Publications by authors named "Gerard Dijkstra"

184 Publications

Riboflavin supplementation promotes butyrate production in the absence of gross compositional changes in the gut microbiota.

Antioxid Redox Signal 2022 Aug 9. Epub 2022 Aug 9.

University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Hanzeplein 1, Groningen, Groningen, Netherlands, 9713 GZ;

We performed a randomized, placebo-controlled trial, RIBOGUT, to study the effect of two weeks supplementation with either 50 or 100 mg/d of riboflavin on: a) abundance, b) gut microbiota composition, c) short chain fatty acid (SCFA) profiles and d) the satiety and gut hormones. ClinicalTrials.gov Identifier: NCT02929459. Neither dose of riboflavin, analyzed separately, impacted the abundance of and only minor differences in SCFA concentrations were observed. However, combining the results of the 50 and 100 mg/d groups showed a significant increase in butyrate production. While the gut bacterial diversity was not affected by riboflavin supplementation, the complexity and stability of the bacterial network were enhanced. Oral glucose tolerance tests showed a trend of increased plasma insulin concentration and GLP-1 after 100 mg/d supplementation. Dietary supplements, such as vitamins, promote health by either directly targeting host physiology or indirectly via gut microbiota modulation. Here we show for the first time that riboflavin intervention changes the activity of the microbiota. The butyrate production increased after intervention and although the composition did not change significantly, the network of microbial interactions was enforced. This RIBOGUT study suggests that oral riboflavin supplementation promotes butyrate production in the absence of major shifts in gut microbiota composition.
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http://dx.doi.org/10.1089/ars.2022.0033DOI Listing
August 2022

Serological Biomarkers of Intestinal Collagen Turnover Identify Early Response to Infliximab Therapy in Patients With Crohn's Disease.

Front Med (Lausanne) 2022 12;9:933872. Epub 2022 Jul 12.

Biomarkers and Research, Nordic Bioscience A/S, Herlev, Denmark.

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 ( = 10) and associated with response at baseline ( < 0.05). Additionally, C6Ma3, PRO-C3, and PRO-C6 were elevated at week 14 in responders compared with non-responders ( = 8) and could differentiate between the two groups ( < 0.05). Two biomarker ratios (C4M/C4G and PRO-C4/C4G) were elevated at week 14 in non-responders ( = 5) without a surgical history compared with responders ( = 40) and could differentiate between the response groups ( < 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.
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http://dx.doi.org/10.3389/fmed.2022.933872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315105PMC
July 2022

Serological Biomarkers of Extracellular Matrix Turnover and Neutrophil Activity Are Associated with Long-Term Use of Vedolizumab in Patients with Crohn's Disease.

Int J Mol Sci 2022 Jul 23;23(15). Epub 2022 Jul 23.

Biomarkers and Research, Nordic Bioscience, 2730 Herlev, Denmark.

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 ( = 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 ( < 0.05). C1M, C3M, C4M, C6Ma3, and PRO-C4 were also significantly increased at baseline in non-responders compared with responders (all < 0.05). All biomarkers were associated with response to VEDO (all < 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.
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http://dx.doi.org/10.3390/ijms23158137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329899PMC
July 2022

Mucosal Eosinophil Abundance in Non-Inflamed Colonic Tissue Is Associated with Response to Vedolizumab Induction Therapy in Inflammatory Bowel Disease.

J Clin Med 2022 Jul 16;11(14). Epub 2022 Jul 16.

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Vedolizumab is used as a treatment for patients with inflammatory bowel disease (IBD), but induction therapy leads to clinical response and remission in approximately 55% and 30% of patients with IBD, respectively. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1 regarding response to vedolizumab induction therapy. Eighty-four (84) patients with IBD (37 Crohn's disease [CD], 47 ulcerative colitis [UC]) were included. For 24 patients with IBD, histopathology was assessed for eosinophil counts in non-inflamed colonic tissue prior to vedolizumab treatment. For 64 patients with IBD, serum eotaxin-1 levels were quantified prior to (baseline) and during vedolizumab treatment. Serum samples of 100 patients with IBD (34 CD, 66 UC) from the GEMINI 1 and 2 trials were used for external validation. Baseline mucosal eosinophil numbers in non-inflamed colonic tissue were significantly higher in responders to vedolizumab induction therapy when compared to primary non-responders (69 [34-138] vs. 24 [18-28] eosinophils/high-power field, respectively, < 0.01). Baseline serum eotaxin-1 levels in the discovery cohort were significantly elevated in responders, compared to primary non-responders (0.33 [0.23-0.44] vs. 0.20 [0.16-0.29] ng/mL, < 0.01). Prediction models based on mucosal eosinophil counts and serum eotaxin-1 showed an area under the curve (AUC) of 0.90 and 0.79, respectively. However, the predictive capacity of baseline serum eotaxin-1 levels could not be validated in the GEMINI cohort. Mucosal eosinophil abundance in non-inflamed colonic tissue was associated with response to vedolizumab induction therapy in patients with IBD. Future studies are warranted to further validate the potential value of mucosal eosinophils and serum eotaxin-1 as biomarkers for response to vedolizumab therapy.
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http://dx.doi.org/10.3390/jcm11144141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318498PMC
July 2022

Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel diseases.

