Role of Gut Microbial Dysbiosis and Aging on HIV-associated neurocognitive and brain dysfunction

肠道微生物失调和衰老对 HIV 相关神经认知和脑功能障碍的作用

• 批准号: 10410552
• 负责人: SHIRISH S BARVE
• 金额: $ 74.24万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410552
• 关键词: 16S ribosomal RNA sequencing; Acquired Immunodeficiency Syndrome; Address; Adult; Age; Aging; Automobile Driving; Bacterial Genes; Brain; Cerebrum; Clinical Research; Cognitive aging; Data; Diffusion Magnetic Resonance Imaging; Elderly; Endotoxemia; Florida; Functional disorder; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Impaired cognition; Individual; Infection; Inflammaging; Inflammation; Intestinal permeability; Longitudinal Studies; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Metabolic; Nerve Degeneration; Neurocognitive; Neuropathogenesis; Pathogenicity; Peripheral; Persons; Phylogeny; Play; Population; Prevalence; Process; Resolution; Rest; Role; Sample Size; Serum; Severities; Shotguns; Structure; Taxonomy; Testing; United States National Institutes of Health; Universities; White Matter Hyperintensity; age effect; alcohol research; base; brain abnormalities; brain dysfunction; cognitive function; cooking; cytokine; dysbiosis; gut dysbiosis; gut microbiome; gut-brain axis; healthy aging; immune activation; immunosenescence; metagenomic sequencing; microbial; microbial community; microbiome; microbiome alteration; microbiota; multimodality; neuroinflammation; pre-clinical; rRNA Genes; systemic inflammatory response; white matter; whole genome

Although AIDS-defining illnesses have decreased, the prevalence of HIV-associated non-AIDS conditions such as HIV-Associated Neurocognitive Disorders (HAND) remains high and is estimated to be over 50%, particularly in aging individuals with long-standing HIV infection. However, the pathophysiology of HAND in aging HIV+ adults remains unresolved. Current evidence and our preliminary data suggest that interactions of altered gut microbiome (dysbiosis), gut-derived microbial translocation, and systemic inflammation contribute to neurodegenerative processes. It is becoming increasingly evident that in both HIV-1 infection and aging, alterations in gut microbiome (dysbiosis) and ensuing increase in intestinal permeability and microbial translocation (MT) are major pathogenic drivers of local and systemic inflammation. Importantly, aging- associated microbiota changes are shown to be connected to immunosenescence and inflammaging. Preclinical/clinical studies using bacterial 16S ribosomal RNA (rRNA) gene sequencing, indicate that microbial dysbiosis associated with HIV-1 infection or aging has several common pathogenic features. However, these studies were largely hypothesis-generating with limited sample sizes, and were not adequately powered to address microbiome endpoints after correction for multiple testing, and did not reveal the functional potential of the microbiota (pathogenic or beneficial), or yield bacterial resolution to species or strain level. The current proposal will address these limitations by using an adequately powered longitudinal study and will conduct 16S rRNA gene and Whole Genome Shotgun (WGS) metagenomic sequencing that will determine bacterial composition and diversity, provide identification at the species and strain level, and enable the functional characterization of the bacterial genes. Our overarching hypothesis is that the interactive effects of aging and HIV-1 infection at the level of gut dysbiosis and permeability, and ensuing local and systemic inflammation play a major pathogenic role in driving HIV infection and aging-associated neuroinflammation and cognitive dysfunction. To test these hypotheses, we will leverage and utilize HIV+ and healthy aging populations from ongoing NIH-sponsored longitudinal studies at the Universities of Louisville (UofL) and Florida (UF) with the following specific aims: Aim 1: To assess longitudinal qualitative and quantitative changes in the gut microbiome (dysbiosis) in older persons living with HIV-1 infection. Aim 2: To determine the impact of HIV-1 infection and age associated gut dysbiosis on (A) intestinal permeability and microbial translocation (MT), and resultant peripheral endotoxemia, and inflammation; and (B) multimodal MRI/MRS measures of neuroinflammation and cerebral metabolic disturbance. Aim 3: To investigate the impact of gut dysbiosis and peripheral and neuroinflammation, and cerebral metabolic disturbance on cognitive dysfunction and functional brain abnormalities (FMRI) relative to age and HIV status.

尽管定义艾滋病的疾病有所下降，但与HIV相关的非AIDS条件的患病率这样 由于艾滋病毒相关的神经认知障碍（手）仍然很高，据估计超过50％， 特别是在长期患有艾滋病毒感染的人的老年人中。但是，手中的病理生理学 衰老的HIV+成年人仍未解决。当前的证据和我们的初步数据表明相互作用 肠道微生物组改变（营养不良），肠衍生的微生物易位和全身炎症 有助于神经退行性过程。越来越明显的是，在HIV-1感染和 衰老，肠道微生物组（营养不良）的改变以及随之而来的肠道通透性和微生物的增加 易位（MT）是局部和全身性炎症的主要病原体驱动因素。重要的是，老化 - 相关的微生物群变化显示与免疫衰老和炎症有关。 使用细菌16S核糖体RNA（RRNA）基因测序的临床前/临床研究，表明微生物 与HIV-1感染或衰老有关的营养不良具有几种常见的致病特征。但是，这些 研究在很大程度上是假设生成的，样本量有限，并且没有足够的动力 校正后处理微生物组的端点，以进行多次测试，并且没有揭示 微生物群（致病性或有益），或产生细菌分辨率到物种或应变水平。电流 提案将通过使用足够动力的纵向研究来解决这些局限性，并将进行16S rRNA基因和全基因组shot弹枪（WGS）元基因组测序将决定细菌 组成和多样性，在物种和应变水平上提供识别，并启用功能 细菌基因的表征。我们的总体假设是衰老的互动效应 在肠道营养不良和渗透率水平上感染HIV-1感染，随之而来的是局部和全身性 炎症在驱动艾滋病毒感染和衰老相关方面起着主要的致病作用 神经炎症和认知功能障碍。为了检验这些假设，我们将利用和利用HIV+ 以及来自路易斯维尔大学正在进行的NIH赞助的NIH赞助的纵向研究的健康老龄化人群 （UOFL）和佛罗里达州（UF）具有以下具体目的：目标1：评估纵向定性和 HIV-1感染的老年人的肠道微生物组（营养不良）的定量变化。 目的2：确定HIV-1感染和与年龄相关的肠癌对（a）肠道的影响 渗透性和微生物易位（MT）以及由此导致的外周内毒素血症和 炎; （b）神经炎症和大脑代谢的多模式MRI/MRS测量 干扰。目标3：研究肠道营养不良，周围和神经炎症的影响， 以及对认知功能障碍和功能性脑异常（fMRI）的脑代谢紊乱（fMRI） 相对于年龄和艾滋病毒状况。