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Crohn's disease (CD) is a clinical subset of inflammatory bowel disease that is characterized by patchy transmural inflammation across the gastrointestinal tract. Although the exact etiology remains unknown, recent findings suggest that it is a complex multifactorial disease with contributions from the host genetics and environmental factors such as the microbiome. We have previously shown that the T cell repertoire of individuals with CD harbors a group of highly expanded T cells which hints toward an antigen-mediated pathology. We simultaneously profiled the αβ and γδ T cell repertoire in addition to the B cell repertoire of both the blood and the colonic mucosa of 27 treatment-naïve individuals with CD and 27 age-matched symptomatic controls. Regardless of disease status, we observed multiple physiological differences between the immune repertoire of blood and colonic mucosa. Additionally, by comparing the repertoire of individuals with CD relative to controls, we observed different alterations that were only detected in the blood or colonic mucosa. These include a depletion of mucosal-associated invariant T (MAIT) cells and an expansion of clonotypes in the blood repertoire of individuals with CD. Also, a significant depletion of multiple and clonotypes in the blood and gut IGH repertoire of individuals with CD. Our findings highlight the importance of studying the immune repertoire in a tissue-specific manner and the need to profile the T and B cell immune repertoire of gut tissues as not all disease-induced alterations will be detected in the blood.

Background Inflammatory bowel disease (IBD) is an incurable immune-mediated inflammatory disease, affecting the gut with a high rate of primary- and secondary- loss-of-response to therapy. By investigating the T cell receptor repertoire of individuals with IBD, novel therapeutic and preventive strategies can be identified, and a better understanding of IBD can be obtained. Methods To identify and validate T cell clonotypes implicated in the pathogenesis of IBD, we profiled the T cell receptor alpha (TRA) repertoire of three cohorts containing treatment-naive, treated individuals, and individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 1,732 individuals. Results Using the generated datasets, we were able to replicate previous findings describing the expansion of Crohn’s-associated invariant T (CAIT) cells in individuals with Crohn’s disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified clonotypes. Conclusions The identified clonotypes are novel therapeutic targets to treat IBD, for example, through targeted depletion. By identifying antigens recognized by these T cells, a better understanding of the etiopathology of IBD, particularly CD, can be obtained.

Background Stool consistency is an important outcome measure to evaluate in the investigation of several gastrointestinal diseases. The Bristol Stool Scale (BSS) is one of the most commonly used tools for evaluation of stool consistency. BSS ranges from 1-7 and each score is assigned to a given consistency of the feces. Self-reported characterizations can differ from an expert evaluation, and the reliability of BSS is unclear. We aimed to evaluate the reliability of BSS by comparing patient scores with expert scores. Methods Patients with inflammatory bowel disease collected stool samples throughout a 3-year follow-up. The stool´s consistency was evaluated with BSS by the patients and matched with an expert score. Agreement between patient and expert scores was assessed using Cohen's kappa. Results BSS scores from 2280 fecal samples collected from 992 patients at up to five time points were included. When all samples were compared, there was good to substantial agreement between patient and expert scores (Cohen's weighted kappa: 0.66-0.72). When the BSS scores were simplified and categorized as 1 (scores 1-2), 2 (scores 3-5) or 3 (scores 6-7), the agreement improved slightly (Cohen's weighted kappa: 0.73-0.77). When the scores from the first sample per patient were compared, the experts were more likely to assign higher scores compared to the patient. The proportion of the lowest assigned scores (1-2) was 12.1% for patients and 8.1% for experts. Conclusions The agreement between patient and expert BSS scores is good to substantial, especially when the BSS scores are simplified into three categories.

Background and aimsThe functional luminal imaging probe (FLIP) can provide measurements of lower esophageal sphincter (LES) distensibility. Studies report that use of intraoperative FLIP examination during peroral endoscopic myotomy (POEM) for achalasia is associated with treatment success, but evidence is limited and inconsistent. The main aim of the present study was to assess associations between intraoperative FLIP values and 1-year outcomes. Additionally, associations between 1-year FLIP measurements and other 1-year outcome variables were studied.MethodsWe performed a single-center prospective study of consecutive achalasia patients treated with POEM with a standardized 1-year follow-up. The inclusion period was from June 2017 to January 2020. We compared 1-year outcomes (FLIP measurement values, Eckardt score (ES), reflux esophagitis, timed barium esophagogram (TBE), and lower esophageal sphincter resting pressure (LES-rp)) in patients with and without intraoperative FLIP examination. We also assessed associations between intraoperative FLIP values, 1-year FLIP values, and other 1-year outcomes. Results are given as median (IQR), and non-parametrical statistical analyses were applied.ResultsSixty-two patients (27 females) with median age 45 years (35–54) were included. Baseline characteristics were similar in patients with (n = 32) and without (n = 30) intraoperative FLIP examination. In patients with intraoperative FLIP, ES was 2 (1–3) and LES distensibility index (DI) 3.7 (2.6–5.4) after 1 year, compared with ES 2 (1–3) and DI 4.0 (3.1–6.8)) in patients without intraoperative FLIP (ns). Intraoperative DI was not correlated with 1-year ES or DI. One-year DI correlated significantly with 1-year ES (rs − 0.42), TBE (rs − 0.34), and LES-rp (rs − 0.29).ConclusionsUse of intraoperative FLIP measurements in POEM for achalasia is not associated with improved 1-year outcome, and the clinical value of intraoperative FLIP in POEM for achalasia is questioned. Follow-up FLIP measurements are moderately associated with symptomatic outcome, and may serve as an additional diagnostic modality in post-treatment evaluation.

