# Interrogating the pathophysiological mechanisms of constipation in patients with systemic sclerosis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $605,667

## Abstract

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 rele...

## Key facts

- **NIH application ID:** 10896425
- **Project number:** 5R01AR081382-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Jiande Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,667
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896425

## Citation

> US National Institutes of Health, RePORTER application 10896425, Interrogating the pathophysiological mechanisms of constipation in patients with systemic sclerosis (5R01AR081382-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10896425. Licensed CC0.

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