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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胃肠道 (GI) 并发症导致系统性硬化症患者显着发病 (SSc)，严重疾病的死亡率很高。在 SSc 胃肠道疾病中，便秘可能特别严重，最终导致反复出现假性梗阻、小肠细菌过度生长、巨结肠和/或维持生命所需的全肠外营养。尽管对生活质量产生负面影响由于 SSc 便秘与不良预后相关，导致 SSc 便秘的因素尚不清楚。这呈现临床挑战，因为 SSc 便秘患者可能有相似的症状，但经历各不相同对治疗的反应。重要的是，最近的数据表明便秘的独特生理机制可以区分 SSc 便秘亚组。例如，肛门肌肉松弛不足与排便失调（DD），而异常的神经控制被假设导致直肠敏感性低下（RH）和慢结肠运输（SCT）。我们组和其他人发现自主神经系统的症状 SSc 中存在 (ANS) 功能障碍，并伴有更严重的胃肠道功能障碍。由于 ANS 协调结肠运输并包含触发及时排便的感觉通路，ANS 功能障碍可能是破坏正常结直肠机制并导致 SSc 中的 SCT 和 RH。为了确定 ANS 刺激是否可以改善 SSc 便秘患者的结直肠生理机能，我们开发了一种方便且耐受性良好的干预措施，称为经皮电针刺激（TEA），增强神经反射并促进便秘患者的肠道蠕动和排便通过 ANS 途径。我们之前的研究表明，TEA 可以增强副交感神经活动并改善 SCT 和无 SSc 的便秘患者的 RH。在一项试点研究中，我们还确定 TEA 显着改善 SSc 便秘患者 2 周后出现胃肠道症状。最后，我们的数据还表明 TEA 有所改善 ANS 功能并抑制炎症细胞因子的产生（例如 IL-6），这与改善相关迷走神经介导的炎症和胃肠道症状的平衡。我们假设 SSc 便秘是由独特的临床相关机制驱动，TEA 将增强 ANS 功能，从而改善 SCT 和相对湿度。为了检验这一假设，我们首先确定有症状的人中 RH、SCT 和 DD 的患病率使用综合客观胃肠道测试对 SSc 便秘患者进行研究。然后我们将询问答复对有症状的 SSc 便秘患者进行为期 4 周的家庭无创 TEA 的胃肠道生理学研究。最后，我们将研究 TEA 与自主神经功能和炎症相关的机制。这工作将 1) 确定 RH、SCT 和 DD 对 SSc 便秘的相对贡献； 2) 确定涉及自主神经功能障碍的亚组。这项工作不仅与 SSc 相关，也与其他胃肠道并发症和 ANS 功能障碍同时存在的风湿性疾病。