Purpose This unselected, population-based cohort study aimed to determine the level of health-related quality of life (HRQoL) in patients with Crohn’s disease (CD) and ulcerative colitis (UC) at the time of diagnosis compared with a reference population and identify the demographic factors, psychosocial measures, and disease activity markers associated with HRQoL. Methods Adult patients newly diagnosed with CD or UC were prospectively enrolled. HRQoL was measured using the Short Form 36 (SF-36) and Norwegian Inflammatory Bowel Disease Questionnaires. Clinical significance was assessed using Cohen’s d effect size and further compared with a Norwegian reference population. Associations between HRQoL and symptom scores, demographic factors, psychosocial measures, and disease activity markers were analyzed. Results Compared with the Norwegian reference population, patients with CD and UC reported significantly lower scores in all SF-36 dimensions, except for physical functioning. Cohen’s d effect sizes for men and women in all SF-36 dimensions were at least moderate, except for bodily pain and emotional role for men with UC and physical functioning for both sexes and diagnoses. In the multivariate regression analysis, depression subscale scores ≥ 8 on the Hospital Anxiety and Depression Scale, substantial fatigue, and high symptom scores were associated with reduced HRQoL. Conclusion Patients newly diagnosed with CD and UC reported statistically and clinically significantly lower scores in seven of the eight SF-36 dimensions than the reference population. Symptoms of depression, fatigue, and elevated symptom scores were associated with poorer HRQoL.

Abstract Background Distinguishing irritable bowel syndrome (IBS) from inflammatory bowel disease (IBD) flare-ups is challenging. This study used objective remission markers to accurately determine IBS prevalence in a population-based cohort of patients with IBD. Methods Adults with ulcerative colitis and Crohn’s disease were recruited from the IBD in South-Eastern Norway III cohort study. Irritable bowel-like symptoms were assessed using the Rome IV criteria for patients in remission from IBD at 1- and 3-year follow-ups. Remission was defined objectively using the biochemical marker fecal calprotectin (FC) ≤ 250 µg/g, and comparisons to remission based on endoscopic indices were made at 1-year follow-up. Results Among patients with FC ≤ 250 µg/g, IBS prevalences were 21.9% (n = 62/283) and 16.1% (n = 49/304) at the 1- and 3-year follow-ups, respectively, which were higher than that in the Norwegian population (9.5%; P < .005). Of patients in endoscopic remission at 1-year follow-up, 19.2% (n = 43/224) reported IBS-like symptoms, which was not significantly different from IBS prevalence for patients with FC ≤ 250 µg/g. Irritable bowel syndrome was independently associated with substantial fatigue (odds ratio: 3.05 [95% CI, 1.48-6.27]) and female sex (odds ratio: 2.67 [95% CI, 1.34-5.32]) at the 1-year follow-up. Patients with IBS reported significantly reduced health-related quality of life (HRQoL) scores. Conclusions The prevalence of IBS among patients in remission from IBD was approximately twice as common as that in the Norwegian population. Irritable bowel syndrome was independently associated with substantial fatigue, female sex, and reduced HRQoL. Lay Summary In this prospective cohort of newly diagnosed patients with inflammatory bowel disease (IBD), patients in remission from IBD reported irritable bowel-like symptoms 2 to 3 times more frequently than the general Norwegian population at both the 1- and 3-year follow-ups. Graphical Abstract Graphical Abstract

Abstract Background and Aims The emergence of biologic therapy has coincided with a decline in surgery rates for Crohn’s disease (CD). This study aims to describe the disease course, including intra-abdominal surgery rates, biologic therapy use, and variables associated with biologic therapy initiation in a cohort of newly diagnosed CD patients. Methods The Inflammatory Bowel Disease in South-Eastern Norway (IBSEN) III study is a population-based inception cohort study. From 2017 to 2019, newly diagnosed inflammatory bowel disease patients were included for prospective follow-up. The present study included CD patients ≥ 18 years. Clinical, endoscopic, and demographic data were collected at diagnosis and 1-year follow-up. Data were analyzed by using the Kaplan–Meier method and regression analyses. Results In total, 424 CD patients (median age 37.0 years (range 18-80), female 55.0%) were included. At diagnosis, 50.5% presented with ileal disease and 80.7% with inflammatory behavior. Within a 1-year follow-up, 39.6% of patients received their first biologic therapy and 5.2% required intra-abdominal surgery. Systemic steroid treatment, CRP ≥ 5.0 mg dL−1, Harvey–Bradshaw Index score > 4, ileocolonic disease and penetrating disease behavior at diagnosis were independently associated with increased risk of initiation of biologic therapy, while age > 40 years was associated with decreased risk. Conclusion A high proportion of patients had ileal disease and inflammatory behavior at diagnosis. Still, nearly 40% started biologic therapy within the 1-year follow-up, while only 5% required intra-abdominal surgery. Lay Summary In this new, population-based inception cohort (Inflammatory Bowel Disease in South-Eastern Norway III), two-fifths of incident Crohn’s disease patients started biologic therapy within 1-year follow-up, despite predominantly mild disease with ileal location and inflammatory behavior at diagnosis. Only 5.2% required intra-abdominal surgery. Graphical Abstract Graphical Abstract

