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

尽管艾滋病定义的疾病已经减少，但艾滋病毒相关的非艾滋病疾病的流行率 由于与艾滋病毒相关的神经认知障碍(HAND)仍然很高，估计超过50%， 特别是在长期感染艾滋病毒的老年个人中。然而，手牵手的病理生理学 老龄化的艾滋病毒+成年人仍然没有得到解决。目前的证据和我们的初步数据表明，相互作用 肠道微生物群改变(生物失调)、肠源性微生物易位和全身炎症 有助于神经退化过程。越来越明显的是，在艾滋病毒-1感染和 衰老、肠道微生物群的改变(生物失调)以及随之而来的肠道通透性和微生物的增加 移位(MT)是局部和全身炎症的主要致病因素。重要的是，老化- 相关的微生物区系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物失调有几个共同的致病特征。然而，这些 研究主要是假设产生的，样本量有限，没有足够的动力来 在多次测试校正后定位微生物组终点，并未揭示其功能潜力 微生物区系(致病的或有益的)，或产生细菌分解到物种或菌株水平。海流 Proposal将通过使用足够强大的纵向研究来解决这些限制，并将进行16 RRNA基因和全基因组鸟枪法(WGS)元基因组测序将决定细菌 组成和多样性，在物种和菌株水平上提供鉴定，并使功能 细菌基因的特征。我们的主要假设是，老龄化的交互影响 以及肠道生物失调和渗透性水平的艾滋病毒-1感染，以及随后的局部和全身感染 炎症是导致HIV感染和衰老的主要致病因素 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+ 来自路易斯维尔大学正在进行的NIH赞助的纵向研究的健康老龄化人口 (UofL)和佛罗里达(UF)，具体目标如下：目标1：评估纵向定性和 感染HIV-1的老年人肠道微生物群的数量变化(生物失调)。 目的2：确定HIV-1感染和年龄相关性肠道菌群失调对(A)肠道的影响 通透性和微生物易位(MT)以及由此产生的外周内毒素血症，以及 炎症；以及(B)神经炎症和脑代谢的多模式MRI/MRS测量 骚乱。目的3：探讨肠道菌群失调与外周和神经性炎症的关系。 认知功能障碍和功能性脑异常的脑代谢障碍(FMRI) 与年龄和艾滋病毒状况有关。

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.