Aliment Pharmacol Ther 2022 Jul 23. Epub 2022 Jul 23.

Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Subcutaneous (SC) vedolizumab is effective in inflammatory bowel diseases (IBD) when administered after induction with two infusions.

Aim: To assess the effectiveness, safety and pharmacokinetics of a switch from intravenous (IV) to SC maintenance vedolizumab in patients with IBD.

Methods: In this prospective cohort study, patients with IBD who had ≥4 months IV vedolizumab were switched to SC vedolizumab. We studied the time to discontinuation of SC vedolizumab, adverse events (AEs), changes in clinical and biochemical outcomes and vedolizumab concentrations at baseline, and weeks 12 and 24.

Results: We included 135 patients, 82 with Crohn's disease (CD) and 53 with ulcerative colitis (UC). Eleven (13.4%) CD and five (9.4%) UC patients discontinued SC vedolizumab after a median of 18 (IQR 8-22) and 6 weeks (IQR 5-10), respectively. Four patients (all CD) switched to a different drug due to loss of response, nine switched back to IV vedolizumab due to adverse events, and three due to needle fear. Common AEs were injection site reactions (n = 15) and headache (n = 6). Median clinical and biochemical disease activity remained stable after the switch. Median vedolizumab serum concentrations increased from 19 μg/ml at the time of the switch to 31 μg/ml 12 weeks after the switch (p < 0.005).

Conclusions: Switching from IV to SC vedolizumab maintenance treatment is effective in patients with CD or UC. However, 9% of patients were switched back to IV vedolizumab due to adverse events or fear of needles.
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http://dx.doi.org/10.1111/apt.17153DOI Listing
July 2022

Use of Tumor Necrosis Factor-α Antagonists Is Associated With Attenuated IgG Antibody Response Against SARS-CoV-2 in Vaccinated Patients With Inflammatory Bowel Disease.

Front Immunol 2022 5;13:920333. Epub 2022 Jul 5.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

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 . non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655-2935] . 5002 [4089-6116] AU/ml, <0.001). In multivariable models, use of TNF-α-antagonists (<0.001), vector vaccines (<0.001), age (>50 years) (<0.01) and CD (<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 (<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.
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http://dx.doi.org/10.3389/fimmu.2022.920333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294156PMC
July 2022

HIF1α-Dependent Induction of by a Combination of Intestinal Inflammation and Systemic Iron Deficiency in Inflammatory Bowel Disease.

Front Physiol 2022 8;13:889091. Epub 2022 Jun 8.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Iron deficiency (ID) is a frequent extra-intestinal manifestation in patients with Inflammatory Bowel Disease (IBD), who often do not respond to iron supplementation. Iron is a cofactor for hydroxylases that suppress the hypoxia-inducible factor-1α (HIF1α), a transcription factor regulating iron homeostasis. We hypothesized that iron deficiency affects mucosal HIF1α activity in IBD. IBD patients ( = 101) were subdivided based on iron status (ferritin levels or transferrin saturation) and systemic inflammation (C-reactive protein levels). 154 corresponding ileal and colonic biopsies were analyzed for differential expression of 20 HIF1α pathway-associated genes and related to iron and inflammation status. expression of selected HIF1α pathway genes were analyzed in wild-type and null Caco-2 cells. Gene expression of the mucosal HIF1α pathway was most affected by intestinal location and inflammatory status. Especially, ileal mucosal expression, encoding the transferrin receptor TFR1, was increased in inflamed tissue ( < 0.001), and further enhanced in ID. Accordingly, expression in inflamed tissue associated negatively with serum iron levels, which was not observed in the non-inflamed mucosa. The HIF1α pathway agonist DMOG increased expression in Caco-2 cells, which was blunted in -null cells. We demonstrate that inflammation and anatomical location primarily determine HIF1α pathway activation and downstream expression in the intestinal mucosa. IBD patients with ID may benefit from treatment with HIF1α-agonists by 1) increasing -mediated iron absorption in non-inflamed tissue and 2) decreasing mucosal inflammation, thereby improving their responsiveness to oral iron supplementation.
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http://dx.doi.org/10.3389/fphys.2022.889091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214203PMC
June 2022

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease.