Abstract Introduction We aimed to determine the diagnostic and prognostic potential of baseline microbiome profiling in inflammatory bowel disease (IBD). Methods Participants with ulcerative colitis (UC), Crohn’s disease (CD), suspected IBD, and non-IBD symptomatic controls were included in the prospective population-based cohort Inflammatory Bowel Disease in South-Eastern Norway III (third iteration) based on suspicion of IBD. The participants donated fecal samples that were analyzed with 16S rRNA sequencing. Disease course severity was evaluated at the 1-year follow-up. A stringent statistical consensus approach for differential abundance analysis with 3 different tools was applied, together with machine learning modeling. Results A total of 1404 individuals were included, where n = 1229 samples from adults were used in the main analyses (n = 658 UC, n = 324 CD, n = 36 IBD-U, n = 67 suspected IBD, and n = 144 non-IBD symptomatic controls). Microbiome profiles were compared with biochemical markers in machine learning models to differentiate IBD from non-IBD symptomatic controls (area under the receiver operating curve [AUC] 0.75-0.79). For UC vs controls, integrating microbiome data with biochemical markers like fecal calprotectin mildly improved classification (AUC 0.83 to 0.86, P < .0001). Extensive differences in microbiome composition between UC and CD were identified, which could be quantified as an index of differentially abundant genera. This index was validated across published datasets from 3 continents. The UC-CD index discriminated between ileal and colonic CD (linear regression, P = .008) and between colonic CD and UC (P = .005), suggesting a location-dependent gradient. Microbiome profiles outperformed biochemical markers in predicting a severe disease course in UC (AUC 0.72 vs 0.65, P < .0001), even in those with a mild disease at baseline (AUC 0.66 vs 0.59, P < .0001). Conclusions Fecal microbiome profiling at baseline held limited potential to diagnose IBD from non-IBD compared with standard-of-care. However, microbiome shows promise for predicting future disease courses in UC. Lay Summary This study assessed the diagnostic and prognostic potential of baseline microbiome profiling in IBD. The microbiome holds the potential to differentiate IBD from controls and enhanced predictive capacity for UC severity. A UC-CD microbial index distinguished disease types and was validated with a global cohort.

Background Stool consistency is an important outcome measure to evaluate in the investigation of several gastrointestinal diseases. The Bristol Stool Scale (BSS) is one of the most commonly used tools for evaluation of stool consistency. BSS ranges from 1-7 and each score is assigned to a given consistency of the feces. Self-reported characterizations can differ from an expert evaluation, and the reliability of BSS is unclear. We aimed to evaluate the reliability of BSS by comparing patient scores with expert scores. Methods Patients with inflammatory bowel disease collected stool samples throughout a 3-year follow-up. The stool´s consistency was evaluated with BSS by the patients and matched with an expert score. Agreement between patient and expert scores was assessed using Cohen's kappa. Results BSS scores from 2280 fecal samples collected from 992 patients at up to five time points were included. When all samples were compared, there was good to substantial agreement between patient and expert scores (Cohen's weighted kappa: 0.66-0.72). When the BSS scores were simplified and categorized as 1 (scores 1-2), 2 (scores 3-5) or 3 (scores 6-7), the agreement improved slightly (Cohen's weighted kappa: 0.73-0.77). When the scores from the first sample per patient were compared, the experts were more likely to assign higher scores compared to the patient. The proportion of the lowest assigned scores (1-2) was 12.1% for patients and 8.1% for experts. Conclusions The agreement between patient and expert BSS scores is good to substantial, especially when the BSS scores are simplified into three categories.

Whereas altered immune processes have been identified in individuals with inflammatory bowel disease (IBD), potentially causative antigens remain to be identified. By interrogating the immune repertoire of individuals with IBD, an identification of common antigenic exposures associated with the disease can be obtained. We analyzed the T cell receptor beta (TRB) chain repertoire of 1,890 individuals with Crohn’s disease (CD) and 914 individuals with ulcerative colitis (UC), enabling the identification of 327 TRB clonotypes associated with CD and 130 with UC. We validated the expansion of these clonotypes in a cohort of treatment-naïve individuals with either CD, UC or symptomatic control (n=855). These disease-associated clonotypes were restricted to disease-associated risk HLA alleles and their expansion correlated with disease-severity but not with surgery or treatment trajectory. In conclusion, we identified and validated TRB clonotypes that are associated with either CD or UC, these clonotypes are a novel therapeutic target in IBD.