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Background and aimsLeucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis.MethodsIn this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03–10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α4β7+ lymphocytes was measured to demonstrate drug activity.ResultsNo obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α4β7+ lymphocytes in patients receiving PF-00547,659.ConclusionsThe favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment.Trial Register No:NCT00928681.

OBJECTIVES: Catabolism and growth impairment are well known complications of chronic inflammatory bowel disease (CIBD). This may be caused by disease activity itself and/or the medical treatment, which may lead to changes in the growth hormone and insulinlike growth factor I (IGF-I) axis. Interest has focused on corticosteroids, as they are known to influence the growth hormone/IGF-I axis. METHODS: The aim of the present study was to examine changes in total and free IGF-I, IGF binding proteins (IGFBPs), and IGFBP-3 protease activity in 10 patients with severe acute activity in colon CIBD before and during high dose prednisolone treatment (1 wk) and 3 months tapering. Eight healthy subjects served as controls. RESULTS: Total and free IGF-I were significantly reduced by 35% and 53%, respectively, before prednisolone treatment ( p < 0.05), and free IGF-I remained reduced even by the end of the study period relative to controls ( p < 0.05). IGFBP-3 was reduced by 16% before ( p < 0.05), with normalization during prednisolone treatment and tapering relative to controls. There was no evidence of increase in IGFBP-3 protease activity. IGFBP-1 was increased before and tended also to be increased during prednisolone treatment and tapering. CONCLUSIONS: Marked changes in serum total and free IGF-I and IGFBPs were demonstrated in patients with severe exacerbation of CIBD without complete normalization during high dose prednisolone treatment and tapering. These changes may partly be involved in the catabolism of active CIBD patients.

More than 400 million humans are estimated to be infected with the intestinal helminth parasite, Trichuris trichiura. The infection is chronic in nature and high-intensity infection can lead to colitis, anaemia, Trichuris Dysentery Syndrome and reduced cognitive performance. Single doses of 400 mg albendazole or 500 mg mebendazole (MBZ) are used in mass drug administration programmes, but this has been shown to be insufficient. In this study, worm expulsion dynamics are described after MBZ treatment, given as a multi-dose and single-dose treatment in two separate T. trichiura self-infection studies. Worm expulsion dynamics post-treatment showed a similar pattern regardless of the dose regime, with the first worms observed on day 2 and the last worms expelled on days 9 and 13 post-treatment. Establishment of a chronic infection was observed following the inefficient single-dose treatment. The prepatent period was 13–16 weeks in both studies and worms were found to have a lifespan of at least 1 year and 10 months. These self-infection studies provide key information on the chronicity of T. trichiura infections, expulsion dynamics after anthelmintic treatment and the prepatent period, as well as the fecundity of female worms, which was around 18,000 eggs/female per day.

Objective The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East–West gradient in the incidence of IBD in Europe exists. Design A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. Results 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100 000 in 2010 for CD were 6.5 (range 0–10.7) in Western European centres and 3.1 (range 0.4–11.5) in Eastern European centres, for UC 10.8 (range 2.9–31.5) and 4.1 (range 2.4–10.3), respectively, and for IBDU 1.9 (range 0–39.4) and 0 (range 0–1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. Conclusions An East–West gradient in IBD incidence exists in Europe. Among this inception cohort—including indolent and aggressive cases—international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Recently, the intestinal microbiota has been emphasised as an important contributor to the development of metabolic syndrome. Dietary fibre may exert beneficial effects through modulation of the intestinal microbiota and metabolic end products. We investigated the effects of a diet enriched with two different dietary fibres, arabinoxylan and resistant starch type 2, on the gut microbiome and faecal short-chain fatty acids. Nineteen adults with metabolic syndrome completed this randomised crossover study with two 4-week interventions of a diet enriched with arabinoxylan and resistant starch and a low-fibre Western-style diet. Faecal samples were collected before and at the end of the interventions for fermentative end-product analysis and 16S ribosomal RNA bacterial gene amplification for identification of bacterial taxa. Faecal carbohydrate residues were used to verify compliance. The diet enriched with arabinoxylan and resistant starch resulted in significant reductions in the total species diversity of the faecal-associated intestinal microbiota but also increased the heterogeneity of bacterial communities both between and within subjects. The proportion of Bifidobacterium was increased by arabinoxylan and resistant starch consumption (P<0.001), whereas the proportions of certain bacterial genera associated with dysbiotic intestinal communities were reduced. Furthermore, the total short-chain fatty acids (P<0.01), acetate (P<0.01) and butyrate concentrations (P<0.01) were higher by the end of the diet enriched with arabinoxylan and resistant starch compared with those resulting from the Western-style diet. The concentrations of isobutyrate (P = 0.05) and isovalerate (P = 0.03) decreased in response to the arabinoxylan and resistant starch enriched diet, indicating reduced protein fermentation. In conclusion, arabinoxylan and resistant starch intake changes the microbiome and short-chain fatty acid compositions, with potential beneficial effects on colonic health and metabolic syndrome. ClinicalTrials.gov NCT01618526.