Nutrients 2022 Jun 17;14(12). Epub 2022 Jun 17.

Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

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.
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http://dx.doi.org/10.3390/nu14122522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228369PMC
June 2022

Patients With Inflammatory Bowel Disease Show IgG Immune Responses Towards Specific Intestinal Bacterial Genera.

Front Immunol 2022 25;13:842911. Epub 2022 May 25.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Introduction: Inflammatory bowel disease (IBD) is characterized by a disturbed gut microbiota composition. Patients with IBD have both elevated mucosal and serum levels of IgG-antibodies directed against bacterial antigens, including flagellins. In this study, we aimed to determine to which intestinal bacteria the humoral immune response is directed to in patients with IBD.

Methods: Fecal and serum samples were collected from patients with IBD (=55) and age- and sex-matched healthy controls (=55). Fecal samples were incubated with autologous serum and IgG-coated fractions were isolated by magnetic-activated cell sorting (MACS) and its efficiency was assessed by flow cytometry. The bacterial composition of both untreated and IgG-coated fecal samples was determined by 16S rRNA-gene Illumina sequencing.

Results: IgG-coated fecal samples were characterized by significantly lower microbial diversity compared to the fecal microbiome. Both in patients with IBD and controls, serum IgG responses were primarily directed to , , , , and , as well as against specific bacteria, including and (all <0.001), and to -like bacteria (<0.05). In contrast, serological IgG responses against typical commensal, anaerobic and colonic microbial species were rather low, e.g. to the members and , to , as well as to . Patients with IBD showed more IgG-coating of , , and bacteria compared to healthy controls (all <0.05). No differences in IgG-coated bacterial fractions were observed between Crohn's disease and ulcerative colitis, between active or non-active disease, nor between different disease locations.

Conclusion: The IgG immune response is specifically targeted at distinct intestinal bacterial genera that are typically associated with the small intestinal microbiota, whereas responses against more colonic-type commensals are lower, which was particularly the case for patients with IBD. These findings may be indicative of a strong immunological exposure to potentially pathogenic intestinal bacteria in concordance with relative immune tolerance against commensal bacteria.
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http://dx.doi.org/10.3389/fimmu.2022.842911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174456PMC
May 2022

Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohn's disease.

Aliment Pharmacol Ther 2022 Aug 6;56(4):675-693. Epub 2022 Jun 6.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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.
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http://dx.doi.org/10.1111/apt.17063DOI Listing
August 2022

Superior Effectiveness of Tofacitinib Compared to Vedolizumab in Anti-TNF-experienced Ulcerative Colitis Patients: A Nationwide Dutch Registry Study.

Clin Gastroenterol Hepatol 2022 May 26. Epub 2022 May 26.

Department of Gastroenterology, Radboud university medical centre, Nijmegen, The Netherlands. Electronic address:

Background & Aims: Clinicians face difficulty in when and in what order to position biologics and Janus kinase inhibitors in patients with anti-tumor necrosis factor-alpha (TNF) refractory ulcerative colitis (UC). We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF-exposed patients with UC in our prospective nationwide Initiative on Crohn and Colitis Registry.

Methods: Patients with UC who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment were identified in the Initiative on Crohn and Colitis Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (Simple Clinical Colitis Activity Index ≤2), biochemical remission (C-reactive protein ≤5 mg/L or fecal calprotectin ≤250 μg/g), and safety outcomes were compared after 52 weeks of treatment. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias.

Results: Overall, 83 vedolizumab- and 65 tofacitinib-treated patients were included. Propensity score-weighted analysis showed that tofacitinib-treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at weeks 12, 24, and 52 compared with vedolizumab-treated patients (odds ratio [OR], 6.33; 95% confidence interval [CI], 3.81-10.50; P < .01; OR, 3.02; 95% CI, 1.89-4.84; P < .01; and OR, 1.86; 95% CI, 1.15-2.99; P = .01; and OR, 3.27; 95% CI, 1.96-5.45; P < .01; OR, 1.87; 95% CI, 1.14-3.07; P = .01; and OR, 1.81; 95% CI, 1.06-3.09; P = .03, respectively. There was no difference in infection rate or severe adverse events.

