Role of Gut Microbiome- Brain Axis in Modulating CNS Inflammasomes in the Neuropathology Produced by Opioid Exposure and HIV

肠道微生物组-脑轴在阿片类药物暴露和 HIV 产生的神经病理学中调节中枢神经系统炎症小体的作用

• 批准号: 10020183
• 负责人: Sabita Roy
• 金额: $ 37.97万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020183
• 关键词: Acquired Immunodeficiency Syndrome; Alcohol or Other Drugs use; Animals; Antibiotics; Attention; Attenuated; Bacterial Translocation; Binding; Biological; Brain; Breeding; Cells; Chronic; Complex; Data; Development; Disease; Disease Progression; Drug abuse; Drug usage; Drug user; Endotoxins; Enterococcus faecalis; Extravasation; Firmicutes; Functional disorder; Genes; Germ-Free; Gram-Negative Bacteria; Gram-Positive Bacteria; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Immune; Immune system; Individual; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Leaky Gut; Ligands; LoxP-flanked allele; Microglia; Modeling; Molecular; Morphine; Mus; Neurocognitive; Neuropathogenesis; Opiate Addiction; Opioid; Patients; Pattern; Predisposition; Prevalence; Probiotics; Production; Proteins; Ribosomes; Rodent Model; Role; Signal Pathway; Signal Transduction; TLR2 gene; Testing; Tissues; Toll-like receptors; bacterial community; cytokine; drug abuser; dysbiosis; gut microbiome; gut microbiota; marenostrin; microbial; microbiota; neurocognitive disorder; neuroinflammation; neuropathology; opioid abuse; opioid exposure; opioid use; pathogen; receptor; sex

Abstract/Project Summary Chronic opioid use is associated with gut microbial dysbiosis, gut barrier disruption and systemic bacterial translocation. Gut leakiness, microbial translocation and systemic inflammation are hallmarks of HIV disease progression. In recent years, much attention has been focused towards elucidating the impact of Toll-like receptors (TLRs) in microglial activation and NLRP3 inflammasome assembly as a mechanism for sustained neuroinflammation and neurocognitive disease progression. While previous studies have investigated the direct effect of HIV associated toxic proteins (TAT and gp120) and opioids on inflammasome activation on microglial little is known about the role of gut derived products and their impact on inflammasome activation and neurocognitive disorders that are prevalent in substance using HIV patients. Although most studies correlate endotoxin levels and bacterial products derived from gram-negative bacteria with inflammation and HIV disease progression, recent studies clearly show a distinct enrichment and prevalence of gram positive bacterial communities in HIV infected patients when compared to normal healthy individuals. Our central hypothesis is that microbial dysbiosis with predominant expansion of Gram positive bacterial communities leading to systemic leakage of G+ bacterial products serve as cognate ligands on TLR2 on microglial cells leading to TLR2 activation and induction of inflammasome components assembly. Our central hypothesis is supported by the following preliminary data. Using a rodent model of HIV in the context of drug abuse, we demonstrate 1) Significant increase in a) gut bacterial translocation b) systemic inflammation c) NLRP3 expression on microglial cells in HIV infected animals that are dramatically exacerbated in HIV+ Morphine treated animals when compared to their respective controls. 2) Morphine induced NLRP3 expression is only observed in the presence of TLR2 cognate ligand in BV2 microglial cells. We will test the hypothesis that gut- microbiota immune brain axis activate inflammasome signaling pathways in brain microglial cells leading to sustained inflammation contributing to the neuropathology of HAND in an opioid abusing HIV infected patients. Aim 1: We will establish the role of the gut microbiota in microglial inflammasome activation using a) germ free mice b) differential antibiotic (gram specific depletion)treated mice and c) infection with gram positive Enterococcus Faecalis. We will also investigate if sex of the animals serves as a biological variable in microglia NLRP3 activation in our model of opioid dependence in the context of HIV infection. Aim 2: Determine the role of TLR2 in NLRP3 induction in microglial cells using tissue specific deletion by breeding floxed TLR2 with microglial specific cre expression using Cx3Cr1 Cre mice. Aim 3: Determine if combination of probiotics and TLR2 antagonist attenuate NLRP3 induction on microglial cells.

抽象/项目总结