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

结缔组织疾病相关胃肠功能障碍的脑肠免疫分析

• 批准号: 10551342
• 负责人: Katja Kristina Karrento
• 金额: $ 10.06万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551342
• 关键词: Abdominal Pain; Address; Adolescent; Affect; Age; Anatomy; Anti-Inflammatory Agents; Anxiety; Autonomic nervous system; Autonomic nervous system disorders; Blood Vessels; Blood flow; Brain; Brain Stem; Cardiac; Cell Nucleus; Chronic; Chronic Fatigue Syndrome; Collaborations; Connective Tissue; Connective Tissue Diseases; Data; Dermal; Diagnosis; Diagnostic tests; Discipline; Disease; Dizziness; Duodenum; Dyspepsia; Ehlers-Danlos Syndrome; Fasting; Fatigue; Feasibility Studies; Female; Female Adolescents; Fibroblasts; Fibromyalgia; Functional Gastrointestinal Disorders; Functional disorder; Gastrointestinal Diseases; Gastroparesis; Gene Expression; Genetic Transcription; Heart Rate; Hypersensitivity; Immune; Immune signaling; Impaired cognition; Inflammation; Inflammation Mediators; Inherited; International; Knowledge; Label; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Modeling; Morbidity - disease rate; Motor; Nature; Nausea; Nervous System Physiology; Nervous System control; Organ; Pathway interactions; Patients; Perception; Phase; Physiological; Physiology; Posture; Productivity; Protocols documentation; Psychophysiologic Disorders; Refractory; Role; Scientist; Sensorimotor functions; Signal Transduction; Sinus Arrhythmia; Sleep disturbances; Stomach; Symptoms; System; Techniques; Technology; Testing; Tissues; Transforming Growth Factor beta; Visceral; Vomiting; biobank; cholinergic; clinical care; cohort; comorbidity; comparison control; cytokine; disorders of gut-brain interaction; gastrointestinal; gastrointestinal function; gastrointestinal symptom; gut-brain axis; hemodynamics; immune function; improved; indexing; motor disorder; multimodality; neurophysiology; novel; potential biomarker; respiratory; response; stem; stressor; targeted treatment; theories; transcriptome; transcriptome sequencing; transcriptomics; variant detection

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.

项目概要/摘要 过度活动性埃勒斯-当洛斯综合征 (hEDS) 和过度活动性谱系障碍 (HSD) 很常见，但 尽管人们对疾病的认识有所提高，但许多患者仍存在诊断不足的情况。 仍被误诊为慢性疲劳综合症、纤维肌痛、心身和功能性胃肠道疾病等。 现在有充足的数据将 hEDS/HSD 与“功能性”胃肠道症状和自主神经紊乱联系起来 然而，对于连接这些致残的病理生理学知之甚少。 由于缺乏机制数据，自然就完全缺乏针对性的治疗方案。 ANS 反应回路失调与胃肠道内脏超敏反应密切相关。 多迷走神经理论（Porges 1995）描述了 ANS 的进化模型，并且与 肠-脑相互作用功能障碍（DGBIs）的异常脑-肠轴概念。 由调节器官功能的脑干核控制的身体扰动可以是非侵入性的 通过经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。 通过这些措施，我们最近记录了患有 HSD 的青少年迷走神经张力较差的情况。 还解释了心脏抑制信号如何在具有明显症状的 hEDS/HSD 患者中失调 “功能性”消化症状。 关于炎症在 hEDS/HSD 中与 DGBIs 的作用的数据很少。我们的初步数据来自于 DGBIs。 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。 频繁的进餐相关症状可能预示着潜在的胃运动障碍，但未被发现 当前测试。胃生理学的多模式评估（收缩性、调节性、排空性和血液） 现在可以通过一种新颖的胃 MRI 方案同时评估餐前和餐后的流量。 膳食 ANS 功能测试可能会进一步描述脑肠轴的改变，这项可行性研究将进行调查。 脑-肠-免疫轴以及转录组研究，以检测易受组织和血液影响的变异 患有 hEDS/HSD 和功能性胃肠道疾病的青少年的血管松弛 我们将调查 ANS 功能。 测量（目标 1）、十二指肠成纤维细胞的细胞因子分析和 RNASeq（目标 2）以及动态胃 与健康对照组相比，一小群女性的 MRI（目标 3）提供了一个结果。 一种常见的多系统疾病的综合模型，该模型可能是 DGBIs 数据子集的基础。 研究可能会解决跨多个医学学科的重要科学知识差距。