Zlatan Mujagic

Irritable bowel syndrome (IBS) is heterogenous disorder of gut-brain interaction, with a key role for the dysregulated host-gut microbiota interplay. IBS subtyping is based only on symptoms of bowel habits, reflecting limited insight into underlying biological mechanisms. This study aimed to define microbiota-based IBS phenotypes and to compare these to traditional stool-based subtyping. The study utilized data from the Maastricht IBS cohort. Gut microbiota composition was analysed using shotgun metagenomic sequencing. Faecal volatile organic compounds (VOCs) were measured by gas chromatography mass spectrometry. Dietary intake and gastrointestinal and mental health symptoms were assessed using a food frequency questionnaire, the Dutch Healthy Diet-15 index, the gastrointestinal symptom rating scale, and hospital anxiety and depression scores, respectively. Machine-learning approaches were applied to identify microbiota-based phenotypical clusters, which were compared with established Rome III subtypes, and associated with faecal VOCs, gastrointestinal symptom severity, diet and mental health. 178 IBS patients and 134 healthy controls were included. Gut microbiota composition distinguished IBS patients from healthy controls with an AUCROC 0 · 8. This discriminatory profile was not associated with Rome III subtypes, while statistically significant associations were found with faecal VOCs profiles (i.e. R = 0 · 67, p = 4 · 46e-4) and symptom severity scores of abdominal pain ( p = 0 · 05), reflux ( p = 0 · 03), diarrhoea ( p = 0 · 01) and depression ( p < 0 · 001). Dietary associations varied across clusters. These results suggest that gut microbiota profiling might provide a basis to define relevant IBS endotypes. Further exploration and validation efforts into this direction are needed using longitudinal studies to refine IBS patient stratification ultimately.

Purpose Wearable-derived digital biomarkers represent a new frontier in remote management of inflammatory bowel disease (IBD). They may enable continuous disease surveillance and early flare detection while reducing reliance on questionnaire-based remote monitoring. However, successful implementation into clinical practice critically depends on patient acceptance and perceived relevance. To guide patient-centered digital health strategies, we aimed to investigate patient perspectives on digital biomarkers for (early) flare detection. Methods A nationwide cross-sectional survey-based study was conducted among patients with IBD (≥ 16 years) in the Netherlands. A study-specific questionnaire was distributed through the Dutch patient organization Crohn & Colitis NL to assess acceptance, preferences, and perspectives on the use of wearable technology for flare detection. Results 1,080 participants were included: 72.5% women, 53.4% aged >50 years, and 28.7% current wearable users. Overall, 88% considered remote monitoring for flare detection potentially useful, and over 90% believed wearables could support this. Motivations for using wearables included flare detection, better understanding of symptoms, and health monitoring. User-friendliness, clear alerts, and time efficiency were key device preferences, and smartwatches were the preferred wearable device. Shorter disease duration (pp=0.029), younger age (p=0.016), and current wearable use (p<0.001) were identified as predictors for willingness to use wearables. Conclusion Patients with IBD value wearables for flare detection and disease-monitoring. Most participants expressed willingness to use digital biomarkers and believed that wearables could support routine care. Incorporating patient preferences into digital biomarker development will likely improve patient acceptance and adherence to remote monitoring.

Aim: Fatigue is a common and debilitating symptom in patients with inflammatory bowel disease (IBD) and may be linked to physical fitness and physical activity. However, their interrelationships are not fully understood. More objective knowledge is needed to guide physical interventions to reduce fatigue. This study aimed to investigate the association of physical fitness and physical activity with fatigue in patients with IBD. Additionally, the association between physical fitness and physical activity was investigated. Methods: Patients with IBD in remission or with mild-to-moderate disease activity were included. Fatigue was defined as a score of ≥35 on the subjective fatigue subscale of the checklist individual strength. Physical fitness measurements were performed using gold standard methodologies for body composition, cardiorespiratory fitness, muscular strength, muscular endurance, and flexibility. Physical activity was quantified using accelerometry. Results: In total, 53 patients were included, of whom 17 (32.1%) experienced fatigue. Fatigued patients exhibited a higher fat-mass index (P = .014), lower cardiorespiratory fitness (P = .017), and less quadriceps muscular endurance (P = .026, P = .008). No differences were observed in physical activity. Multiple linear regression showed that fat-mass index and cardiorespiratory fitness independently predicted fatigue (P = .029, P = .012). Significant correlations were found between fatigue and physical fitness, but not with physical activity. Conclusions: Reduced physical fitness was associated with fatigue in patients with IBD, suggesting that enhancing physical fitness could help alleviate fatigue. Physical activity was not associated with fatigue or physical fitness, indicating that simply increasing physical activity may have limited impact on reducing fatigue or improving physical fitness in this population.