Conclusions: Tofacitinib was associated with superior effectiveness outcomes compared with vedolizumab in anti-TNF-experienced patients with UC along with comparable safety outcomes.
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http://dx.doi.org/10.1016/j.cgh.2022.04.038DOI Listing
May 2022

Indications, Postoperative Management, and Long-term Prognosis of Crohn's Disease After Ileocecal Resection: A Multicenter Study Comparing the East and West.

Inflamm Bowel Dis 2022 Jun;28(Supplement_2):S16-S24

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: The Crohn's disease (CD) phenotype differs between Asian and Western countries and may affect disease management, including decisions on surgery. This study aimed to compare the indications, postoperative management, and long-term prognosis after ileocecal resection (ICR) in Hong Kong (HK) and the Netherlands (NL).

Methods: CD patients with primary ICR between 2000 and 2019 were included. The endpoints were endoscopic (Rutgeerts score ≥i2b and/or radiologic recurrence), clinical (start or switch of inflammatory bowel disease medication), and surgical recurrences. Cumulative incidences of recurrence were estimated with a Bayesian multivariable proportional hazards model.

Results: Eighty HK and 822 NL patients were included. The most common indication for ICR was penetrating disease (HK: 32.5%, NL: 22.5%) in HK vs stricturing disease (HK: 32.5%, NL: 48.8%) in the NL (P < .001). Postoperative prophylaxis was prescribed to 65 (81.3%) HK patients (28 [35.0%] aminosalicylates [5-aminosalicylic acid]; 30 [37.5%] immunomodulators; 0 biologicals) vs 388 (47.1%) NL patients (67 [8.2%] 5-aminosalicylic acid; 187 [22.8%] immunomodulators; 69 [8.4%] biologicals; 50 [6.1%] combination therapy) (P < .001). Endoscopic or radiologic evaluation within 18 months was performed in 36.3% HK vs 64.1% NL (P < .001) patients. No differences between both populations were observed for endoscopic (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.24-1.21), clinical (HR, 0.91; 95% CI, 0.62-1.32), or surgical (HR, 0.61; 95% CI, 0.31-1.13) recurrence risks.

Conclusion: The main indication for ICR in CD patients is penetrating disease in HK patients and stricturing disease in NL patients. Although considerable pre- and postoperative management differences were observed between the two geographical areas, the long-term prognosis after ICR is similar.
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http://dx.doi.org/10.1093/ibd/izab316DOI Listing
June 2022

Western and Carnivorous Dietary Patterns are Associated with Greater Likelihood of IBD Development in a Large Prospective Population-based Cohort.

J Crohns Colitis 2022 Jul;16(6):931-939

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, The Netherlands.

Objective: Nutrition plays a role in the development of Crohn's disease [CD] and ulcerative colitis [UC]. However, prospective data on nutrition and disease onset are limited. Here, we analysed dietary patterns and scores in relation to inflammatory bowel disease [IBD] development in a prospective population-based cohort.

Methods: We analysed 125 445 participants of whom 224 individuals developed de novo UC and 97 CD over a maximum 14-year follow-up period. Participants answered health-related [also prospectively] and dietary questionnaires [FFQ] at baseline. Principal component analysis [PCA] was conducted deriving a-posteriori dietary patterns. Hypotheses-based a-priori dietary scores were also calculated, including the protein score, Healthy Eating Index, LifeLines Diet Score [LLDS], and alternative Mediterranean Diet Score. Logistic regression models were performed between dietary patterns, scores, and IBD development.

Results: PCA identified five dietary patterns. A pattern characterised by high intake of snacks, prepared meals, non-alcoholic beverages, and sauces along with low vegetables and fruit consumption was associated with higher likelihood of CD development (odds ratio [OR]: 1.16, 95% confidence interval [CI]: 1.03-1.30, p = 0.013). A pattern comprising red meat, poultry, and processed meat, was associated with increased likelihood of UC development [OR: 1.11, 95% CI: 1.01-1.20, p = 0.023]. A high diet quality score [LLDS] was associated with decreased risk of CD [OR: 0.95, 95% CI: 0.92-0.99, p = 0.009].

Conclusions: A Western dietary pattern was associated with a greater likelihood of CD development and a carnivorous pattern with UC development, whereas a relatively high diet quality [LLDS] was protective for CD development. Our study strengthens the importance of evaluating dietary patterns to aid prevention of IBD in the general population.
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http://dx.doi.org/10.1093/ecco-jcc/jjab219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282880PMC
July 2022

Inulin-grown cross-feeds fructose to the human intestinal epithelium.

