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

基本信息

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
项目类别：
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

项目摘要

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.

尽管艾滋病定义的疾病有所减少，但与艾滋病毒相关的非艾滋病疾病的流行率，例如由于 HIV 相关神经认知障碍 (HAND) 仍然很高，估计超过 50%，尤其是长期感染艾滋病毒的老年人。然而，HAND 的病理生理学艾滋病病毒感染者的老龄化问题仍未得到解决。目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（生态失调）、肠道源性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、肠道微生物组的改变（生态失调）以及随之而来的肠道通透性和微生物的增加易位（MT）是局部和全身炎症的主要致病驱动因素。重要的是，衰老—— 相关的微生物群变化被证明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 感染或衰老相关的生态失调有几个常见的致病特征。然而，这些研究主要是在样本量有限的情况下提出假设，并且没有足够的动力在多次测试校正后解决微生物组终点，并且没有揭示其功能潜力微生物群（致病性或有益性），或将细菌分辨率达到物种或菌株水平。目前的提案将通过使用充分有力的纵向研究来解决这些局限性，并将进行 16S rRNA 基因和全基因组鸟枪法 (WGS) 宏基因组测序将确定细菌组成和多样性，提供物种和菌株水平的鉴定，并启用功能细菌基因的表征。我们的首要假设是衰老的相互作用和 HIV-1 感染在肠道菌群失调和通透性水平，以及随之而来的局部和全身炎症在驱动艾滋病毒感染和衰老相关的过程中发挥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 HIV+ 和健康老龄化人口来自美国国立卫生研究院资助的路易斯维尔大学正在进行的纵向研究（UofL）和佛罗里达州（UF）的具体目标如下：目标 1：评估纵向定性和 HIV-1 感染老年人肠道微生物群的数量变化（菌群失调）。目标 2：确定 HIV-1 感染和年龄相关肠道菌群失调对 (A) 肠道的影响渗透性和微生物易位（MT），以及由此产生的外周内毒素血症，以及炎; (B) 神经炎症和脑代谢的多模态 MRI/MRS 测量干扰。目标 3：研究肠道菌群失调以及外周和神经炎症的影响，和脑代谢紊乱对认知功能障碍和功能性脑异常（FMRI）的影响与年龄和艾滋病毒状况有关。