Background Anxiety or depression, in other words, psychological distress, are common comorbidities in patients with irritable bowel syndrome (IBS), but their interaction with pathophysiological factors and other symptoms are unclear. Methods Patients with IBS (Rome III criteria), thoroughly characterized regarding pathophysiology (colonic transit time, visceral sensitivity, and autonomic nervous system [ANS] function), symptom profile (IBS severity, somatic symptoms, gastrointestinal [GI]‐specific anxiety and fatigue), and quality of life, were explored for differences regarding pathophysiology and symptoms between patients with and without reported psychological distress in univariate and multivariate analyses (Principal Component Analysis [PCA] with Hotelling's T2 and Orthogonal Partial Least Squares‐Discriminant Analysis [OPLS‐DA]). Key Results When using Hospital Anxiety and Depression Scale score ≥8 as cut‐off score, including both borderline and clinically significant cases, 345 (44.9%) out of 769 IBS patients reported anxiety, and 198 (25.7%) depression. In univariate analyses, patients reporting psychological distress demonstrated more severe GI and non‐GI symptoms, fatigue, GI‐specific anxiety and lower quality of life, and differences for some pathophysiological measures. IBS patients with and without reported psychological distress showed significant differences between the multivariate means in symptom reporting (PCA; both P < 0.001), and in pathophysiological measures in patients with and without anxiety (P = 0.018). Visceral hypersensitivity, altered ANS function, more severe GI‐specific anxiety, fatigue, and higher somatic non‐GI symptoms were the factors that most strongly separated patients with and without psychological distress (OPLS‐DA). Conclusions and Inferences Reported anxiety and depression are common in IBS patients, and our study demonstrates that they are interwoven in the complex pathophysiological and clinical picture of IBS.

Irritable bowel syndrome (IBS) is a common and multifactorial functional gastrointestinal (GI) disorder characterized by altered gut-brain communication. Due to the complexity of gut-brain interactions, the aim of this thesis was to enhance the understanding of associations between GI symptom severity and measures from multiple levels along the gut-brain axis in IBS patients.In this thesis, various indications of altered gut-brain interactions were demonstrated: I. IBS patients with anxiety or depression reported more severe GI and non-GI symptoms than patients without psychological distress. Visceral hypersensitivity, aberrant function of the autonomic nervous system, GI-specific anxiety, and non-GI somatic symptoms differentiated between patients with and without psychological distress. II. Overall, modest associations were discovered among neurophysiological factors, and between neurophysiological factors and the severity of IBS symptoms. The most important combination of neurophysiology measures for GI symptom severity in IBS patients were extracted through a computerized method and were found to be visceral hypersensitivity and psychological distress. III. Alterations in a wide range of psychological measures were common in IBS. A strong cumulative effect of psychological alterations on the severity of GI symptoms was found. IV. Central sensitization was frequent in IBS patients, but the severity of central sensitization and GI symptoms were only modestly associated in IBS, suggesting that the presence, rather than the level, of central sensitization is of importance for GI symptoms in IBS.In conclusion, the results from this thesis support the current view of IBS being a disorder of gut-brain interaction, where both peripheral and central factors contribute to this multifactorial disease. Complex associations between psychological and neurophysiology measures, and the severity of GI symptoms were demonstrated in the studies included in this thesis.

Background: Central sensitization has been suggested as an explanation of the wide range of gastrointestinal and extraintestinal symptoms commonly seen in irritable bowel syndrome (IBS). In this study, the presence and level of central sensitization, and its association to gastrointestinal (GI) symptoms were explored in IBS in comparison with control groups. Methods:We investigated patients with IBS (n = 215), chronic pain disorders (n = 36), and inflammatory bowel disease (IBD) (n = 40) and volunteers without chronic diseases (n = 112). The Central Sensitization Inventory (CSI) was translated and validated in Swedish and used together with the Highly Sensitive Person (HSP) scale to measure the presence and level of central sensitization. Furthermore, severity of GI symptoms (GSRS-IBS and IBS-SSS), and anxiety and depression (HAD) were determined. Key results:The Swedish translation of CSI demonstrated excellent validity. Central sensitization, defined by validated cut-off levels for CSI and HSP, was common in the whole cohort (40% and 28%) and in IBS (57% and 35%). Study participants with central sensitization had more severe GI symptoms, anxiety and depression, than participants without central sensitization. Strong associations were seen between CSI and GI symptom severity in the whole cohort (GSRS-IBS: partial η 2 = 0.455, p < 0.001; IBS-SSS: partial η 2 = 0.408, p < 0.001), with decreasing strength in patients with chronic pain, IBD, IBS, and volunteers. Conclusion and Inferences:Central sensitization was common in IBS and associated with GI symptom severity, but with stronger associations in chronic pain disorders and IBD. This implies that other mechanisms may be of equal or greater importance for GI symptom severity in IBS.