Background: Risankizumab, a monoclonal antibody targeting interleukin-23, is approved for the treatment of Crohn’s disease (CD). Real-world evidence on its effectiveness remains limited. We assessed 1-year effectiveness and safety of risankizumab in a prospective cohort of patients with CD, emphasizing difficult-to-treat disease. Methods: Data were retrieved from the Dutch Initiative on Crohn and Colitis Registry. At baseline and at weeks 12, 24, and 52, clinical remission (Harvey-Bradshaw Index ≤4), biochemical remission (fecal calprotectin ≤250 µg/g and C-reactive protein levels ≤5 mg/L), systemic corticosteroids use, and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission (CSFCR) at week 24. Difficult-to-treat disease was defined as the failure of advanced therapies with at least 2 different mechanisms of action. Results: In total, 151 patients initiated risankizumab before August 1, 2025; 136 (90.1%) of 151 patients had difficult-to-treat disease. At baseline, 90 (59.6%) patients had Harvey-Bradshaw Index >4. Of those, at week 24, 31 (50%) of 62 patients were in CSFCR; this rate was 53.3% when including all patients. Analysis including only patients with difficult-to-treat disease revealed that 51.8% of these patients were in CSFCR at week 24. Twenty-two (14.6%) patients discontinued treatment after a median of 183.5 days (Q1-Q3: 90.0-295.2 days), most following nonresponse. Regarding adverse events, 35.3 possibly and 16.6 probably risankizumab-related events per 100 person-years were reported. Conclusion: In this prospective multicenter study, risankizumab demonstrated favorable effectiveness and safety profile in patients with CD, including those with difficult-to-treat disease, bowel surgery, and stoma. These findings support the use of risankizumab in patients with difficult-to-treat disease.

Irritable bowel syndrome (IBS), a disorder of gut–brain interaction, is diagnosed using symptom-based Rome criteria. These criteria classify IBS patients into four subtypes in accordance to their stool patterns. However, whether this subtyping approach is based on true differences in the underlying biology of IBS patients, is unclear. Volatile organic compounds (VOCs) in the faecal headspace reflect both the gut microbial and host intestinal intraluminal processes and thereby may be used to study pathophysiological differences between IBS and its subtypes. We profiled faecal headspace VOCs in a cohort of 164 patients with IBS and 143 healthy controls using gas chromatography-mass spectrometry. Random forest models were employed to impute missing values and identify discriminatory VOCs to differentiate IBS patients from healthy controls. We corrected for faecal water content using partial least squares regression. Multivariate associations between the obtained volatile profiles and Rome III IBS subtypes were evaluated using regularized MANOVA. A total of 39 VOCs, including short-chain fatty acid esters, neurotransmitter-related metabolites, alcohols, and sulphides, were selected as significantly altered in patients with IBS. Our classification model achieved an area under the curve of 0.82 on both training and independent test sets, demonstrating robust separation between IBS patients and healthy individuals. However, VOC profiles did not associate to Rome III -based IBS subtypes. This study highlights the potential of faecal VOC profiling as a non-invasive tool for studying and characterizing IBS, yet they also reveal a disconnect between metabolic signatures and current stool-based subtypes. While the Rome criteria remain the clinical standard for diagnosis and subtyping of IBS, they offer limited insight into underlying disease mechanisms. Future research should focus on integrating VOC analysis with other omics approaches to refine IBS sub-classification into biologically relevant clusters, which may aid to improve personalized therapeutic strategies.

