Interrogating the pathophysiological mechanisms of constipation in patients with systemic sclerosis

项目摘要 胃肠道（GI）并发症导致系统性硬化症患者的发病率显着 (SSc)重症患者死亡率高。在SSc GI疾病中，便秘可能特别重要， 最终导致复发性假性梗阻、小肠细菌过度生长、巨结肠和/或 需要全胃肠外营养来维持生命。尽管对生活质量和 与不良结局相关，导致Ssc便秘的因素尚未得到很好的理解。这呈现 临床挑战，因为Ssc便秘患者可能有类似的症状，但经历不同的 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-便秘亚组。例如，肛门肌肉放松不足与以下因素有关： 协同失调排便（DD），而异常神经控制被假设为驱动直肠低敏感性（RH） 结肠传输缓慢（SCT）。我们和其他人发现自主神经系统的症状 (ANS)功能障碍存在于与更严重GI功能障碍相关的SSc中。当ANS协调结肠 运输和包含触发及时排便的感觉通路，这是合理的，ANS功能障碍可能 破坏正常的结直肠机制并导致SSc中的SCT和RH。 为了确定ANS刺激是否改善了Ssc便秘的结直肠生理学，我们 开发了一种方便，耐受性良好的干预措施，称为经皮电刺激（TEA）， 增强神经反射，促进便秘患者的肠蠕动和排空 通过ANS途径。我们先前的研究表明，TEA增强副交感神经活动，改善SCT 和RH在无SSc的便秘患者中。在一项初步研究中，我们还确定TEA显著改善了 Ssc便秘患者2周后的GI症状。最后，我们的数据还表明， ANS功能和抑制炎性细胞因子的产生（例如IL-6），这与改善 平衡迷走神经介导的炎症和胃肠道症状。我们假设SSc-便秘是 由不同的临床相关机制驱动，TEA将增强ANS功能以改善SCT， RH。 为了验证这一假设，我们将首先确定有症状的患者中RH、SCT和DD的患病率。 使用全面客观GI测试的Ssc便秘患者。然后我们会询问 在有症状的Ssc便秘患者中进行为期4周的家庭非侵入性TEA。 最后，我们将研究TEA的机制，因为它们与自主神经功能和炎症有关。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有关，而且与其他 胃肠道并发症和ANS功能障碍并存的风湿性疾病。

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.