Gut Microbes 2021 Jan-Dec;13(1):1993582

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Many chronic diseases are associated with decreased abundance of the gut commensal . This strict anaerobe can grow on dietary fibers, e.g., prebiotics, and produce high levels of butyrate, often associated to epithelial metabolism and health. However, little is known about other metabolites that may affect the colonic epithelium. Here, we analyzed prebiotic cross-feeding between and intestinal epithelial (Caco-2) cells in a "Human-oxygen Bacteria-anaerobic" coculture system. Inulin-grown enhanced Caco-2 viability and suppressed inflammation- and oxidative stress-marker expression. Inulin-grown produced excess butyrate and fructose, but only fructose efficiently promoted Caco-2 growth. Finally, fecal microbial taxonomy analysis (16S sequencing) from healthy volunteers (n = 255) showed the strongest positive correlation for abundance and stool fructose levels. We show that fructose, produced and accumulated in a fiber-rich colonic environment, supports colonic epithelium growth, while butyrate does not.
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http://dx.doi.org/10.1080/19490976.2021.1993582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604389PMC
March 2022

Efficacy of anti-TNF dosing interval lengthening in adolescents and young adults with inflammatory bowel disease in sustained remission (FREE-study): protocol for a partially randomised patient preference trial.

BMJ Open 2021 11 3;11(11):e054154. Epub 2021 Nov 3.

Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Centre Groningen, Beatrix Childrens Hospital, Groningen, The Netherlands

Introduction: Anti-tumour necrosis factor (TNF) therapy has greatly improved treatment outcomes in patients with inflammatory bowel disease (IBD), but long-term use is associated with cutaneous reactions, susceptibility to infections and frequent injections or hospital visits. Several non-controlled studies have demonstrated that dose reduction is feasible for a subset of patients, provided that early detection of a disease flare is possible. Here, we aim to compare the effectiveness of interval lengthening with standard dosing in maintaining remission in young patients with IBD.

Methods And Analysis: In this international, prospective, non-inferiority, partially randomised patient preference trial, we aim to recruit 148 patients aged 12-25 years with luminal Crohn's disease or ulcerative colitis in sustained remission (ie, three consecutive in-range faecal calprotectin (FC) results or recently confirmed endoscopic remission). In the interventional arm, the dosing interval will be lengthened from 8 to 12 weeks for infliximab users and from 2 to 3 weeks for adalimumab users. In the control group, standard dosing will be continued. Rapid tests will be performed for FC every 4 weeks and for anti-TNF trough levels every 12 weeks. The primary outcome is the cumulative incidence of out-of-range FC results at 48-week follow-up. Secondary endpoints include time to get out-of-range FC results, cumulative incidence of adverse effects, proportion of patients progressing to loss of response and identification of predictors of successful interval lengthening.

Ethics And Dissemination: The protocol has been approved by the Medical Ethics Review Committee of the University Medical Centre Groningen and is pending at the other participating centres. Results will be disseminated in peer-reviewed journals and presented at scientific meetings.

Trial Registration Number: EudraCT number: 2020-001811-26; ClinicalTrials.gov Identifier: NCT04646187. Protocol version 4, date 17 September 2021.
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http://dx.doi.org/10.1136/bmjopen-2021-054154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572401PMC
November 2021

Development and Characterisation of Antibody-Based Optical Imaging Probes for Inflammatory Bowel Disease.

Pharmaceuticals (Basel) 2021 Sep 13;14(9). Epub 2021 Sep 13.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Monoclonal antibodies are an important addition to the medicinal treatment paradigm for IBD patients. While effective, these agents show a high degree of primary and secondary non-response, and methods to predict response are highly desired. Information on drug distribution at the target level is often lacking. Fluorescent endoscopic imaging using labelled antibody drugs may provide insight regarding drug distribution, target engagement and drug response, but these assessments require stable and functional fluorescently-conjugated probes. Infliximab, vedolizumab, adalimumab and ustekinumab were conjugated to IRDye 800CW, IRDye 680LT and ZW800-1. The resulting 12 tracer candidates were analysed and characterised on SE-HPLC, SDS-PAGE, iso-electric focussing (IEF) and ELISA in order to evaluate their feasibility as candidate clinical tracers for cGMP development. Major differences in the conjugation results could be seen for each conjugated drug. For Infliximab, 2 conjugates (800CW and 680LT) showed formation of aggregates, while conjugates of all drugs with ZW800-1 showed reduced fluorescent brightness, reduced purification yield and formation of fragments. All 6 of these candidates were considered unfeasible. From the remaining 6, ustekinumab-680LT showed reduced binding to IL23, and was therefore considered unfeasible. Out of 12 potential tracer candidates, 5 were considered feasible for further development: vedolizumab-800CW, vedolizumab-680LT, adalimumab-800CW, adalimumab-680LT and ustekinumab-800CW. Infliximab-680LT and ustekinumab-680LT failed to meet the standards for this panel, but may be rendered feasible if tracer production methods were further optimized.
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http://dx.doi.org/10.3390/ph14090922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468533PMC
September 2021

Polygenetic risk scores do not add predictive power to clinical models for response to anti-TNFα therapy in inflammatory bowel disease.

