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

虽然艾滋病定义疾病有所减少，但与艾滋病毒有关的非艾滋病状况， 由于HIV相关的神经认知障碍（HAND）仍然很高并且估计超过50%， 特别是在长期感染艾滋病毒的老年人中。然而，HAND的病理生理学在 艾滋病毒阳性成年人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， 肠道微生物组改变（生态失调）、肠道源性微生物易位和全身性炎症 导致神经退行性病变越来越明显的是，在HIV-1感染和 衰老、肠道微生物组的改变（生态失调）以及随后的肠道通透性和微生物 易位（MT）是局部和全身性炎症的主要致病驱动因素。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16 S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具有几个共同的致病特征。但这些 研究主要是假设生成，样本量有限，没有足够的把握度， 在多次测试校正后解决微生物组终点，并且没有揭示 微生物群（致病的或有益的），或将细菌分解到物种或菌株水平。当前 提案将通过使用充分把握度的纵向研究来解决这些限制，并将进行16 S rRNA基因和全基因组鸟枪（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，并使功能 细菌基因的特征。我们的总体假设是， 和HIV-1感染在肠道生态失调和渗透性水平，以及随后的局部和全身 炎症在驱动HIV感染和衰老相关疾病中起主要致病作用 神经炎症和认知功能障碍。为了验证这些假设，我们将利用艾滋病毒+ 和健康的老龄化人口从正在进行的美国国立卫生研究院赞助的纵向研究在路易斯维尔大学 （UofL）和佛罗里达（UF），具体目标如下：目标1： 感染艾滋病毒的老年人肠道微生物组的数量变化（生态失调）。 目的2：确定HIV-1感染和年龄相关的肠道生态失调对（A）肠道 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 （B）神经炎症和脑代谢的多模式MRI/MRS测量 扰动目的3：研究肠道生态失调和外周及神经炎症的影响， 脑代谢紊乱对认知功能障碍和脑功能异常的影响 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.