To Örebro University

Introduction: Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterized by abdominal pain and altered bowel habits, often comorbid with anxiety, depression, chronic fatigue syndrome, and fibromyalgia. Psychosocial stress has been implicated in IBS, yet the underlying neural mechanisms and the role of comorbidities remain unclear. Therefore, we aimed to investigate (1) whether IBS patients exhibit in-creased self-reported negative affect (NA) and brain responses to stress, (2) the impact of comorbidities on these responses, and (3) the brain circuits mediating group differences in NA.

Methods: We analyzed data from 96 IBS patients in the European DISCOvERIE project, and 64 healthy controls (HCs). 54 (56.3%) patients met criteria of depression, anxiety, chronic atigue syndrome, and/or fibromyalgia. Psychological stress was induced using the Montreal Imaging Stress Test during functional magnetic resonance imaging scanning, while NA ratings were collected across time (Figure 1A). Group differences in NA were tested using mixed models (all IBS vs. HCs; IBS-comorbid vs. IBS-alone), and stress-related brain activity was compared using general linear models. Multivariate mediation models were applied to identify brain response patterns mediating group differences in NA.

Results: IBS patients reported more NA than HCs during stress (p < 0.01), driven by higher ratings from patients with comorbidities (p < 0.01; Fig 1B). The stress task induced higher brain activations in default mode network in IBS (Fig 1C), but no significant differences were found between comorbidity groups. Increased NA reporting in IBS patients vs HCs was mediated via heightened default mode network, salience network, and damp-ened central autonomic network responses (Fig 1D), and in IBS-comorbid vs. IBS-alone through altered responses in multiple somatosensory areas (Fig 1E).

Conclusions: IBS patients experienced more negative affect than HCs under stress, driven by the presence of comorbidities. The hyperactive default mode network and salience net-work, combined with hypoactive central autonomic network as mediators of case-control differences in negative affect, indicate dysregulated central stress processing in IBS patients. Comorbidities may further amplify negative affect through altered somatosensory processing.