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Background: Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas.Methods/design: Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma > or = 3 cm, located between 1-15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment. Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures. Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group.Discussion: The TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas.Trial Registration Number: (trialregister.nl) NTR1422. [ABSTRACT FROM AUTHOR]

Importance: Patients with painful chronic pancreatitis and a dilated pancreatic duct can be treated by early surgery or an endoscopy-first approach., Objective: To compare long-term clinical outcomes of early surgery vs an endoscopy-first approach using follow-up data from the ESCAPE randomized clinical trial., Design, Setting, and Participants: Between April 2011 and September 2018, 88 patients with painful chronic pancreatitis were randomly assigned to early surgery or an endoscopy-first approach in 30 hospitals in the Netherlands collaborating in the Dutch Pancreatitis Study Group as part of the ESCAPE randomized clinical trial. For the present cohort study, long-term clinical data were collected after the initial 18-month follow-up. Follow-up was completed in June 2022, and data analysis was performed in June 2023., Exposure: Patients with chronic pancreatitis were randomly assigned to early surgery or an endoscopy-first approach., Main Outcomes and Measures: The primary end point was pain, assessed by the Izbicki pain score; secondary end points included patient-reported complete pain relief and satisfaction. Predefined subgroups included patients who progressed from endoscopy to surgery and those with ductal clearance obtained by endoscopy. Analysis was performed according to the intention-to-treat principle., Results: In this cohort study, 86 of 88 overall patients could be evaluated, with a mean (SD) follow-up period of 98 (16) months. Of 88 initial patients, 21 patients (24%) were female, and mean (SD) patient age was 61 (10) years. At the end of long-term follow-up, the mean (SD) Izbicki pain score was significant lower (33 [31] vs 51 [31]) in the early surgery group, as was the rate of patient-reported complete pain relief (14 of 31 patients [45%] vs 6 of 30 patients [20%]), compared to the endoscopy-first group. After the initial 18-month follow-up, 11 of 43 patients in the early surgery group (26%) underwent reinterventions vs 19 of 43 patients in the endoscopy-first group (44%). At the end of follow-up, more patients in the early surgery group were "very satisfied" with their treatment (22 of 31 patients [71%] vs 10 of 30 patients [33%]). Patients who progressed from endoscopy to surgery (22 of 43 patients [51%]) had significantly worse mean (SD) Izbicki pain scores (33 [31] vs 52 [24]) compared to the early surgery group and had a lower rate of complete pain relief (55% for early surgery vs 12% for endoscopy first). In the endoscopy-first group, patients with endoscopic ductal clearance had similar mean (SD) Izbicki pain scores as the remaining patients (49 [34] vs 53 [28])., Conclusions and Relevance: In this cohort study evaluating long-term outcomes of the ESCAPE randomized clinical trial, after approximately 8 years of follow-up, early surgery was superior to an endoscopy-first approach in patients with painful chronic pancreatitis and a dilated main pancreatic duct in pain scores and patient satisfaction. Notably, patients who progressed from endoscopy to surgery had worse outcomes compared to patients undergoing early surgery, and obtaining endoscopic ductal clearance did not improve outcomes.

Disrupted host-microbe interactions at the mucosal level are key to the pathophysiology of IBD. This study aimed to comprehensively examine crosstalk between mucosal gene expression and microbiota in patients with IBD. To study tissue-specific interactions, we perform transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 697 intestinal biopsies (645 derived from 335 patients with IBD and 52 from 16 non-IBD controls). Mucosal gene expression patterns in IBD are mainly determined by tissue location and inflammation, whereas the mucosal microbiota composition shows a high degree of individual specificity. Analysis of transcript-bacteria interactions identifies six distinct groups of inflammation-related pathways that are associated with intestinal microbiota (adjusted P < 0.05). An increased abundance of Bifidobacterium is associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides correlates with increased metallothionein signaling. In patients with fibrostenosis, a transcriptional network dominated by immunoregulatory genes is associated with Lachnoclostridium bacteria in non-stenotic tissue (adjusted P < 0.05), while being absent in CD without fibrostenosis. In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes is linked to Ruminococcaceae (adjusted P < 0.05). Mucosal microbiota composition correlates with enrichment of intestinal epithelial cells, macrophages, and NK-cells. Overall, these data demonstrate the presence of context-specific mucosal host-microbe interactions in IBD, revealing significantly altered inflammation-associated gene-taxa modules, particularly in patients with fibrostenotic CD and patients using TNF-α-antagonists. This study provides compelling insights into host-microbe interactions that may guide microbiota-directed precision medicine and fuels the rationale for microbiota-targeted therapeutics as a strategy to alter disease course in IBD., (© 2024. The Author(s).)