PLoS One 2021 17;16(9):e0256860. Epub 2021 Sep 17.

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256860PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448323PMC
November 2021

The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease.

J Crohns Colitis 2022 Mar;16(3):414-429

Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1093/ecco-jcc/jjab157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919819PMC
March 2022

Are all dietary fibers equal for patients with inflammatory bowel disease? A systematic review of randomized controlled trials.

Nutr Rev 2022 04;80(5):1179-1193

Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

Context: Conflicting practice-based dietary recommendations are sometimes given to patients with inflammatory bowel disease (IBD); whereas intake of fiber should increase during remission, it should be avoided during relapse. Moreover, European countries set daily requirements of total fiber and do not specify any types.

Objective: This systematic review appraised data from randomized clinical trials (RCTs) of the types of fibers beneficial for patients in the treatment of IBD to guide dietary fiber advice.

Data Sources: The PubMED database was searched following PRISMA guidelines.

Data Extraction: RCTs evaluating the effects of any type of fiber on clinical and physiological outcomes in patients with IBD were assessed. Quality assessment of the selected full-text articles was conducted using the Cochrane Risk of Bias Tool.

Data Analysis: Eight studies were included reporting on 5 types of fibers. In 2 RCTs, germinated barley foodstuff (GBF) was shown to lower pro-inflammatory cytokines and clinical disease activity scores. Fructo-oligosaccharides (FOS) were demonstrated to lower IBD Questionnaire scores (lower well-being), in contrast to inulin, which decreased disease activity scores. An RCT could not find lower remission rates in the psyllium treatment group, while another RCT reported that administration led to less symptoms in patients. In RCTs, no concrete evidence was found that wheat bran improves disease course.

Conclusions: Although the evidence is sparse, GBF and inulin seem propitious and merit further exploration. Evidence on wheat bran and psyllium is still too limited. Adequately powered long-term human RCTs with objective outcomes are needed to improve dietary advice on types of fiber in IBD.
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http://dx.doi.org/10.1093/nutrit/nuab062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990763PMC
April 2022

Vitamin C Supplementation in Healthy Individuals Leads to Shifts of Bacterial Populations in the Gut-A Pilot Study.

Antioxidants (Basel) 2021 Aug 12;10(8). Epub 2021 Aug 12.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

Gut microbes are crucial to human health, but microbial composition is often disturbed in a number of human diseases. Accumulating evidence points to nutritional modulation of the gut microbiota as a potentially beneficial therapeutic strategy. Vitamin C (ascorbic acid) may be of particular interest as it has known antioxidant and anti-inflammatory properties. In this study, we investigated whether supplementation with high-dose vitamin C may favourably affect the composition of the gut microbiota. In this pilot study, healthy human participants received 1000 mg vitamin C supplementation daily for two weeks. Gut microbiota composition was analysed before and after intervention by performing faecal 16S rRNA gene sequencing. In total, 14 healthy participants were included. Daily supplementation of high-dose vitamin C led to an increase in the relative abundances of ( < 0.05), whereas decreases were observed for ( < 0.01), Enterococci ( < 0.01) and ( < 0.05). In addition, trends for bacterial shifts were observed for (increase) and (decrease). High-dose vitamin C supplementation for two weeks shows microbiota-modulating effects in healthy individuals, with several beneficial shifts of bacterial populations. This may be relevant as these bacteria have anti-inflammatory properties and strongly associate with gut health.
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http://dx.doi.org/10.3390/antiox10081278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389205PMC
August 2021

Bioelectrical Impedance Analysis and Mid-Upper Arm Muscle Circumference Can Be Used to Detect Low Muscle Mass in Clinical Practice.

Nutrients 2021 Jul 9;13(7). Epub 2021 Jul 9.

