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

项目总结/摘要 高活动性埃勒斯-当洛斯综合征（hEDS）和高活动性谱系障碍（HSD）是普遍的，但 与高发病率相关的诊断不足的情况。尽管认识有所改善，但许多患者 仍被误诊为慢性疲劳综合征、纤维肌痛、心身和功能性胃肠疾病等。 现在有足够的数据将hEDS/HSD与“功能性”GI症状和自主神经紊乱联系起来 系统（ANS）控制。然而，很少有人知道的病理生理学，连接这些致残 合并症。完全缺乏有针对性的治疗方案自然遵循缺乏机制数据。 ANS反应回路失调与增强的GI内脏高敏感性密切相关。这个生物- ANS的进化模型在多迷走神经理论（Porges 1995）中描述，并且与 肠-脑相互作用功能障碍（DGBI）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， 通过经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。使用 通过这些措施，我们最近记录了患有HSD的青少年的迷走神经张力差。没有研究 还解释了心脏抑制信号如何可能在hEDS/HSD患者中失调， “功能性”消化症状。 关于炎症在hEDS/HSD伴DGBI中的作用的数据很少。我们的初步数据来自 hEDS中的真皮成纤维细胞表现出异常的TGF-β信号传导，这是一种重要的细胞因子调节剂。此外，本发明还 频繁的进餐相关症状可能是潜在的胃运动障碍的信号， 目前的测试胃生理学的多模式评估（收缩性、调节性、排空和血液 响应于进餐的血流）现在可以用新的胃MRI方案来评估。同时进行术前和术后 膳食ANS功能测试可进一步描绘脑-肠轴改变。本可行性研究将调查 脑-肠-免疫轴沿着与转录组研究，以检测易患组织和血液的变异 患有hEDS/HSD和功能性GI投诉的青少年的血管松弛。我们将研究ANS功能 测量（目的1），细胞因子谱和十二指肠成纤维细胞的RNASeq（目的2），以及动态胃 与健康对照相比，在一小群女性中进行MRI（目标3）。拟议的研究提供了 一种常见的多系统疾病的综合模型，可能是DGBI子集的基础。数据从该 这项研究可以解决跨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.