Background: Malignant gastric outlet obstruction (GOO) is a debilitating condition that frequently occurs in patients with malignancies of the distal stomach and (peri)ampullary region. The standard palliative treatment for patients with a reasonable life expectancy and adequate performance status is a laparoscopic surgical gastrojejunostomy (SGJ). Recently, endoscopic ultrasound-guided gastroenterostomy (EUS-GE) emerged as a promising alternative to the surgical approach. The present study aims to compare these treatment modalities in terms of efficacy, safety, and costs., Methods: The ENDURO-study is a multicentre, open-label, parallel-group randomized controlled trial. In total, ninety-six patients with gastric outlet obstruction caused by an irresectable or metastasized malignancy will be 1:1 randomized to either SGJ or EUS-GE. The primary endpoint is time to tolerate at least soft solids. The co-primary endpoint is the proportion of patients with persisting or recurring symptoms of gastric outlet obstruction for which a reintervention is required. Secondary endpoints are technical and clinical success, quality of life, gastroenterostomy dysfunction, reinterventions, time to reintervention, adverse events, quality of life, time to start chemotherapy, length of hospital stay, readmissions, weight, survival, and costs., Discussion: The ENDURO-study assesses whether EUS-GE, as compared to SGJ, results in a faster resumption of solid oral intake and is non-inferior regarding reinterventions for persistent or recurrent obstructive symptoms in patients with malignant GOO. This trial aims to guide future treatment strategies and to improve quality of life in a palliative setting., Trial Registration: International Clinical Trials Registry Platform (ICTRP): NL9592. Registered on 07 July 2021., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Hepcidin, the systemic iron regulator, could be critical in differentiating iron deficiency (ID) from functional iron restriction in inflammatory bowel disease (IBD). We assessed hepcidin as a diagnostic ID marker and explored the relationship between hepcidin and its regulators in patients with IBD undergoing induction therapy with infliximab (IFX) or vedolizumab (VEDO)., Methods: Patients with active IBD receiving induction therapy with IFX or VEDO were included. Serum samples at baseline and after 6 weeks of induction therapy were analyzed for hepcidin, inflammation- and hypoxia-associated cytokines, and oxidative stress. Data were analyzed by stratifying based on the response at week 14. Results were compared with samples from age- and sex-matched healthy control subjects., Results: Patients receiving induction therapy with IFX (n = 71) or VEDO (n = 51) and healthy control subjects (n = 50) were included. At baseline, hepcidin correlated positively with ferritin and negatively with soluble transferrin receptor/log ferritin index (P < .001). ID was prevalent in 96.7% of patients who had hepcidin levels below the median. Hepcidin accurately identified ID: the area under the curve (hepcidin) was 0.89 (95% confidence interval, 0.82-0.95; P < .001). In total, 75.4% of patients responded to induction therapy; inflammation, hepcidin, and ferritin decreased significantly, while transferrin increased during induction therapy. These changes were observed only in patients who responded to the therapy., Conclusions: Hepcidin levels in IBD are primarily determined by ID, even in an inflammatory state. In addition, induction therapy can decrease hepcidin levels, which might lead to better bioavailability of iron supplements. Therefore, hepcidin is a potential diagnostic ID biomarker that could assist therapeutic decision making., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Objective: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings., Design: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design., Results: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92)., Conclusion: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group., Trial Registration Number: ISRCTN15545919., Competing Interests: Competing interests: JEvH received personal speakers fees from Medtronic, Abbvie, Cook and Boston Scientific outside of the submitted work. PF reports personal fees from Olympus and Cook Endoscopy outside the submitted work. MJB reports personal fees from Boston Scientific, Cook Medical, Pentax Medical and Mylan, and grants from Boston Scientific, Cook Medical, Pentax Medical, 3M, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammatory bowel diseases (IBDs), e.g., Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases. A comprehensive overview of an IBD-specific antibody epitope repertoire is, however, lacking. Using high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq), we identified antibodies against 344,000 antimicrobial, immune, and food antigens in 497 individuals with IBD compared with 1,326 controls. IBD was characterized by 373 differentially abundant antibody responses (202 overrepresented and 171 underrepresented), with 17% shared by both IBDs, 55% unique to CD, and 28% unique to UC. Antibody reactivities against bacterial flagellins dominated in CD and were