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

1/2 HIV 酒精相关合并症和微生物组评估 (ACME HIV)

• 批准号: 9408280
• 负责人: SHIRISH S BARVE
• 金额: $ 68.42万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408280
• 关键词: Address; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Animals; Attenuated; Bacteria; Biodiversity; Bioinformatics; Biological Markers; Blood; Blood Circulation; Brain; Butyrates; Cardiac; Cardiovascular Diseases; Cohort Analysis; Collection; Comorbidity; Data; EFRAC; Endotoxins; Enrollment; Evaluation; Evaluation Studies; Funding; Future; Gastrointestinal tract structure; Genomics; HIV; HIV Infections; Heart failure; Heavy Drinking; Hepatic; Human; Inflammation; Inflammatory; Interleukin-6; Intervention; Intestines; Knowledge; Left Ventricular Ejection Fraction; Measures; Membrane; N-terminal; Oxidative Stress; Participant; Pathway interactions; Patient Self-Report; Peptides; Permeability; Pharmacotherapy; Prevotella; Probiotics; Process; Production; Randomized Controlled Trials; Recruitment Activity; Resources; Sample Size; Sampling; Serum; Site; Smoking; Structure; Testing; Tight Junctions; Work; alcohol measurement; alcohol research; antiretroviral therapy; cardiovascular disorder risk; gastrointestinal; gut microbiome; heart disease risk; heart function; immune activation; intestinal fatty acid binding protein; microbial; microbiome; microbiota; mouse model; new therapeutic target; pro-brain natriuretic peptide (1-76); reduced alcohol use; response; sex; therapeutic target; therapy design; trimethyloxamine

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.

感染艾滋病毒（HIV+）的酗酒者存在通过多种途径罹患心血管疾病（CVD）的风险。重的 饮酒会导致微生物移位 (MT) 和炎症。此外，与酒精相关的变化 胃肠道微生物组（称为生态失调）是这种促炎症级联反应的核心，可以作为新的 降低艾滋病毒+重度饮酒者的心血管疾病风险的治疗目标。酒精相关的生态失调是 其特征是肠道细菌生物多样性丧失、“有益”细菌减少和/或细菌数量增加 有害或“促炎”细菌（例如，产生三甲胺 N-氧化物 (TMAO) 的细菌，一种 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 即使在持续饮酒的情况下，益生菌也会减弱，但仍然不足 确定人类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）人类研究样本量小，HIV+参与者很少，并且缺乏纵向研究 评估与胃肠道微生物群相关的酒精摄入量、炎症和心血管疾病风险。这个应用程序 解决这些差距。我们假设酒精相关的生态失调将：（1）在 HIV+ 中更为严重 重度饮酒者（AUDIT 评分≥20）与重度饮酒者（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) TMAO； (3) 增加血清生物标志物并改变心脏超声心动图 (Echo) 测量值 功能（N 端脑自然肽原、NT 脑钠肽原、左心室射血分数、LVEF、 分别）。为了检验这些假设，我们将招募 200 名来自 St. PETER HIV 的 HIV+ 参与者，St. PETER HIV 是一家受资助的机构。 使用药物疗法来降低饮酒、吸烟、炎症和心血管疾病风险的随机对照试验。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) 利用圣路易斯的现有资源。 PETER HIV：参与者招募、饮酒量测量、生物样本和生物标志物收集； 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：粪便样本来表征 胃肠道微生物组、血清生物标志物和回声测量。为了响应 RFA-AA-17-014，我们将与 南方艾滋病毒和酒精研究联盟（SHARC，ACME HIV 2/2）证实了我们的研究结果 目标 1 和 2 并进行组合的跨队列分析。我们将完成以下具体目标 HIV+ 重度饮酒者：目标 1：评估肠道的纵向定性和定量变化 微生物组（生态失调）与大量饮酒有关。目标 2：确定效果 肠道通透性、MT、炎症和TMAO水平的菌群失调。目标 3：调查影响 心脏结构和功能的生物标志物和回波测量的生态失调。完成这些目标 将为针对酒精相关生态失调的干预措施奠定基础，这可能会大大减少 炎症并对 HIV+ 重度饮酒者的 CVD 风险产生有利影响。