Bidirectional Brain-Gut Signaling in the Persistence of IBS-like Symptoms in Inflammatory Bowel Disease - ABSTRACT Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders that impair quality of life and drive rising healthcare costs. IBD, encompassing ulcerative colitis (UC) and Crohn’s disease, is marked by intestinal mucosal inflammation, whereas IBS is a disorder of gut–brain interaction involving visceral hypersensitivity, altered motility, and dysregulated central nervous system (CNS) processing of visceral stimuli, without overt inflammation. Despite differing diagnostic criteria, the two conditions often overlap symptomatically. Notably, 30%–50% of patients with clinically quiescent IBD continue to experience IBS- like symptoms, including abdominal pain, urgency, and altered bowel habits, even in the absence of active inflammation as confirmed by biomarkers like fecal calprotectin. These patients represent a distinct population, referred to as IBD–IBS, whose symptoms are often not responsive to conventional anti-inflammatory therapies and who are commonly excluded from IBD clinical trials. Consequently, there is a significant unmet need to understand the non-inflammatory mechanisms driving symptom persistence in this overlooked subgroup. We hypothesize that symptoms in IBD–IBS are driven primarily by dysregulated centrally-mediated mechanisms involving the central autonomic network (CAN) and autonomic nervous system (ANS), resulting in visceral hypersensitivity and altered gut motility manifesting as abdominal pain and diarrhea. To test this hypothesis, we will conduct an integrated, multimodal investigation combining advanced neuroimaging, continuous wearable- based physiologic monitoring, and a randomized controlled trial (RCT) of non-invasive vagal nerve stimulation (nVNS) as a a therapeutic approach that targets the CAN and ANS, potentially reducing symptoms in IBD-IBS. In Aim 1, we will use functional magnetic resonance imaging (fMRI) to identify functional connectivity signatures within the (CAN) that compare patients with UC with IBS-like symptoms (UC–IBS) from those with inflammation- driven symptoms (Moderate-Severe UC) and with altered brain-gut interactions (diarrhea-predominant IBS), focusing on functional connectivity signatures that represent central sensitization and impaired pain modulation. In Aim 2, we will assess autonomic dysfunction by collecting 4 weeks of real-world data using wearable sensors to measure heart rate, heart rate variability (HRV), and circadian rhythms to distinguish centrally-mediated symptoms from inflammation-driven symptoms in patients with UC-IBS and Mild UC, who have no or little inflammation, respectively. We also hypothesize that ANS profiles will correlate with brain connectivity patterns. In Aim 3, we will conduct a RCT comparing nVNS versus Usual Care in patients with UC-IBS and Mild UC, evaluating effects on CAN connectivity, ANS activity, symptoms, and fecal calprotectin. The findings will transform mechanistic understanding of persistent symptoms in IBD–IBS, enable biologically-based patient stratification, and inform the development of mechanism-targeted treatments beyond anti-inflammatory approaches, advancing personalized care in both IBD and IBS populations.
