Interrogating the pathophysiological mechanisms of constipation in patients with systemic sclerosis

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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.