associated with ileal involvement, fibrostenotic disease, and anti-Saccharomyces cerevisiae antibody positivity, but not with fecal microbiome composition. Antibody epitope repertoires accurately discriminated CD from controls (area under the curve [AUC] = 0.89), and similar discrimination was achieved when using only ten antibodies (AUC = 0.87). Individuals with IBD thus show a distinct antibody repertoire against selected peptides, allowing clinical stratification and discovery of immunological targets., Competing Interests: Declaration of interests G.D. received an unrestricted research grant from Takeda and speaker fees from Pfizer and Janssen Pharmaceuticals. R.K.W. acted as consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico, and Ferring and received speaker fees from MSD, AbbVie, and Janssen Pharmaceuticals. M.C.V. received speaker fees from Janssen-Cilag, Galapagos, and Ferring B.V., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Lumen-apposing metal stents (LAMS) are believed to clinically improve endoscopic transluminal drainage of infected necrosis when compared with double-pigtail plastic stents. However, comparative data from prospective studies are very limited., Design: Patients with infected necrotising pancreatitis, who underwent an endoscopic step-up approach with LAMS within a multicentre prospective cohort study were compared with the data of 51 patients in the randomised TENSION trial who had been assigned to the endoscopic step-up approach with double-pigtail plastic stents. The clinical study protocol was otherwise identical for both groups. Primary end point was the need for endoscopic transluminal necrosectomy. Secondary end points included mortality, major complications, hospital stay and healthcare costs., Results: A total of 53 patients were treated with LAMS in 16 hospitals during 27 months. The need for endoscopic transluminal necrosectomy was 64% (n=34) and was not different from the previous trial using plastic stents (53%, n=27)), also after correction for baseline characteristics (OR 1.21 (95% CI 0.45 to 3.23)). Secondary end points did not differ between groups either, which also included bleeding requiring intervention-5 patients (9%) after LAMS placement vs 11 patients (22%) after placement of plastic stents (relative risk 0.44; 95% CI 0.16 to 1.17). Total healthcare costs were also comparable (mean difference -€6348, bias-corrected and accelerated 95% CI -€26 386 to €10 121)., Conclusion: Our comparison of two patient groups from two multicentre prospective studies with a similar design suggests that LAMS do not reduce the need for endoscopic transluminal necrosectomy when compared with double-pigtail plastic stents in patients with infected necrotising pancreatitis. Also, the rate of bleeding complications was comparable., Competing Interests: Competing interests: MGB reports grants from Intuitive, grants from Ethicon Endo-Surgery, grants from Medtronic, outside the submitted work; MBo reports grants and personal fees from Johnson & Johnson, grants and personal fees from Acelity/KCI, grants and personal fees from Bard, grants from Ipsen, grants from New Compliance, grants from Mylan, personal fees from Gore, personal fees from Smith & Newphew, outside the submitted work; MBr reports grants and personal fees from Boston Scientific, grants and personal fees from Cook Medical, grants from Pentax Medical, grants from Mylan, grants from 3M, grants from InterScope, outside the submitted work; PF reports personal fees from Cook Medical, personal fees from Olympus, personal fees from Ethicon Endo-Surgery, outside the submitted work; J-WP reports personal fees and other from Cook Endoscopy, personal fees and other from Boston Scientific, personal fees and other from Pentax Medical, outside the submitted work; E-JvG reports grants from Mylan, grants from Olympus, personal fees from MTW-Endoskopie, outside the submitted work; JEvH reports personal fees from Olympus Endoscopy, grants from Cook Medical, personal fees from Boston Scientific, personal fees from Medtronic, outside the submitted work; FV reports grants from Boston Scientific, outside the submitted work; RPV reports grants and personal fees from Boston Scientific, grants from Zambon, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index < 5 or Simple Clinical Colitis Activity Index < 2.5) and biochemical remission (C-reactive protein < 5 mg/L and absence of anemia) at time of fatigue assessment. Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (nominal P < 0.05). Although solely LIF-R showed weak ability to discriminate between mild and severe fatigue (area under the curve [AUC] = 0.61, 95%CI: 0.53-0.69, P < 0.05), a combined set of the top seven (7) fatigue-associated proteins (all P < 0.10) was observed to have reasonable discriminative performance (AUC = 0.82 [95%CI: 0.74-0.91], P < 0.01). Fatigue in patients with IBD is not clearly reflected by distinct protein signatures, suggesting there is no subclinical inflammation defined by the studied inflammatory proteins. Future studies are warranted to investigate other proteomic markers that may reflect fatigue in clinically quiescent IBD., (© 2022. The Author(s).)

