Brain-gut-immune Profiling in Connective Tissue Disorder-related Gastrointestinal Dysfunction

项目摘要/摘要 高活动度Ehler-Danlos综合征(HEDS)和高活动度谱系障碍(HSD)很常见，但 与过度发病率相关的未被诊断的情况。尽管认知度有所提高，但许多患者 仍被误诊为慢性疲劳综合征、纤维肌痛、心身和功能性胃肠道疾病等。 现在有大量数据将HEDS/HSD与“功能性”胃肠道症状和自主神经紊乱联系起来 系统(ANS)控制。然而，人们对连接这些失能的病理生理学知之甚少。 合并症。完全缺乏有针对性的治疗选择自然伴随着机械性数据的缺乏。 失调的ANS反应通路与增强的胃肠道内脏高敏感性密切相关。这本传记- 多发性迷走神经理论(Porges1995)描述了ANS的进化模式，并与 肠脑相互作用功能障碍的异常脑-肠轴概念。这种高反应性 由调节器官功能的脑干核团控制的身体扰动可以是非侵入性的 通过验证的心脏迷走神经张力指数(迷走神经效率和呼吸性窦性心律失常)进行测量。vbl.使用 根据这些措施，我们最近发现患有HSD的青少年迷走神经张力较差。没有研究表明 还解释了心脏抑制信号如何在HEDS/HSD患者中失调， “功能性”消化症状。 关于炎症在合并DGBI的HEDS/HSD中的作用的数据很少。我们的初步数据来自 真皮成纤维细胞显示转化生长因子-β信号异常，这是一个重要的细胞因子调节因子。此外， 频繁的与进食有关的症状可能预示着潜在的胃运动障碍，而不是 目前的测试。胃生理(收缩、调节、排空和血液)的多模式评估 对进餐的反应)现在可以用一种新的胃MRI方案进行评估。前、后同时进行 膳食和功能测试可能会进一步描绘出脑-肠轴的改变。这项可行性研究将调查 大脑-肠道-免疫轴和转录组研究以检测易受组织和血液影响的变异 患有HDS/HSD和功能性胃肠道疾病的青少年的血管松弛。我们将研究ANS的功能 测量(目标1)、十二指肠成纤维细胞的细胞因子谱和RNA序列(目标2)以及动态胃 在一小部分女性队列中与健康对照组进行磁共振成像(AIM 3)。拟议的研究提供了一个 一种常见的多系统疾病的综合模型，可能是DGBI子集的基础。来自于此的数据 这项研究可能会解决跨越多个医学学科的重要科学知识差距。

PROJECT SUMMARY/ABSTRACT Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) are prevalent but underdiagnosed conditions associated with excess morbidity. Despite improved recognition, many patients are still misdiagnosed with chronic fatigue syndrome, fibromyalgia, psychosomatic and functional GI disorders etc. There is now ample data linking hEDS/HSD with `functional' GI symptoms and disordered autonomic nervous system (ANS) control. However, little is known about the pathophysiology that connects these disabling comorbidities. A complete lack of targeted treatment options naturally follows the paucity of mechanistic data. A dysregulated ANS response circuit is closely linked to enhanced GI visceral hypersensitivity. This bio- evolutionary model of the ANS is described in the Polyvagal Theory (Porges 1995) and aligns well with the aberrant brain-gut axis concept of functional disorders of gut-brain interaction (DGBIs). This hyperreactivity to bodily perturbations, controlled by brainstem nuclei that regulate organ function, can be non-invasively measured via validated indices of cardiac vagal tone (vagal efficiency and respiratory sinus arrhythmia). Using these measures, we have recently documented a poor vagal tone in adolescents with HSD. No studies have yet explained how cardiac inhibitory signals may be dysregulated in hEDS/HSD patients with apparent `functional' digestive symptoms. There is paucity of data on the role of inflammation in hEDS/HSD with DGBIs. Our preliminary data from dermal fibroblasts in hEDS demonstrate abnormal TGF-β signaling, an important cytokine regulator. Further, the frequent meal-related symptoms may signal an underlying gastric motor disturbance not captured by current tests. Multimodal assessment of gastric physiology (contractility, accommodation, emptying and blood flow in response to meal) can now be assessed with a novel gastric MRI protocol. Simultaneous pre- and post- meal ANS function testing may further delineate brain-gut axis alterations. This feasibility study will investigate the brain-gut-immune axis along with transcriptome studies to detect variants predisposing to tissue and blood vessel laxity in adolescents with hEDS/HSD and functional GI complaints. We will investigate ANS function measures (Aim 1), cytokine profiling and RNASeq of duodenal fibroblasts (Aim 2), as well as dynamic gastric MRI (Aim 3) in a small cohort of females compared to healthy controls. The proposed studies provide an integrative model for a common, multi-system disorder that may underlie a subset of DGBIs. Data from this study may address an important scientific knowledge gap that crosses multiple medical disciplines.