Department of Gastroenterology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Identification of low muscle mass becomes increasingly relevant due to its prognostic value in cancer patients. In clinical practice, mid-upper arm muscle circumference (MAMC) and bioelectrical impedance analysis (BIA) are often used to assess muscle mass. For muscle-mass assessment, computed tomography (CT) is considered as reference standard. We investigated concordance between CT, BIA, and MAMC, diagnostic accuracy of MAMC, and BIA to detect low muscle mass and their relation with the clinical outcome malnutrition provided with the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF). This cross-sectional study included adult patients with advanced esophageal and gastrointestinal cancer. BIA, MAMC, and PG-SGA-SF were performed. Routine CT-scans were used to quantify psoas muscle index (PMI) and skeletal muscle area. Good concordance was found between CT and both BIA (ICC 0.73), and BIA (ICC 0.69) but not with MAMC (ICC 0.37). BIA (94%), BIA (86%), and MAMC (86%) showed high specificity but low sensitivity. PG-SGA-SF modestly correlated with all muscle-mass measures (ranging from -0.17 to -0.43). Of all patients with low muscle mass, 62% were also classified with a PG-SGA-SF score of ≥4 points. Although CT remains the first choice, since both BIA and MAMC are easy to perform by dieticians, they have the potential to be used to detect low muscle mass in clinical practice.
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http://dx.doi.org/10.3390/nu13072350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308498PMC
July 2021

Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis.

Virchows Arch 2021 Dec 2;479(6):1119-1129. Epub 2021 Aug 2.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn's disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn's disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn's disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn's disease.
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http://dx.doi.org/10.1007/s00428-021-03170-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724151PMC
December 2021

New Therapeutic Approach for Intestinal Fibrosis Through Inhibition of pH-Sensing Receptor GPR4.

Inflamm Bowel Dis 2022 01;28(1):109-125

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.

Background: Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of pH-sensing receptors compared with non-IBD controls. Acidification leads to angiogenesis and extracellular matrix remodeling. We aimed to determine the expression of pH-sensing G protein-coupled receptor 4 (GPR4) in fibrotic lesions in Crohn's disease (CD) patients. We further evaluated the effect of deficiency in Gpr4 or its pharmacologic inhibition.

Methods: Paired samples from fibrotic and nonfibrotic terminal ileum were obtained from CD patients undergoing ileocaecal resection. The effects of Gpr4 deficiency were assessed in the spontaneous Il-10-/- and the chronic dextran sodium sulfate (DSS) murine colitis model. The effects of Gpr4 deficiency and a GPR4 antagonist (39c) were assessed in the heterotopic intestinal transplantation model.

Results: In human terminal ileum, increased expression of fibrosis markers was accompanied by an increase in GPR4 expression. A positive correlation between the expression of procollagens and GPR4 was observed. In murine disease models, Gpr4 deficiency was associated with a decrease in angiogenesis and fibrogenesis evidenced by decreased vessel length and expression of Edn, Vegfα, and procollagens. The heterotopic animal model for intestinal fibrosis, transplanted with terminal ileum from Gpr4-/- mice, revealed a decrease in mRNA expression of fibrosis markers and a decrease in collagen content and layer thickness compared with grafts from wild type mice. The GPR4 antagonist decreased collagen deposition. The GPR4 expression was also observed in human and murine intestinal fibroblasts. The GPR4 inhibition reduced markers of fibroblast activation stimulated by low pH, notably Acta2 and cTgf.

Conclusions: Expression of GPR4 positively correlates with the expression of profibrotic genes and collagen. Deficiency of Gpr4 is associated with a decrease in angiogenesis and fibrogenesis. The GPR4 antagonist decreases collagen deposition. Targeting GPR4 with specific inhibitors may constitute a new treatment option for IBD-associated fibrosis.
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http://dx.doi.org/10.1093/ibd/izab140DOI Listing
January 2022

Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options.

Therap Adv Gastroenterol 2021 29;14:17562848211012595. Epub 2021 Apr 29.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

In the wake of the coronavirus disease 2019 (COVID-19) pandemic, it is unclear how asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients who present with acute severe ulcerative colitis (UC) can be treated effectively and safely. Standard treatment regimens consist of steroids, immunomodulatory drugs, and biological therapies, but therapeutic decision-making becomes challenging as there are uncertainties about how to deal with these drugs in patients with COVID-19 and active UC. Importantly, guidelines for this particular group of patients with UC are still lacking. To inform therapeutic decision-making, we describe three consecutive cases of patients with active UC and COVID-19 and discuss their treatments based on theoretical knowledge, currently available evidence and clinical observations. Three patients were identified through our national inflammatory bowel disease network [Initiative on Crohn's and Colitis (ICC)] for whom diagnosis of SARS-CoV-2-infection was established by reverse transcription-polymerase chain reaction (RT-PCR) testing in nasopharynx, stools, and/or biopsies. Acute severe UC was diagnosed by clinical parameters, endoscopy, and histopathology. Clinical guidelines for SARS-CoV-2-negative patients advocate the use of steroids, calcineurin inhibitors, or tumor necrosis factor alpha (TNF-α)-antagonists as induction therapy, and experiences from the current three cases show that steroids and TNF-α-antagonists could also be used in patients with COVID-19. This could potentially be followed by TNF-α-antagonists, vedolizumab, or ustekinumab as maintenance therapy in these patients. Future research is warranted to investigate if, and which, immunomodulatory drugs should be used for COVID-19 patients that present with active UC. To answer this question, it is of utmost importance that future cases of patients with UC and COVID-19 are documented carefully in international registries, such as the SECURE-IBD registry.
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http://dx.doi.org/10.1177/17562848211012595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111526PMC
April 2021