Background: Increased collagen remodelling is a key pathophysiological component underlying intestinal stricture and fistula development in Crohn's disease (CD)., Aims: To investigate associations between serological biomarkers of collagen turnover and disease behaviour according to the Montreal classification in patients with CD., Methods: Serological biomarkers of type III/IV collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP) or granzyme-B (GrzB)-mediated type I, III, IV and VI collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) were measured using neo-epitope protein fingerprint assays in 101 patients with CD (Montreal B1: n = 37; B2: n = 27; B3: n = 37) and 96 controls. Patients were followed up until their last outpatient visit to monitor stricturing/penetrating disease progression and recurrence and the occurrence of surgical interventions., Results: C1M, C3M and C4M were significantly reduced in patients with stricturing disease (Montreal B2) and accurately differentiated them from patients with either non-stricturing, non-penetrating (B1) or penetrating (B3) disease (all p < 0.001, multivariable analysis). Similarly, the type IV collagen formation/degradation (PRO-C4/C4M) ratio demonstrated high discriminative capacity (B1/B2: AUC = 0.90; B1/B3: AUC = 0.87, both p < 0.001, multivariable analysis). Prospectively, higher baseline levels of C1M and C4G were associated with an increased risk of penetrating disease progression (C4G: hazard ratio [HR] 1.71 [1.05-2.81], p < 0.05)., Conclusions: Elevated degradation of type I, III and IV collagen and excessive (relative) formation of type IV collagen strongly associates with stricturing CD. Type I and IV collagen fragments show predictive potential for the risk of penetrating disease progression. These biomarkers may become valuable tools for detection and prediction of stricturing and penetrating CD., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Crohn’s disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by increased extracellular matrix (ECM) remodeling. The introduction of the α4β7-integrin inhibitor vedolizumab (VEDO) has improved disease management, although there is a high rate of primary non-response in patients with CD. We studied whether ECM biomarkers of neutrophil activity and mucosal damage could predict long-term response to VEDO in patients with CD. Serum levels of human neutrophil elastase (HNE)-derived fragments of calprotectin (CPa9-HNE), and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen, type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n = 32) before VEDO therapy. Long-term response was defined as VEDO treatment of at least 12 months. CPa9-HNE was significantly increased at baseline in non-responders compared with responders (p < 0.05). C1M, C3M, C4M, C6Ma3, and PRO-C4 were also significantly increased at baseline in non-responders compared with responders (all p < 0.05). All biomarkers were associated with response to VEDO (all p < 0.05). To conclude, baseline levels of serum biomarkers for neutrophil activity and mucosal damage are linked to the pathology of CD, and are associated with long-term use of VEDO in patients with CD. Therefore, these biomarkers warrant further validation and could aid in therapeutic decision-making concerning vedolizumab therapy.

Background: Crohn's disease (CD) is characterized by excessive protease activity and extracellular matrix (ECM) remodeling. To date, 30-50% of patients experience non-response to anti-TNF-α treatment. This study aimed to assess whether serological biomarkers of ECM turnover could monitor or predict response to infliximab (IFX) induction therapy in patients with and without a surgical history., Methods: Serum biomarkers of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen degradation, type III (PRO-C3) and VI (PRO-C6) collagen formation, basement membrane turnover (PRO-C4), and T-cell activity (C4G), were measured at baseline and week 14, in 63 patients with CD undergoing IFX induction therapy. Patients were stratified according to surgical history., Results: C4M was elevated at baseline in responders with a surgical history ( n = 10) and associated with response at baseline ( P < 0.05). Additionally, C6Ma3, PRO-C3, and PRO-C6 were elevated at week 14 in responders compared with non-responders ( n = 8) and could differentiate between the two groups ( P < 0.05). Two biomarker ratios (C4M/C4G and PRO-C4/C4G) were elevated at week 14 in non-responders ( n = 5) without a surgical history compared with responders ( n = 40) and could differentiate between the response groups ( P < 0.05)., Conclusion: Baseline levels of a serological biomarker for type IV collagen degradation associated with response to IFX induction therapy, and biomarkers of type III and VI collagen formation may be used to monitor response at the end of induction therapy in patients with a surgical history. Biomarker ratios of type IV collagen turnover demonstrated promising results in monitoring treatment response in patients without a surgical history., Competing Interests: MA, MP, MK, and JM are employees of Nordic Bioscience A/S. MK owns stocks in Nordic Bioscience A/S. GD received research grants from Royal DSM and speaker’s fees from Janssen Pharmaceuticals, Takeda, Pfizer, and Abbvie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alexdottir, Bourgonje, Karsdal, Pehrsson, Loveikyte, van Dullemen, Visschedijk, Festen, Weersma, Faber, Dijkstra and Mortensen.)

