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

2/2 HIV 中酒精相关合并症和微生物组评估 (ACME HIV)

• 批准号: 9768891
• 负责人: SHIRISH S BARVE
• 金额: $ 59.94万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768891
• 关键词: 16S ribosomal RNA sequencing; Address; Adverse effects; Alcohol abuse; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Automobile Driving; Bacteria; Bacterial Genes; Behavior assessment; Biodiversity; Biological Markers; Brain; Chronic; Clinical Research; Cognition; Cognitive; Cohort Analysis; Cohort Studies; Collection; Comorbidity; Data; Development; Endotoxemia; Enrollment; Evaluation; Evaluation Studies; Florida; Functional disorder; Funding; Goals; HIV; HIV Infections; HIV-1; Heavy Drinking; Immune; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Intervention; Intestinal permeability; Link; Longitudinal Studies; Measures; Neurobiology; Neurocognitive; Neurocognitive Deficit; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Patient Recruitments; Peripheral; Phylogeny; Prospective cohort study; Research; Resolution; Resources; Role; Sample Size; Shotguns; Structure; Taxonomy; Testing; Virulence Factors; alcohol effect; alcohol measurement; alcohol research; clinically relevant; cognitive function; cognitive performance; cognitive testing; combinatorial; contingency management; cooking; drinking; dysbiosis; gut microbiome; gut microbiota; gut-brain axis; immune activation; improved; metagenomic sequencing; microbial; microbial community; microbiome; microbiome alteration; microbiota; motivational enhancement therapy; neuroimaging; neuroinflammation; outcome prediction; payment; preclinical study; prospective; relating to nervous system; response; targeted treatment; whole genome

Heavy alcohol drinking and HIV-1 infection are independently associated with the development of abnormalities in the brain function and cognition, and increasing evidence indicates that the combinatorial effects of HIV infection and alcohol are likely to worsen these abnormalities. Significantly, both HIV- 1 infection and chronic alcohol abuse cause alterations in gut microbiome (dysbiosis) and increase intestinal permeability and microbial translocation (MT) which are major pathogenic factors driving local and systemic inflammation. The dysbiosis is characterized by loss of gut bacterial biodiversity, a reduction in beneficial bacteria, and/or an expansion of harmful or pro-inflammatory bacteria. However, there is limited understanding of (i) the interactive effects of heavy alcohol drinking and HIV-1 infection on gut dysbiosis and (ii) the longitudinal qualitative (microbial membership) and quantitative (relevant abundance) determinants of dysbiosis. The current proposal addresses these gaps with an overall goal to promote the development of rational therapies targeting gut dysbiosis. Accordingly, we pursue a unifying hypothesis that in HIV-infected individuals, heavy alcohol use compounds gut dysbiosis and consequent peripheral immune inflammation leading to exacerbation of neuro- inflammation and cognitive dysfunction. To test these hypotheses, we will enroll 100 HIV+ participants from “30-to-90-day challenge” Florida SHARC study (AA020797). This is a funded prospective cohort study in which enrolled heavy drinkers are challenged to stop drinking for 30 to 90 days, assisted by contingency management (CM) payments and motivational interviewing. This application, Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV 2/2) leverages the existing resources of “30-to-90-day challenge” Florida SHARC study: participant recruitment, measures of alcohol consumption, biospecimen and biomarker collection; expertise in alcohol, HIV and neuroimaging. New data include: longitudinal changes in gut dysbiosis, correlative changes in peripheral inflammation, and measures of cognition and neuroinflammation. In response to RFA-AA-17-014, we will partner with the St. PETER HIV study (ACME HIV 1/2) 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 impact of HIV infection and alcohol abuse induced gut dysbiosis on intestinal permeability, microbial translocation (MT), and resultant peripheral endotoxemia, immune activation and inflammation. AIM 3: To investigate the impact of dysbiosis and peripheral inflammation on development of neuro-inflammation and cognitive function. Completion of these aims will lay groundwork for an intervention targeting alcohol-associated dysbiosis, which could profoundly reduce inflammation and improve cognitive functions in HIV+ heavy drinkers.

大量饮酒和 HIV-1 感染与以下疾病的发生独立相关： 大脑功能和认知的异常，并且越来越多的证据表明组合 值得注意的是，HIV 感染和酒精的影响可能会使这些异常情况恶化。 长期酗酒会导致肠道微生物组改变（菌群失调）并增加肠道通透性 和微生物易位（MT），它们是驱动局部和全身炎症的主要致病因素。 生态失调的特征是肠道细菌生物多样性丧失、有益细菌减少和/或 然而，对（i）相互作用的了解有限。 大量饮酒和 HIV-1 感染对肠道菌群失调的影响以及 (ii) 纵向定性 （微生物成员）和定量（相关丰度）生态失调的决定因素。 这些解决了差距，总体目标是促进针对肠道的合理疗法的开发 因此，我们追求一个统一的假设，即艾滋病毒感染者会大量饮酒。 肠道菌群失调和随之而来的外周免疫炎症导致神经系统恶化 为了测试这些假设，我们将招募 100 名 HIV + 参与者。 “30 至 90 天挑战”佛罗里达 SHARC 研究 (AA020797) 这是一项受资助的前瞻性队列研究，其中 登记的重度饮酒者面临 30 至 90 天内戒酒的挑战，并有应急援助 管理（CM）付款和动机访谈此应用程序与酒精相关。 HIV 合并症和微生物组评估 (ACME HIV 2/2) 利用以下机构的现有资源： “30 至 90 天的挑战”佛罗里达 SHARC 研究：参与者招募、饮酒量测量、 生物样本和生物标志物收集；酒精、艾滋病毒和神经影像学方面的专业知识包括： 肠道菌群失调的纵向变化、周围炎症的相关变化以及 为了响应 RFA-AA-17-014，我们将与 St. PETER HIV 合作。 研究（ACME HIV 1/2）以证实我们在目标 1 和 2 中的发现并进行联合跨队列研究 我们将在 HIV+ 重度饮酒者中完成以下具体目标： 目标 1：评估。 与非常重的肠道菌群相关的纵向定性和定量变化（菌群失调） 目标 2：确定 HIV 感染和酗酒引起的肠道菌群失调的影响。 肠道通透性、微生物易位（MT）以及由此产生的外周内毒素血症、免疫 目标 3：研究生态失调和外周炎症对细胞的影响。 神经炎症和认知功能的发展将为实现这些目标奠定基础。 针对酒精相关生态失调的干预措施，可以显着减少和改善炎症 HIV+重度饮酒者的认知功能。