Interrogating the pathophysiological mechanisms of constipation in patients with systemic sclerosis

项目总结 系统性硬化症患者中胃肠道(GI)并发症的发病率很高 (SSC)，严重疾病的死亡率很高。在SSc GI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 维持生命所需的全胃肠外营养。尽管对生活质量和 由于预后不佳，导致SSc便秘的因素尚未得到很好的了解。这是一份 临床挑战，因为SSc便秘患者可能有相似的症状，但经历不同 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 可区分SSc-便秘亚组。例如，肛门肌肉松弛不足与 协同排便障碍(DD)，而异常的神经控制被认为是导致直肠敏感性低下(RH)的原因 慢结肠运输(SCT)。我们团队和其他人发现，自主神经系统的症状 (ANS)功能障碍与更严重的胃肠道功能障碍相关。作为ANS坐标的结肠 ，并包含触发及时排便的感觉通路，因此ANS功能障碍可能 破坏正常的结直肠机制，导致SSC的SCT和RH。 为了确定刺激ANS是否能改善SSc便秘患者的结直肠生理，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，促进便秘患者的肠道动力和排空 通过ANS小路。我们先前的研究表明，茶可以增强副交感神经活动，改善SCT 无SSC便秘患者的RH。在一项初步研究中，我们还确定茶显著改善了 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，茶可以改善 ANS发挥作用并抑制炎性细胞因子的产生(如IL-6)，这与改善有关 在介导的炎症和胃肠道症状之间取得平衡。我们假设SSc便秘是 由不同的、临床相关的机制驱动，TEA将增强ANS功能，以改善SCT和 啊哈。 为了验证这一假设，我们将首先确定RH、SCT和DD在有症状的人群中的患病率 对SSc便秘患者进行综合客观胃肠功能测试。然后我们将审问他们的回答 对有症状的SSc便秘患者进行为期4周的家庭无创TEA的胃肠生理学研究。 最后，我们将研究TEA与自主神经功能和炎症有关的机制。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有关，而且对其他 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.