Introduction: Patients with Inflammatory Bowel Disease (IBD) frequently receive immunomodulating treatment, which may render them at increased risk of an attenuated immune response upon vaccination. In this study, we assessed the effects of different types of commonly prescribed immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD., Methods: In this prospective observational cohort study, IgG antibody titers against SARS-CoV-2 were measured 2-10 weeks after completion of standard vaccination regimens in patients with IBD. Clinical characteristics, previous history of SARS-CoV-2 infection, type of vaccine (mRNA- or vector-based) and medication use were recorded at the time of sampling. Subsequently, a chemiluminescent microparticle immunoassay was used for the quantitative determination of IgG antibodies against the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2., Results: Three hundred and twelve (312) patients with IBD were included (172 Crohn's disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of >50 AU/ml) was achieved in 98.3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs . non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655-2935] vs . 5002 [4089-6116] AU/ml, P <0.001). In multivariable models, use of TNF-α-antagonists ( P <0.001), vector vaccines ( P <0.001), age (>50 years) ( P <0.01) and CD ( P <0.05) were independently associated with lower anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of thiopurines (either prescribed as monotherapy or in combination with biologicals) demonstrated significantly lower antibody titers compared to thiopurine non-users ( P <0.05)., Conclusion: Despite reassuring findings that most patients with IBD have detectable antibodies after anti-SARS-CoV-2 vaccination, TNF-α-antagonists were found to be strongly associated with an attenuated IgG antibody response after vaccination against SARS-CoV-2, independent of vaccine type, the time elapsed after vaccination and blood sampling, prior SARS-CoV-2 infection and patient age. Patients treated with thiopurines and receiving mRNA-based vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with non-users., Competing Interests: GD received research grants from Royal DSM and speaker’s fees from Janssen Pharmaceuticals, Takeda, Pfizer and Abbvie. RW acted as consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring, and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. MV has served on the advisory board for Janssen-Cilag and received a speaker’s fee from Takeda, outside the submitted work. The funders had no role in the design of the study, collection, analysis, or interpretation of data or in writing the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Otten, Bourgonje, Horinga, van der Meulen, Festen, van Dullemen, Weersma, van Leer-Buter, Dijkstra and Visschedijk.)

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn’s disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) < 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR < 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR < 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet−inflammation relationship.

Background & Aims: Patients with inflammatory bowel disease are at increased risk of colorectal neoplasia (CRN) due to mucosal inflammation. As current surveillance guidelines form a burden on patients and healthcare costs, stratification of high-risk patients is crucial. Cigarette smoke reduces inflammation in ulcerative colitis (UC) but not Crohn's disease (CD) and forms a known risk factor for CRN in the general population. Due to this divergent association, the effect of smoking on CRN in IBD is unclear and subject of this study., Methods: In this retrospective cohort study, 1,386 IBD patients with previous biopsies analyzed and reported in the PALGA register were screened for development of CRN. Clinical factors and cigarette smoke were evaluated. Patients were stratified for guideline-based risk of CRN. Cox-regression modeling was used to estimate the effect of cigarette smoke and its additive effect within the current risk stratification for prediction of CRN., Results: 153 (11.5%) patients developed CRN. Previously described risk factors, i.e. first-degree family member with CRN in CD (p-value=.001), presence of post-inflammatory polyps in UC (p-value=.005), were replicated. Former smoking increased risk of CRN in UC (HR 1.73; 1.05-2.85), whereas passive smoke exposure yielded no effect. For CD, active smoking (2.20; 1.02-4.76) and passive smoke exposure (1.87; 1.09-3.20) significantly increased CRN risk. Addition of smoke exposure to the current risk-stratification model significantly improved model fit for CD., Conclusions: This study is the first to describe the important role of cigarette smoke in CRN development in IBD patients. Adding this risk factor improves the current risk stratification for CRN surveillance strategies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD., Methods: A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses., Results: Thirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria., Conclusions: This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Fatigue