Ustekinuma b for Crohn's Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, a Nationwide Prospective Observational Cohort Study.

J Crohns Colitis 2021 Nov;15(11):1920-1930

Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.

Aims: Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel diseases. We assessed the 2-year effectiveness and safety of ustekinumab in a real world, prospective cohort of patients with Crohn's disease [CD].

Methods: Patients who started ustekinumab were prospectively enrolled in the nationwide Initiative on Crohn and Colitis [ICC] Registry. At weeks 0, 12, 24, 52 and 104, clinical remission Harvey Bradshaw Index≤ 4 points], biochemical remission (faecal calprotectin ≤ 200 μg/g and/or C-reactive protein ≤5 mg/L], perianal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission at week 104.

Results: In total, 252 CD patients with at least 2 years of follow-up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission was 32.3% [81/251], 41.4% [104/251], 39% [97/249] and 34.0% [84/247] at weeks 12, 24, 52 and 104, respectively. In patients with combined clinical and biochemical disease activity at baseline [n = 122], the corticosteroid-free clinical remission rates were 23.8% [29/122], 35.2% [43/122], 40.0% [48/120] and 32.8% [39/119] at weeks 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks in all patients was 64.3% and 54.8%, respectively. The main reason for discontinuing treatment after 52 weeks was loss of response [66.7%]. No new safety issues were observed.

Conclusion: After 104 weeks of ustekinumab treatment, one-third of CD patients were in corticosteroid-free clinical remission.
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http://dx.doi.org/10.1093/ecco-jcc/jjab081DOI Listing
November 2021

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.

Brain 2021 06;144(5):1451-1466

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan.

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.
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http://dx.doi.org/10.1093/brain/awab056DOI Listing
June 2021

Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome.

Gut 2021 07 2;70(7):1287-1298. Epub 2021 Apr 2.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands

Objective: The microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. We aim to unravel interactions between diet, gut microbiota and their functional ability to induce intestinal inflammation.

Design: We investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn's disease, ulcerative colitis, irritable bowel syndrome and the general population. Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation.

Results: We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn's disease and UC (false discovery rate<0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, species of the genus and endotoxin synthesis pathways. The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism.

Conclusion: We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.
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http://dx.doi.org/10.1136/gutjnl-2020-322670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223641PMC
July 2021

Food and Food Groups in Inflammatory Bowel Disease (IBD): The Design of the Groningen Anti-Inflammatory Diet (GrAID).

Nutrients 2021 Mar 25;13(4). Epub 2021 Mar 25.

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

Diet plays a pivotal role in the onset and course of inflammatory bowel disease (IBD). Patients are keen to know what to eat to reduce symptoms and flares, but dietary guidelines are lacking. To advice patients, an overview of the current evidence on food (group) level is needed. This narrative review studies the effects of food (groups) on the onset and course of IBD and if not available the effects in healthy subjects or animal and in vitro IBD models. Based on this evidence the Groningen anti-inflammatory diet (GrAID) was designed and compared on food (group) level to other existing IBD diets. Although on several foods conflicting results were found, this review provides patients a good overview. Based on this evidence, the GrAID consists of lean meat, eggs, fish, plain dairy (such as milk, yoghurt, kefir and hard cheeses), fruit, vegetables, legumes, wheat, coffee, tea and honey. Red meat, other dairy products and sugar should be limited. Canned and processed foods, alcohol and sweetened beverages should be avoided. This comprehensive review focuses on anti-inflammatory properties of foods providing IBD patients with the best evidence on which foods they should eat or avoid to reduce flares. This was used to design the GrAID.
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http://dx.doi.org/10.3390/nu13041067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064481PMC
March 2021

Trajectories of Fatigue in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 11;27(12):1919-1930

Department of Health Sciences, University of Groningen and University Medical Center, Groningen, the Netherlands.

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.
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http://dx.doi.org/10.1093/ibd/izab007DOI Listing
November 2021
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