Background: Filgotinib is a preferential Janus kinase 1 (JAK‐1) inhibitor registered for the treatment of ulcerative colitis (UC). Real‐world effectiveness of filgotinib, especially for difficult‐to‐treat (DTT, failure of ≥ 2 prior advanced therapies) patients, has been scarcely reported. Objective: This study aimed to assess the effectiveness and safety of filgotinib for UC patients in routine care. Methods: The Dutch ICC registry enrolled UC patients initiating filgotinib and prospectively evaluated outcomes up to 52 weeks. The primary outcome was corticosteroid‐free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤ 2 without steroid use) at week 52. Secondary outcomes included clinical remission (SCCAI ≤ 2), biochemical remission (C‐reactive protein serum concentration < 5 mg/L and/or faecal calprotectin level < 250 μg/g), treatment persistence and safety. Results: A total of 96 UC patients were included. At 52 weeks, 39.5% (34/76) of patients with disease activity at baseline were in CSFR. Out of the patients that met the criteria for DTT disease ( n = 68; 71%), 36.4% achieved CSFR. Treatment persistence at 52 weeks was 71.4% (CI 56.5–90.3) and 53.4% (CI 42.6–67.0) for non‐DTT and DTT patients, respectively. The main reasons for discontinuation of filgotinib were primary non‐response ( n = 21, 54%) or secondary loss of response ( n = 8, 23%). No severe infections were documented. Most reported adverse events included headache ( n = 5), nausea ( n = 3) and hypercholesterolemia ( n = 3). Conclusion: Filgotinib is an effective and well‐tolerated treatment option for UC, including DTT disease. No new safety signals were found.

Background: Inflammatory bowel disease (IBD) may negatively affect health-related physical fitness. However, the development of interventions to improve health-related physical fitness and thereby disease outcomes is hindered by insufficient evidence. This study compared health-related physical fitness between patients with IBD and healthy control subjects, examined associations with disease and treatment characteristics, and explored patients’ perspectives. Methods: In this cross-sectional study, 105 patients with IBD and 102 age- and sex-matched healthy control subjects performed validated tests for body fat (4-site skinfold thickness), cardiorespiratory fitness (steep ramp test), muscular strength (steep ramp test, 60-second sit-to-stand test, hand-held dynamometry), muscular endurance (isokinetic dynamometry), and flexibility (sit-and-reach test). Data on disease and treatment characteristics, fatigue, physical activity, and patients’ perspectives were collected. Results: Patients with IBD had higher body fat (29.5% vs 26.9%; P = .012), lower steep ramp test performance (peak work rate 4.2 W/kg vs 4.8 W/kg; P < .001), fewer sit-to-stand repetitions (42 vs 47; P = .002), and reduced hamstring strength (3.0 N/kg vs 3.2 N/kg; P = .011) compared with healthy control subjects. This was associated with higher age, female sex, higher body mass index, fatigue, arthritis, and multiple biologicals used. Most patients considered physical fitness important and beneficial for their symptoms, and the majority expressed interest in professional support. Conclusions: Patients with IBD have higher body fat and reduced cardiorespiratory fitness and muscular strength compared with healthy control subjects. Especially, patients with a higher age, female sex, higher body mass index, fatigue, arthritis, or multiple biologicals used are at risk for such impairments and may benefit from physical exercise interventions.

Purpose Disorders of gut–brain interaction (DGBI) affect up to 40% of people worldwide and in several studies an association with hypermobility spectrum disorders (HSD) was described. HSD patients frequently report gastrointestinal (GI) symptoms and GI dysmotility has been suggested as underlying mechanism. This study evaluates whether individuals with (undiagnosed) joint hypermobility and/or HSD show different GI symptom and motility patterns compared to those without hypermobility/HSD. Methods In this prospective open-label study, patients who were referred for GI motility assessment between 2016 and 2018 were included. Motility assessments included esophageal manometry, gastric emptying test, antro-duodenal manometry, colonic manometry, and/or a colonic transit study. Joint hypermobility was assessed using the Beighton score, and HSD was diagnosed using the Brighton criteria. Symptom severity, anxiety and depression, and quality of life were evaluated through validated questionnaires. Results Eighty-seven participants were included (73 women, median age 42.0 years), and categorized into HSD (n = 23) and non-HSD (n = 64), with further subdivision by Beighton cut-off values (≥ 4, and ≥ 6). GI symptom scores were high, with 37% of the total population exhibiting depressive symptoms (HADS ≥ 8), and 32% experiencing anxiety. Quality of life scores were generally low, with a physical composite score of 26.9 (13.2) and a mental composite score of 47.3 (17.1). Across all comparisons, no significant differences in GI symptoms or motility patterns were found between all groups. Conclusion This exploratory tertiary care study found no distinct GI symptom or dysmotility patterns between patients with and without hypermobility/HSD. Further research is warranted to investigate whether GI dysmotility is related to hypermobility.