is one of the most frequently reported symptoms by patients with inflammatory bowel disease (IBD), both during active disease phases as well as during clinical remission. This study addressed whether different trajectories of fatigue over time can be identified among patients with IBD. Subsequently, we compared the demographic and clinical characteristics between trajectories., Methods: The current study included 849 patients with IBD diagnosed with either Crohn disease (CD; n = 511) or ulcerative colitis (UC; n = 338) who visited the University Medical Center in Groningen (the Netherlands) at least 3 times during a 9-year follow-up. We conducted latent class growth analyses to identify distinct trajectories., Results: In all patients with IBD (and in the subgroup with CD), we found 5 trajectories for fatigue. In the UC subgroup, we found 4 fatigue trajectories. One trajectory present in both patients with CD (11.45%) and patients with UC (4.75%) was characterized by chronic elevated levels of fatigue across time. Women and parents were more prevalent in trajectories with higher fatigue severity. We also found significant associations among the fatigue trajectories with disease activity and psychological well-being., Conclusions: The results clearly showed the existence of distinct fatigue paths over time in patients with IBD. Those reporting more chronic elevated levels of fatigue also reported greater disease activity and reduced well-being. Therefore, reducing disease activity may be important for the treatment of fatigue. In addition, given the significant association with well-being, it is possible that reducing fatigue may improve self-reported well-being., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn's disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity., Materials and Methods: Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC., Results: Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders., Conclusions: We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: G.D. received an unrestricted research grant from Takeda, and received speaker fees from Pfizer and Janssen Pharmaceuticals. R.K.W. acted as consultant for Takeda, received unrestricted research grants from Takeda, Johnson and Johnson, Tramedico and Ferring and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. E.A.M.F. received an unrestricted research grant from Takeda. The remaining authors disclose no conflicts. Our competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Pain in chronic pancreatitis is subdivided in a continuous or intermittent pattern, each thought to represent a different entity, requiring specific treatment. Because evidence is missing, we studied pain patterns in a prospective longitudinal nationwide study., Design: 1131 patients with chronic pancreatitis (fulfilling M-ANNHEIM criteria) were included between 2011 and 2018 in 30 Dutch hospitals. Patients with continuous or intermittent pain were compared for demographics, pain characteristics, quality of life (Short-Form 36), imaging findings, disease duration and treatment. Alternation of pain pattern and associated variables were longitudinally assessed using a multivariable multinomial logistic regression model., Results: At inclusion, 589 patients (52%) had continuous pain, 231 patients (20%) had intermittent pain and 311 patients (28%) had no pain. Patients with continuous pain had more severe pain, used more opioids and neuropathic pain medication, and had a lower quality of life. There were no differences between pain patterns for morphological findings on imaging, disease duration and treatment. During a median follow-up of 47 months, 552 of 905 patients (61%) alternated at least once between pain patterns. All alternations were associated with the Visual Analogue Scale pain intensity score and surgery was only associated with the change from pain to no pain., Conclusion: Continuous and intermittent pain patterns in chronic pancreatitis do not seem to be the result of distinctly different pathophysiological entities. The subjectively reported character of pain is not related to imaging findings or disease duration. Pain patterns often change over time and are merely a feature of how severity of pain is experienced., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The role of Mycobacterium avium paratuberculosis [MAP] in inflammatory bowel disease [IBD], especially Crohn's disease [CD] is controversial due conflicting results and lack of reproducibility and standardised tests. The current study focuses on the role of MAP in disease progression and genetic susceptibility, as MAP is likely one of many factors involved in the complex pathogenesis of IBD, potentially affecting a subgroup depending on genetic susceptibility., Methods: Serum from 812 patients was evaluated with seven immunoglobulin [Ig] isotype-specific serology tests assessing humoral response to three different MAP antigens. For each of these in total 21 tests, the intra-assay and inter-assay coefficients were used to evaluate test accuracy. Reliable assays were subsequently analysed in relation to disease characteristics and need