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.