Autonomic neuropathy, gastrointestinal motility, and inflammation in HIV

HIV 的自主神经病变、胃肠道运动和炎症

• 批准号: 9110258
• 负责人: Jessica Robinson-Papp
• 金额: $ 20.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110258
• 关键词: AIDS/HIV problem; Acetylcholine; Acetylcholinesterase Inhibitors; Address; Anti-Inflammatory Agents; Anti-inflammatory; Autonomic Dysfunction; Autonomic nervous system; Autonomic nervous system disorders; Blood Pressure; Breath Tests; Cells; Chronic; Complex; Constipation; Data; Digestion; Disease; Disease Progression; FDA approved; Functional disorder; Gastric Emptying; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; HIV; Health; Heart Rate; Hydrogen; Immune; Immunologic Markers; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intestines; Life; Lipopolysaccharides; Measures; Mediating; Morbidity - disease rate; Nausea and Vomiting; Nervous System control; Neurotransmitters; Oral; Organ; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Radionuclide Imaging; Recruitment Activity; Research; T-Cell Activation; Testing; Vagus nerve structure; alpha-bungarotoxin receptor; antiretroviral therapy; autonomic neuropathy; cell motility; cholinergic; effective therapy; gastrointestinal; gastrointestinal function; gastrointestinal symptom; heart rate variability; immune activation; immune function; improved; macrophage; meetings; microbial; motility disorder; pyridostigmine; standardize measure; study population

 DESCRIPTION (provided by applicant): HIV-infected patients commonly develop autonomic neuropathy (HIV-AN), which is a heterogeneous disorder characterized by varying degrees of both sympathetic and vagal dysfunction. We hypothesize that the vagal component of HIV-AN contributes to chronic inflammation, both directly via loss of cholinergic activity, and indirectlyvia effects on the gastrointestinal (GI) tract, and that these effects will be treatable using the acetylcholinesterase inhibitor pyridostigmine. The autonomic nervous system controls the inflammatory response to lipopolysaccharide (LPS) via the cholinergic anti-inflammatory pathway. This pathway is mediated by the vagus nerve, and is therefore likely impaired in HIV-AN with vagal dysfunction. Vagal dysfunction also causes slowed GI transit, which could exacerbate LPS-driven inflammation by promoting bacterial overgrowth. However, the anti-inflammatory impact of cholinergic pathways is almost completely unstudied in HIV, despite the known importance of inflammation in HIV disease progression. Therefore, in this exploratory pilot, we seek to establish associations between vagal dysfunction, GI motility and inflammation in virally suppressed, CART- treated individuals with HIV-AN. Specific Aim 1: To determine whether vagal dysfunction is associated with immune activation in CART- treated participants with HIV-AN, and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vaga dysfunction. Specific Aim 2: In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if the immune effect depends on the GI effect. To achieve these aims, we will recruit 80-100 participants with HIV-AN and GI symptoms who will be assessed for: vagal dysfunction (heart rate variability); GI dysmotility (gastric emptying scintigraphy); small intestinal bacterial overgrowth (breath testing); microbial translocation (LPS and sCD14); and immune activation (IL-6 and CRP). Participants meeting threshold criteria for both vagal and GI dysfunction will then be treated with pyridostigmine for 8 weeks, after which GI and immune measures will be reassessed.

 描述（由申请人提供）：HIV 感染者通常会出现自主神经病变（HIV-AN），这是一种异质性疾病，其特征是不同程度的交感神经和迷走神经功能障碍。我们发现 HIV-AN 的迷走神经成分会导致慢性。炎症，直接通过胆碱能活性的丧失，以及间接通过对胃肠道（GI）的影响，并且这些影响可以使用乙酰胆碱酯酶抑制剂来治疗吡啶斯的明。自主神经系统通过胆碱能抗炎途径控制对脂多糖（LPS）的炎症反应，该途径由迷走神经介导，因此迷走神经功能障碍可能会导致 HIV-AN 受损。胃肠道转运可能通过促进细菌过度生长而加剧 LPS 驱动的炎症然而，胆碱能途径的抗炎作用在 HIV 中几乎完全没有被研究过。尽管已知炎症在 HIV 疾病进展中的重要性，因此，在这项探索性试验中，我们试图在病毒抑制、CART 治疗的 HIV-AN 患者中建立迷走神经功能障碍、胃肠道运动和炎症之间的关联。迷走神经功能障碍是否与 CART 治疗的 HIV-AN 参与者的免疫激活有关，如果是，则估计这种关联在多大程度上是由胃肠道效应介导的（即运动减慢、细菌过度生长、具体目标 2：在同时患有迷走神经和胃肠道功能障碍的参与者中，研究 8 周的吡斯的明是否：a) 减少免疫激活，b) 改善胃肠道运动；免疫效果取决于胃肠道效果 为了实现这些目标，我们将招募 80-100 名患有 HIV-AN 和胃肠道症状的参与者，他们将接受以下评估： 迷走神经功能障碍（心率）胃肠道运动障碍（胃排空闪烁扫描）；小肠细菌过度生长（呼吸测试）；微生物易位（LPS 和 sCD14）；以及满足迷走神经和胃肠道功能障碍阈值标准的参与者。使用吡斯的明治疗 8 周，之后将重新评估胃肠道和免疫措施。