for biologic therapy/surgery. Genome-wide genotyping was available for all participants. Genetic determinants of humoral response to MAP antigens were evaluated using genome-wide association analysis and polygenic risk scores [PRS]., Results: High IgA or IgM response to MAP2609 was associated with increased use of biologic therapy in CD and ulcerative colitis [UC] [odds ratios 2.69; 95% confidence interval 1.44-5.01; and 2.60, 1.46-4.64, respectively]. No associations were seen for risk of surgery [p-values > 0.29]. We could not identify genetic determinants nor polygenic risk scores for MAP response with genome-wide significance., Conclusions: Extensive assays for serological response to MAP were evaluated using stringent criteria for reliability. Increased IgA and IgM response to MAP antigens was seen in patients exposed to biologic therapy, but no genetic determinants underlying this humoral response were found., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Diet is associated with the onset of inflammatory bowel disease [IBD]. Up to half of IBD patients believe that diet contributes to flares. However, studies on this topic are sparse and merely focus on specific nutrients, food items or food groups. We aimed to analyse the association between dietary patterns and flare occurrence in two geographically distinct Dutch cohorts., Methods: In this longitudinal study, 724 IBD patients [Northern cohort: n = 486, Southern cohort: n = 238] were included and followed for 2 years. Habitual dietary intake was obtained via semi-quantitative food frequency questionnaires at baseline. Principal component analysis [PCA] was conducted on 22 food groups to identify dietary patterns. Flare occurrence was analysed in 427 patients in remission at baseline, using multivariable Cox proportional hazards., Results: Compared to the Southern cohort, patients in the Northern cohort were younger at diagnosis, comprised more females, and had lower overall energy intakes [all p < 0.05]. PCA revealed three dietary patterns explaining 28.8% of the total variance. The most pronounced pattern [explaining 11.6%] was characterized by intake of grain products, oils, potatoes, processed meat, red meat, condiments and sauces, and sugar, cakes and confectionery. Of the 427 patients, 106 [24.8%] developed an exacerbation during follow-up. The above dietary pattern was associated with flare occurrence (hazard ratio [HR]: 1.51, 95% confidence interval [CI]: 1.04-2.18, p = 0.029), as was female sex [HR: 1.63, 95% CI 1.04-2.55, p = 0.032]., Conclusions: A dietary pattern, which can be seen as a 'traditional [Dutch]' or "Western' pattern was associated with flare occurrence. Confirmation in prospective studies is needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aim: While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best-known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification., Methods: Seven hundred twenty-eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate-adjusted logistic regression modeling., Results: No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated., Conclusions: We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor-made interventions, and preventive strategies in IBD., (© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and study aims  Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) with a lumen-apposing metal stent (LAMS) is a novel, minimally invasive technique in the palliative treatment of malignant gastric outlet obstruction (GOO). Several studies have demonstrated feasibility and safety of EUS-GE, but evidence on long-term durability is limited. The aim of this study was to evaluate patency of EUS-GE in treatment of malignant GOO. Patients and Methods  An international multicenter study was performed in seven centers in four European countries. Patients who underwent EUS-GE with a LAMS between March 2015 and March 2019 for palliative treatment of symptomatic malignant GOO were included retrospectively. Our main outcome was recurrent obstruction due to LAMS dysfunction; other outcomes of interest were technical success, clinical success, adverse events (AEs), and survival. Results  A total of 45 patients (mean age 69.9 ± 12.3 years and 48.9 % male) were included. Median duration of follow-up was 59 days (interquartile range [IQR] 41-128). Recurrent obstruction occurred in two patients (6.1 %), after 33 and 283 days of follow-up. Technical success was achieved in 39 patients (86.7 %). Clinical success was achieved in 33 patients (73.3 %). AEs occurred in 12 patients (26.7 %), of which five were fatal. Median overall survival was 57 days (IQR 32-114). Conclusions  EUS-GE showed a low rate of recurrent obstruction. The relatively high number of fatal AEs underscores the importance of careful implementation of EUS-GE in clinical practice., Competing Interests: Competing interests Dr. Moons, Drs. Masaryk, Dr. Will, Dr. Poley, and Dr. Vleggaar are consultants for Boston Scientific. Dr. Poley is also a consultant for Cook and Pentax. Dr. Perez-Miranda is a consultant for MITech and Boston Scientific, and speaker for Boston Scientific, MITech, Olympus, and Taewoong.

