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: 10242623
• 负责人: SHIRISH S BARVE
• 金额: $ 74.75万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242623
• 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; 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.

虽然艾滋病定义疾病有所减少，但与艾滋病毒相关的非艾滋病疾病的流行率却有所下降