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.

HIV感染（HIV+）的重度饮酒者通过多种途径有患心血管疾病（CVD）的风险。重