Interrogating the pathophysiological mechanisms of constipation in patients with systemic sclerosis

探讨系统性硬化症患者便秘的病理生理机制

• 批准号: 10659640
• 负责人: Jiande Chen
• 金额: $ 63.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659640
• 关键词: Acceleration; Acustimulation; Aftercare; Anus; Automobile Driving; Autonomic Dysfunction; Autonomic nervous system; Central Nervous System; Clinical; Colon; Colorectal; Communication; Constipation; Data; Defecation; Defect; Development; Disease; Enteric Nervous System; Equilibrium; Esthesia; Exclusion; Functional disorder; Gastrointestinal Diseases; Gastrointestinal Physiology; Growth; Home; Inflammation; Inflammatory; Interleukin-6; Intervention; Intestines; Knee; Life; Manometry; Measurement; Measures; Mediating; Megacolon; Morbidity - disease rate; Muscle relaxation phase; Nervous System Physiology; Neuronal Dysfunction; Obstruction; Outcome; Pathway interactions; Patient Outcomes Assessments; Patients; Pelvic floor dysfunction; Pelvis; Physiological; Physiology; Pilot Projects; Play; Prediction of Response to Therapy; Predictive Value; Prevalence; Production; Quality of life; Rectum; Recurrence; Reflex action; Relaxation; Reporting; Resolution; Rheumatism; Role; Sensory; Severities; Site; Small Intestines; Statistical Data Interpretation; Structure of tibial nerve; Subconscious; Subgroup; Surveys; Symptoms; Systemic Scleroderma; Testing; Total Parenteral Nutrition; Work; cell motility; clinically relevant; cytokine; design; experience; gastrointestinal; gastrointestinal symptom; heart rate variability; improved; inflammatory modulation; mortality; neuroregulation; novel therapeutics; peroneal nerve; primary outcome; recruit; rectal; response; sciatic nerve; secondary outcome; sensory system; symptomatic improvement; systemic inflammatory response; treatment response; wearable device; wireless

PROJECT SUMMARY Gastrointestinal (GI) complications cause significant morbidity among patients with systemic sclerosis (SSc), and mortality is high in severe disease. Within SSc GI diseases, constipation can be particularly significant, culminating in recurrent pseudo-obstruction, small intestinal bacterial overgrowth, megacolon, and/or the requirement of total parenteral nutrition to sustain life. Despite the negative influence on quality of life and association with poor outcomes, the factors that cause SSc-constipation are not well-understood. This presents clinical challenges because patients with SSc-constipation may have similar symptoms but experience variable responses to therapy. Importantly, recent data suggests that distinct physiological mechanisms of constipation may distinguish SSc-constipation subgroups. For instance, inadequate anal muscle relaxation is associated with dyssynergic defecation (DD), while abnormal neural control is hypothesized to drive rectal hyposensitivity (RH) and slow colonic transit (SCT). Our group and others have found that symptoms of autonomic nervous system (ANS) dysfunction are present in SSc associate with more severe GI dysfunction. As the ANS coordinates colonic transit and contains sensory pathways which trigger timely defecation, it is plausible that ANS dysfunction may disrupt normal colorectal mechanisms and cause SCT and RH in SSc. In order to determine whether ANS stimulation improves colorectal physiology in SSc-constipation, we developed a convenient, well-tolerated intervention, known as transcutaneous electrical acustimulation (TEA) that enhances nervous reflexes and promotes bowel motility and evacuation in patients with constipation mediated via ANS pathways. Our prior studies demonstrate that TEA enhances parasympathetic activity and improves SCT and RH in constipated patients without SSc. In a pilot study, we also determined that TEA significantly improved GI symptoms after 2 weeks in patients with SSc-constipation. Finally, our data also suggest that TEA improves ANS function and suppresses inflammatory cytokine production (e.g. IL-6), which associates with improvement in the balance of vagally-mediated inflammation and GI symptoms. We hypothesize that SSc-constipation is driven by distinct, clinically-relevant mechanisms, and that TEA will enhance ANS function to improve SCT and RH. To test this hypothesis, we will first determine the prevalence of RH, SCT, and DD among symptomatic patients with SSc-constipation using comprehensive objective GI testing. We will then interrogate the responses of GI physiology to a 4-week home-based noninvasive TEA in symptomatic patients with SSc-constipation. Finally, we will examine the mechanisms of TEA as they pertain to autonomic function and inflammation. This work will 1) determine the relative contributions of RH, SCT, and DD to SSc-constipation; and 2) identify the subgroups where autonomic dysfunction is involved. This work is not only relevant for SSc, but also for other rheumatic diseases where GI complications and ANS dysfunction co-exist.

项目摘要 胃肠道（GI）并发症引起全身性硬化患者的显着发病率 （SSC），死亡率很高。在SSC GI疾病中，便秘可能特别重要， 在复发性假期，小肠道细菌过度生长，巨型巨龙和/或 全部肠胃外营养以维持生命的要求。尽管对生活质量产生了负面影响，并且 与结果不佳相关，引起SSC综合的因素并不理解。这是礼物 临床挑战是​​因为患有SSC结构化的患者可能有类似的症状，但经历了可变的症状 对治疗的反应。重要的是，最近的数据表明便秘的不同生理机制 可以区分SSC综合子组。例如，肛门肌肉放松不足与 Dyssynergic缺陷（DD），而异常的神经对照则可以驱动直肠性低敏（RH） 和缓慢的结肠传输（SCT）。我们的小组和其他人发现自主神经系统的症状 （ANS）功能障碍存在于更严重的GI功能障碍的SSC助理中。作为ANS协调结肠 过境并包含触发及时排便的感觉途径，ANS功能障碍可能是合理的 破坏正常的结直肠机制，并在SSC中导致SCT和RH。 为了确定ANS刺激是否改善了SSC综合中的结直肠生理学，我们 开发了一种方便，耐受性良好的干预措施，称为经皮的刺激（TEA）， 增强神经反射并促进便秘介导的患者的肠运动和疏散 通过ANS路径。我们先前的研究表明，茶可以增强副交感神经并改善SCT 在没有SSC的便秘患者中RH。在一项试点研究中，我们还确定茶有了显着改善 SSC-结化患者2周后出现GI症状。最后，我们的数据还表明茶有所改善 ANS功能并抑制炎性细胞因子的产生（例如IL-6），该因子与改进相关 在模糊介导的炎症和胃肠道症状的平衡中。我们假设SSC构型是 由不同的临床机制驱动，茶将增强ANS功能以改善SCT和 Rh。 为了检验这一假设，我们将首先确定有症状的RH，SCT和DD的患病率 使用全面的客观GI测试患有SSC缔约的患者。然后，我们将询问回应 在有症状的SSC-结化患者中，胃肠道生理学为4周的家庭无创茶。 最后，我们将研究与自主功能和炎症有关的茶的机制。这 工作将1）确定RH，SCT和DD对SSC综合的相对贡献； 2）确定 涉及自主功能障碍的亚组。这项工作不仅与SSC有关，而且与其他工作有关 gi并发症和ANS功能障碍共存的风湿病。