疾病（CVD）的风险。重 饮酒会导致微生物易位（MT）和炎症。此外，酒精相关的变化， 胃肠道微生物组-称为生态失调-是这种促炎级联反应的核心， 降低HIV+重度饮酒者CVD风险的治疗目标。酒精相关的生态失调是 其特征在于肠道细菌生物多样性的丧失，“有益”细菌的减少，和/或“有益”细菌的扩张。 有害或“促炎”细菌（例如，生产N-氧化三甲胺（TMAO）的那些， 与CVD风险增加相关的代谢物）。虽然小鼠模型显示酒精相关的生态失调是 即使在持续饮酒的情况下，益生菌也会减弱， 由于以下两个原因，鉴定人类治疗靶点的知识：1）大多数研究涉及鼠模型; 和2）缺乏人类研究，样本量小，HIV+参与者少，缺乏纵向研究， 评估与GI微生物组相关的酒精摄入、炎症和CVD风险。本申请 弥补这些差距。我们假设，酒精相关的生态失调将：（1）在HIV+非常 重度饮酒者（AUDIT评分≥20）对比重度饮酒者（AUDIT<20）;（2）增加肠道生物标志物水平 渗透性（例如，肠脂肪酸结合蛋白（IFABP），MT（例如，内毒素）、炎症（白细胞介素 6)和TMAO;和（3）增加血清生物标志物，并改变心脏超声心动图（Echo）测量 功能（N-末端脑钠肽前体，NT pro-BNP和左心室射血分数，LVEF， 分别）。为了验证这些假设，我们将招募200名来自圣彼得艾滋病毒的艾滋病毒阳性参与者， 使用药物治疗减少饮酒、吸烟、炎症和CVD风险的RCT。这个应用程序， 酒精相关的CVD和微生物组评估研究（ACME HIV 1/2）利用现有的资源，圣。 PETER HIV：参与者招募、酒精消耗量测量、生物标本和生物标志物收集; 在酒精、HIV、CVD和微生物基因组学方面的专业知识。新的数据包括：粪便样本，以表征 胃肠道微生物组、血清生物标志物和超声心动图测量。作为对RFA-AA-17-014的回应，我们将与 南方艾滋病毒和酒精研究联盟（SHARC，ACME HIV 2/2）证实了我们的发现， 目的1和2，并进行合并的跨队列分析。我们将完成以下具体目标 目的1：评估肠道的纵向定性和定量变化 微生物组（生态失调）与非常沉重的酒精消费。目的2：确定 微生态失调对肠通透性、MT、炎症和TMAO水平的影响。目的3：研究 生态失调对心脏结构和功能的生物标志物和回声测量的影响。实现这些目标 将为针对酒精相关的生态失调的干预奠定基础， 炎症和积极影响HIV+重度饮酒者的CVD风险。

HIV infected (HIV+) heavy drinkers are at risk for cardiovascular diseases (CVD) via myriad pathways. Heavy alcohol use causes microbial translocation (MT) and inflammation. Additionally, alcohol-related changes in the GI tract microbiome—termed dysbiosis—are central to this pro-inflammatory cascade and could serve as novel therapeutic targets for reducing CVD risk among HIV+ heavy drinkers. Alcohol-associated dysbiosis is characterized by a loss of gut bacterial biodiversity, a reduction in “beneficial” bacteria, and/or an expansion of harmful or “pro-inflammatory” bacteria (e.g., those which produce trimethylamine N-oxide (TMAO), a metabolite associated with increased CVD risk). While murine models show alcohol associated dysbiosis was attenuated by probiotics even in the presence of continued alcohol consumption, there remains insufficient knowledge to identify a therapeutic target in humans for two reasons: 1) most studies involve murine models; and 2) scant human studies have small sample sizes with few HIV+ participants, and lack longitudinal assessment of alcohol intake, inflammation, and CVD risk in relation to the GI microbiome. This application addresses these gaps. We hypothesize that alcohol-associated dysbiosis will: (1) be greater in HIV+ very heavy drinkers (AUDIT score≥20) vs. heavy drinkers (AUDIT<20); (2) increase biomarker levels of intestinal permeability (e.g., intestinal fatty acid binding protein (IFABP), MT (e.g., endotoxin), inflammation (interleukin 6) and TMAO; and (3) increase serum biomarkers for and alter echocardiographic (Echo) measures of cardiac function (N-terminal pro Brain Naturetic Peptide, NT pro-BNP, and left ventricular ejection fraction, LVEF, respectively). To test these hypotheses, we will enroll 200 HIV+ participants from St. PETER HIV, a funded RCT using pharmacotherapy to reduce alcohol use, smoking, inflammation, and CVD risk. This application, Alcohol-associated CVD and Microbiome Evaluation Study (ACME HIV 1/2) leverages existing resources of St. PETER HIV: participant recruitment, measures of alcohol consumption, biospecimen and biomarker collection; expertise in alcohol, HIV, CVD, and microbial genomics. New data include: fecal samples to characterize the GI microbiome, serum biomarkers, and echo measures. In response to RFA-AA-17-014, we will partner with the Southern HIV & Alcohol Research Consortium (SHARC, ACME HIV 2/2) to corroborate our findings in Aims 1 and 2 and to conduct combined cross-cohort analyses. We will complete the following SPECIFIC AIMS among HIV+ heavy drinkers: AIM 1: To assess longitudinal qualitative and quantitative changes in the gut microbiome (dysbiosis) associated with very heavy alcohol consumption. AIM 2: To determine the effect of dysbiosis on intestinal permeability, MT, inflammation, and TMAO levels. AIM 3: To investigate the impact of dysbiosis on biomarkers for and echo measures of cardiac structure and function. Completion of these aims will lay groundwork for an intervention targeting alcohol-associated dysbiosis, which could profoundly reduce inflammation and favorably impact CVD risk among HIV+ heavy drinkers.