Effects of Vagal Dysfunction on Gastrointestinal and Inflammatory Pathways in HIV

迷走神经功能障碍对 HIV 胃肠道和炎症通路的影响

• 批准号: 10356148
• 负责人: Jessica Robinson-Papp
• 金额: $ 84.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-11 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356148
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Affect; Age; Bacterial Translocation; Biological Markers; Blood; Breath Tests; Chronic; Collection; Development; Disease Progression; Dose; Double-Blind Method; Functional disorder; Gastric Acid; Gastrointestinal Transit; Gastrointestinal tract structure; Gender; Goals; HIV; HIV Infections; HIV Seronegativity; High Prevalence; Hydrogen; Hypochlorhydria; Immune; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Intervention; Light; Link; Logistic Regressions; Macrophage Activation; Measurement; Mediating; Medical; Methane; Modification; Morbidity - disease rate; Mucous Membrane; Nerve; Neuropathy; Oral; Participant; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Procedures; Process; Production; Proxy; Randomized; Research; Rodent Model; Signal Transduction; Small Intestines; Stimulus; Swab; TNF gene; Testing; Time; Vagus nerve structure; Viral; Work; antiretroviral therapy; capsule; cell motility; cholinergic; cohort; comorbidity; cytokine; follow-up; gastrointestinal; gastrointestinal function; gut microbiome; immune function; inflammatory marker; macrophage; mortality; motility disorder; open label; pyridostigmine; recruit; sample collection; stool sample; vagus nerve stimulation; wireless

Project summary Chronic HIV infection produces pathologic inflammation which drives disease progression and contributes to the development of serious co-morbid medical conditions, even in the setting of effective combination antiretroviral therapy (CART); translocation of bacterial products across the gastrointestinal (GI) mucosa is a major antigenic stimulus for this process. Our research focuses on how vagal dysfunction (VD), which occurs commonly as part of HIV-associated neuropathy, affects GI and immune function in HIV. Our prior work has shown that HIV+ individuals with VD have a high prevalence of small intestinal bacterial overgrowth (SIBO), and that SIBO is associated with elevation of the pro-inflammatory cytokine IL-6, which predicts morbidity and mortality in HIV. We have also demonstrated that treatment with the acetylcholinesterase inhibitor pyridostigmine, reduces indirect markers of bacterial translocation (sCD14) and the pro-inflammatory cytokine TNFα. The current proposal builds on this work, with the overarching goal of examining vagally-mediated GI mechanisms which could contribute to chronic inflammation in individuals with well-controlled HIV. Specifically we will seek to establish that small intestinal dysmotility and hypochlorhydria mediate the relationship between VD and SIBO, and to describe the changes in the GI microbiome in PLWH with SIBO. We will also determine whether VD is associated with elevations in IL-6 and TNFα independent of SIBO, establish to what degree the strength of these relationships depend on the presence of HIV infection, and whether they are reversible using pyridostigmine and/or non-invasive vagal nerve stimulation (nVNS). To achieve these aims, we will recruit 150 HIV+ participants who will undergo autonomic function tests for VD, hydrogen methane breath testing for SIBO, Wireless Motility Capsule (WMC, Smartpill) testing for GI regional transit times and pH measurements, oral and stool sample collection for characterization of the GI microbiome, and blood draw for quantification of inflammatory biomarkers. HIV-negative controls (N=100) will undergo the same assessments. Then a subset of 96 HIV+ participants will enter one of two eight-week interventional phases followed by repetition of the same testing battery: 1) double-blind treatment with pyridostigmine vs. placebo (N=86), or 2) open label treatment with non-invasive vagal nerve stimulation (N=10). These procedures will shed light on mechanisms linking VD to immune dysregulation in HIV, and provide support for potential therapies.

项目总结 慢性HIV感染会产生病理性炎症，从而推动疾病进展并导致 严重的合并症的发展，即使在有效结合的情况下 抗逆转录病毒疗法(CART)；细菌产物跨胃肠道(GI)粘膜的移位是一种 这一过程的主要抗原性刺激。我们的研究重点是迷走神经功能障碍(VD)是如何发生的 通常作为HIV相关神经病的一部分，影响HIV的胃肠道和免疫功能。我们之前的工作是 显示HIV+的VD患者有很高的小肠细菌过度生长(SIBO)的流行， SIBO与促炎细胞因子IL-6的升高有关，IL-6预测发病率和 艾滋病毒死亡率。我们还证明了用乙酰胆碱酯酶抑制剂治疗 吡斯的明，减少细菌易位的间接标志物(SCD14)和促炎细胞因子 肿瘤坏死因子α。目前的提案建立在这项工作的基础上，总体目标是检查迷走神经介导的胃肠道反应 控制良好的艾滋病毒感染者可能导致慢性炎症的机制。特指 我们将寻求建立小肠运动障碍和低盐酸血症之间的关系 VD和SIBO，并描述SIBO时PLWH中胃肠道微生物组的变化。我们还将确定 独立于SIBO的VD是否与IL-6和肿瘤坏死因子α的升高有关，确定在多大程度上 这些关系的强度取决于艾滋病毒感染的存在，以及它们是否可以通过 吡斯的明和/或非侵入性迷走神经刺激(NVNS)。为了实现这些目标，我们将招聘150名员工 HIV+参与者将接受VD的自主功能测试，氢甲烷呼气测试 SIBO，无线运动胶囊(WMC，SmartPill)GI区域转运时间和pH测量测试， 采集口腔和大便样本以确定胃肠道微生物群的特征，并抽取血液以进行定量 炎性生物标志物。艾滋病毒阴性对照(N=100)将接受相同的评估。然后是一个子集 96名HIV+参与者将进入两个为期八周的干预阶段之一，随后重复 相同的试验组合：1)吡斯的明双盲治疗与安慰剂(N=86)，或2)开放标签 采用无创迷走神经刺激治疗(N=10)。这些程序将阐明机制。 将VD与HIV的免疫失调联系起来，并为潜在的治疗提供支持。