Introduction: Idiopathic acute pancreatitis (IAP) remains a dilemma for physicians as it is uncertain whether patients with IAP may actually have an occult aetiology. It is unclear to what extent additional diagnostic modalities such as endoscopic ultrasonography (EUS) are warranted after a first episode of IAP in order to uncover this aetiology. Failure to timely determine treatable aetiologies delays appropriate treatment and might subsequently cause recurrence of acute pancreatitis. Therefore, the aim of the Pancreatitis of Idiopathic origin: Clinical added value of endoscopic UltraSonography (PICUS) Study is to determine the value of routine EUS in determining the aetiology of pancreatitis in patients with a first episode of IAP., Methods and Analysis: PICUS is designed as a multicentre prospective cohort study of 106 patients with a first episode of IAP after complete standard diagnostic work-up, in whom a diagnostic EUS will be performed. Standard diagnostic work-up will include a complete personal and family history, laboratory tests including serum alanine aminotransferase, calcium and triglyceride levels and imaging by transabdominal ultrasound, magnetic resonance imaging or magnetic resonance cholangiopancreaticography after clinical recovery from the acute pancreatitis episode. The primary outcome measure is detection of aetiology by EUS. Secondary outcome measures include pancreatitis recurrence rate, severity of recurrent pancreatitis, readmission, additional interventions, complications, length of hospital stay, quality of life, mortality and costs, during a follow-up period of 12 months., Ethics and Dissemination: PICUS is conducted according to the Declaration of Helsinki and Guideline for Good Clinical Practice. Five medical ethics review committees assessed PICUS (Medical Ethics Review Committee of Academic Medical Center, University Medical Center Utrecht, Radboud University Medical Center, Erasmus Medical Center and Maastricht University Medical Center). The results will be submitted for publication in an international peer-reviewed journal., Trial Registration Number: Netherlands Trial Registry (NL7066). Prospectively registered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Cytomegalovirus (CMV) infection is common in the general population. CMV infection negatively affects disease course in transplant recipients and HIV patients. Whereas primary CMV infections may occur sporadically in seronegative patients, all seropositive patients with inflammatory bowel syndrome (IBD) are at risk for CMV reactivation due to the inflammatory mucosal and use of immunosuppressive medication. It is unclear whether latent CMV infection, and risk of reactivations, influences long-term disease outcomes. In this study, we aim to explore whether CMV infection affects disease outcomes in IBD patients., Methods: We performed a cross-sectional cohort study with 1404 patients with IBD from a single center. Clinical characteristics and disease outcomes were prospectively collected. We scrutinized CMV serology test results and performed additional CMV serology testing if serum was available., Results: Out of 699 IBD patients with CMV serology, 303 (43.3%) were seropositive, comparable to the general Dutch population. CMV seropositivity was associated with older age, longer IBD disease duration, non-Western origin, birth outside the Netherlands and a lower educational level ( p -values ≤ .004). CMV seropositivity was not associated with more complicated long-term disease outcomes of IBD ( p -values > .05). Seropositive patients presented with symptoms and were diagnosed at an older age compared to seronegative patients ( p -values < .01)., Conclusions: CMV seropositivity does not influence disease outcomes of IBD patients and seems to be associated with a delay in IBD onset. Guidelines regarding CMV screening in patients with IBD are currently based on a low level of evidence. These data support the recommendation that routine CMV serology measurement is not necessary in the clinical care of IBD.

Background: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis., Methods: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133., Findings: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group., Interpretation: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis., Funding: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Crohn's disease [CD] is characterised by chronic intestinal inflammation and dysbiosis in the gut. Riboflavin [vitamin B2] has anti-inflammatory, antioxidant and microbiome-modulatory properties. Here, we analysed the effect of riboflavin on oxidative stress, markers of inflammation, clinical symptoms, and faecal microbiome in patients with CD., Methods: In this prospective clinical intervention study, patients received 100 mg riboflavin [DSM, Nutritional Products Ltd] daily for 3 weeks. Clinical disease activity [Harvey-Bradshaw Index: HBI], serum biomarkers of inflammation and redox status [plasma free thiols], and faecal microbiome taxonomical composition and functionality [fluorescent in situ hybridisation: FISH; and metagenomic shotgun sequencing: MGS], were analysed before and after riboflavin intervention., Results: In total, 70 patients with CD with varying disease activity were included. Riboflavin supplementation significantly decreased serum levels of inflammatory markers. In patients with low faecal calprotectin [FC] levels, IL-2 decreased, and in patients with high FC levels, C-reactive protein [CRP] was reduced and free thiols significantly increased after supplementation. Moreover, HBI was significantly decreased by riboflavin supplementation. Riboflavin supplementation led to decreased Enterobacteriaceae in patients with low FC levels as determined by FISH; however, MGS analysis showed no effects on diversity, taxonomy, or metabolic pathways of the faecal microbiome., Conclusions: Three weeks of riboflavin supplementation resulted in a reduction in systemic oxidative stress, mixed anti-inflammatory effects, and a reduction in clinical symptoms [HBI]. FISH analysis showed decreased Enterobacteriaceae in patients with CD with low FC levels, though this was not observed in MGS analysis. Our data demonstrate that riboflavin supplementation has a number of anti-inflammatory and anti-oxidant effects in CD., (© European Crohn’s and Colitis Organisation (ECCO) 2019.)