Background: Abnormal oroanal transit time (OATT) and visceral hypersensitivity are key pathophysiological factors in irritable bowel syndrome (IBS). The lactulose nutrient challenge test (LNCT) has been developed to assess the postprandial symptoms and gut microbial fermentation. We aimed to investigate associations between OATT, rectal sensitivity, and LNCT in IBS patients. Methods:We included 263 IBS patients from two study cohorts, where the link between pathophysiology and symptoms was investigated. During the LNCT, severity of postprandial symptoms was graded, and breath hydrogen/methane concentrations were measured after ingestion of a combined lactulose nutrient drink every 15 min for 4 h. The patients underwent rectal sensitivity (rectal barostat) and OATT (radiopaque markers) investigations. Comorbid conditions (functional dyspepsia, anxiety, depression, and somatization) were assessed with questionnaires.Key Results: After controlling for comorbid conditions, rectal sensitivity was associated with abdominal pain (p < 0.05), and more rapid OATT was associated with higher severity of abdominal discomfort, rumbling, nausea, and urgency (p < 0.05 for all) both pre-and post-prandially. Postprandial nausea, urgency, and abdominal pain changed differently over time depending on OATT (p < 0.05 for all). OATT, but not rectal sensitivity, was associated with hydrogen and methane concentrations (p = 0.002 for both). Trajectories over time of postprandial symptoms and exhaled hydrogen/methane concentrations were correlated with different correlations depending on OATT. Conclusion and Inferences:This study highlights the importance of oroanal transit and hydrogen and methane production in the pathophysiology of IBS and increases our understanding of pathophysiological factors involved in postprandial symptom generation. Treatments targeting oroanal transit and hydrogen and methane production may improve specific postprandial symptoms.

Abnormal gut-brain interactions are common in irritable bowel syndrome (iBS), but the associations between neurophysiological measures and their relation to gastrointestinal (Gi) symptoms are poorly understood. Our aim was to explore these relationships and define the most relevant neurophysiology measures for Gi symptom severity in iBS. iBS patients underwent small intestinal motility (manometry; fasted and fed contraction frequency, phase III time) and secretion (transmural potential difference), rectal sensorimotor (barostat; sensory thresholds, tone response, compliance), autonomic nervous system (baroreceptor sensitivity and effectiveness), and colonic motor function (transit time) examinations. Gi symptom severity (GSRS-iBS), and anxiety and depression (HAD) as a proxy measure of central nervous system (CNS) dysfunction, were assessed. In total 281 IBS patients (Rome II criteria) were included (74% females, median age 36 [interquartile range 28-50] years). Significant correlations between neurophysiology measures were stronger within, rather than between, different neurophysiological examinations. the strongest neurophysiology-symptom correlations occurred between a combination of cnS and visceral sensitivity parameters, and GSRS-iBS total score and pain domain (ρ = 0.40, p < 0.001, and ρ = 0.38, p < 0.001). Associations between GI symptoms in IBS and individual and combinations of neurophysiological factors occurred, primarily in cnS and visceral sensitivity measures, providing new insights into the clinical presentation of iBS. Irritable bowel syndrome (IBS) is a common and complex functional gastrointestinal (GI) disorder where gut-brain interactions 1,2 , and alterations in the gut microenvironment 3 are considered to be central in the pathophysiology. Abdominal pain, related to defecation and associated with changes in stool form or frequency, are the characteristic clinical features of this female predominant disease 1 with 5-10% prevalence worldwide 4-6. The disease leads to high costs for society, due to increased use of health care services 7 , as well as lowered work productivity and higher absenteeism from work 8,9. Different abnormalities involved in gut-brain interactions are present in IBS, leading to a complex clinical presentation, but to date the pathophysiology is not completely understood. Various pathophysiological factors have been brought forward as important for symptom generation in IBS, but none of these is present in all patients with IBS. IBS patients have been reported to have increased psychological distress 10,11 , visceral hypersensitivity 12 , altered colonic motility 13 , aberrant autonomic nervous system (ANS) function 14,15 , rectal sensorimotor dysfunction 16,17 , and dysfunction of motility 18-20 and secretion 21 of the small intestine, in comparison with healthy controls. Although these abnormalities have been described individually in IBS, the associations among these aberrant measures, and the interactions between these parameters and the patient reported IBS symptom ...