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.

感染了艾滋病毒（HIV+）饮酒者有多种途径有心血管疾病（CVD）的风险。重的 酒精使用会导致微生物易位（MT）和炎症。此外，与酒精相关的变化 胃肠道微生物组 - 伴疾病障碍 - 这是这种促炎级联的核心，可以用作新颖的 降低艾滋病毒+饮酒者中CVD风险的治疗靶标。酒精相关的营养不良是 其特征是肠道细菌生物多样性的丧失，“有益”细菌的降低和/或膨胀 有害或“促炎性”细菌（例如，产生三甲胺N-氧化物（TMAO）的细菌，A 代谢物与CVD风险增加有关）。鼠模型显示与酒精相关的营养不良是 即使在持续的饮酒量的情况下，益生菌也会减弱，仍然不足 知识以确定人类的治疗靶标的两个原因：1）大多数研究涉及鼠模型； 2）人类研究很少，较少的HIV+参与者的样本量很小，并且缺乏纵向 评估酒精摄入量，炎症和CVD风险与GI微生物组有关。此应用程序 解决这些差距。我们假设与酒精相关的营养不良将：（1）在HIV+中更大 重量饮酒者（审计得分≥20）与重量饮酒者（审核<20）； （2）提高肠生物标志物水平 渗透性（例如，肠道脂肪酸结合蛋白（IFABP），MT（例如内毒素），炎症（白介素 6）和tmao; （3）增加心脏心动图（Echo）心脏的血清生物标志物 功能（N末端Pro脑自然肽，NT Pro-BNP和左心室射血分数，LVEF， （分别）。为了检验这些假设，我们将注册来自圣彼得艾滋病毒的200名HIV+参与者 RCT使用药物疗法来减少酒精使用，吸烟，注射和CVD风险。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St.的现有资源 彼得·艾滋病毒（Peter HIV）：参与者招募，饮酒量度，生物含量和生物标志物收集； 酒精，艾滋病毒，CVD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 GI微生物组，血清生物标志物和回声测量。为了回应RFA-AA-17-014，我们将与 南部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进行横断面分析。我们将完成以下特定目标 在艾滋病毒+饮酒者中：目标1：评估肠道纵向定性和定量变化 与饮酒非常大的微生物组（营养不良）。目标2：确定 肠道通透性，MT，创新和TMAO水平的营养不良。目标3：调查 心脏结构和功能的生物标志物的营养不良。这些目标的完成 将为针对酒精相关的营养不良的干预措施奠定基础，这可以极大地减少 炎症并有利影响艾滋病毒+饮酒者的CVD风险。