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

感染艾滋病毒(HIV+)的酗酒者有患心血管疾病(CVD)的风险，途径繁多。重的 饮酒会导致微生物易位(MT)和炎症。此外，与酒精相关的变化在 胃肠道微生物组--被称为微生态失调--是这种促炎级联反应的中心，可以作为一种新的 降低HIV+酗酒者心血管疾病风险的治疗目标。酒精相关的生物失调是 以肠道细菌生物多样性的丧失、有益细菌的减少和/或扩展为特征 有害或“促炎”细菌(例如，那些产生三甲胺N-氧化物(TMAO)的细菌、 与心血管疾病风险增加相关的代谢物)。虽然小鼠模型显示酒精相关的生物失调是 即使在持续饮酒的情况下，益生菌也会减弱，但仍然不足。 在人类身上识别治疗靶点的知识有两个原因：1)大多数研究涉及小鼠模型； 2)很少的人体研究样本量小，HIV+参与者很少，而且缺乏纵向研究 评估酒精摄入、炎症和心血管疾病风险与胃肠道微生物群的关系。此应用程序 解决这些差距。我们假设与酒精相关的生物失调将：(1)在HIV+非常严重 酗酒者(AUDIT Score≥20)与大量饮酒者(AUDIT&lt；20)；(2)增加肠道生物标志物水平 通透性(例如，肠道脂肪酸结合蛋白(IFABP)、MT(例如，内毒素)、炎症(IL 6)和TMAO；以及(3)增加血清生物标志物和改变心脏超声心动图(Echo)测量 功能(N-末端脑利尿肽原、NT-BNP原、左心室射血分数、LVEF、 )。为了验证这些假设，我们将从圣彼得艾滋病毒基金会招募200名HIV+参与者。 RCT使用药物治疗来减少饮酒、吸烟、炎症和心血管疾病的风险。此应用程序， 酒精相关的心血管疾病和微生物组评估研究(ACME HIV 1/2)利用圣彼得堡大学现有的资源。 彼得·艾滋病毒：参与者招募、酒精消费衡量、生物样本和生物标记物收集； 在酒精、艾滋病毒、心血管疾病和微生物基因组学方面的专业知识。新数据包括：粪便样本以表征 胃肠道微生物组、血清生物标记物和回声测量。为响应RFA-AA-17-014，我们将与 南方艾滋病毒与酒精研究联盟(SHARC，ACME HIV 2/2)以证实我们在 目标1和目标2，并进行联合交叉队列分析。我们将完成以下具体目标 HIV+酗酒者：目标1：评估肠道的纵向质量和数量变化 与大量饮酒相关的微生物群(微生物失调)。目标2：确定 肠道通透性、MT、炎症和TMAO水平上的生物失调。目标3：调查以下方面的影响 心脏结构和功能的生物标记物和回声测量上的生物失调。完成这些目标 将为针对酒精相关的生物失调的干预奠定基础，这可能会大大减少 炎症和有利地影响艾滋病毒+酗酒者的心血管疾病风险。

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.