Autonomic neuropathy, gastrointestinal motility, and inflammation in HIV

 描述（由申请人提供）：HIV感染患者通常发生自主神经病变（HIV-AN），这是一种异质性疾病，其特征在于不同程度的交感神经和迷走神经功能障碍。我们假设HIV-AN的迷走神经成分直接通过胆碱能活性的丧失和间接通过对胃肠道（GI）的影响导致慢性炎症，并且这些影响可以使用乙酰胆碱酯酶抑制剂吡啶斯的明治疗。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。该通路由迷走神经介导，因此可能在具有迷走神经功能障碍的HIV-AN中受损。迷走神经功能障碍也会导致GI传输减慢，这可能会通过促进细菌过度生长来加剧LPS驱动的炎症。然而，胆碱能途径的抗炎作用在HIV中几乎完全未被研究，尽管炎症在HIV疾病进展中的重要性是已知的。因此，在该探索性试验中，我们寻求在病毒抑制、CART治疗的HIV-AN个体中建立迷走神经功能障碍、GI运动和炎症之间的关联。具体目标1：确定迷走神经功能障碍是否与CART治疗的HIV-AN受试者的免疫激活相关，如果相关，则估计GI效应（即运动减慢、细菌过度生长、微生物易位）与迷走神经功能障碍的直接效应介导的这种相关性的程度。具体目标二：在迷走神经和GI功能障碍的受试者亚组中，研究8周吡啶斯的明是否：a）减少免疫激活，和B）改善GI运动;以及免疫效应是否取决于GI效应。为了实现这些目标，我们将招募80-100名患有HIV-AN和GI症状的受试者，对他们进行以下评估：迷走神经功能障碍（心率变异性）; GI运动障碍（胃排空造影）;小肠细菌过度生长（呼吸测试）;微生物易位（LPS和sCD 14）;和免疫激活（IL-6和CRP）。符合迷走神经和GI功能障碍阈值标准的受试者将接受吡啶斯的明治疗8周，之后将重新评估GI和免疫指标。

 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.