Casein glycomacropeptide (CGMP) is a bioactive milk-derived peptide with potential anti-inflammatory effects. Animal studies suggest that CGMP may work by altering gut microbiota composition and enhancing butyrate production. Its effects on intestinal homoeostasis, microbiota and metabolites in humans are unknown. The aim of the present study was to assess both the intestinal and systemic immunomodulatory effects of orally ingested CGMP. We hypothesised that daily oral CGMP intake would reduce high-sensitive C-reactive protein (hsCRP) in healthy adults. In a single-centre limited but randomised, double-blinded, reference-controlled study, we compared the effects of a 4-week intervention of either 25 g of oral powder-based chocolate-flavoured CGMP or a reference drink. We included twenty-four healthy adults who all completed the study. CGMP had no systemic or intestinal immunomodulatory effects compared with a reference drink, with regard to either hsCRP or faecal calprotectin level, faecal microbiota composition or faecal SCFA content. CGMP ingestion did not affect satiety or body weight, and it caused no severe adverse events. The palatability of CGMP was acceptable, and adherence was high. CGMP did not induce or change gastrointestinal symptoms. In conclusion, we found no immunomodulatory effects of CGMP in healthy adults. In a minor group of healthy adults, oral ingestion of 25 g of CGMP during 4 weeks was safe, well tolerated, had acceptable palatability and was without any effects on body weight.

Background High doses of oral thiamine improve clinical fatigue scores in patients with quiescent inflammatory bowel disease (IBD) and chronic fatigue. In this study we analysed plasma samples obtained in a randomised clinical trial and aimed compare levels of vitamins B1, B2, B3 and B6, and their related vitamers and metabolites in patients with IBD, with or without chronic fatigue and with or without effect of high dose oral thiamine for chronic fatigue. Methods Blood samples from patients with fatigue were drawn prior and after thiamine exposure and only once for patients without fatigue. A wide panel of analysis were done at Bevital AS Lab. Results Concentration of flavin mononucleotide (FMN) was lower in patients with chronic fatigue compared to patients without fatigue (p = 0.02). Patients with chronic fatigue who reported a positive effect on fatigue after 4 weeks of high dose thiamine treatment had a statistically significantly lower level of riboflavin after thiamine treatment (p = 0.01). Conclusion FMN and Riboflavin were associated with chronic fatigue in patients with quiescent IBD. Levels of other B vitamins and metabolites were not significantly different between the investigated groups or related to effect of the thiamine intervention. Clinical trial registration : ClinicalTrials.gov study identifier NCT036347359. Registered 15 August 2018, https://clinicaltrials.gov/study/NCT03634735?cond=Inflammatory%20Bowel%20Diseases&intr=Thiamine&rank=1

Vitamin D treatment may reduce Crohn's disease (CD) activity by modulating the mucosal immune function. We investigated if high-dose vitamin D +/- infliximab modulated the mucosal cytokine expression in active CD. Forty CD patients were randomized into: infliximab + vitamin D; infliximab + placebo-vitamin D; placebo-infliximab + vitamin D or placebo-infliximab + placebo-vitamin D. Infliximab (5 mg/kg) and placebo-infliximab were administered at weeks 0, 2 and 6. Oral vitamin D was administered as bolus 200,000 international units (IU) per week 0 followed by 20,000 IU/day for 7 weeks or placebo. Endoscopy with biopsies was performed at weeks 0 and 7 where endoscopic activity was measured and mucosal mRNA cytokine expression was examined. C-reactive protein (CRP), fecal calprotectin and Harvey-Bradshaw Index (HBI) were measured at weeks 0, 2 and 6. High-dose vitamin D treatment alone and combined with infliximab decreased the IL17A, IFNγ and IL10 expression. High-dose vitamin D alone did not significantly decrease the disease activity, CRP or calprotectin. Combined infliximab and vitamin D treatment was not clinically significantly superior to monotherapy with infliximab. High-dose vitamin D as monotherapy and combined with infliximab decreases IL17A, IFNγ and IL-10 expression in mucosa within treatment groups. This did not induce a statistically significant decreased disease activity. EudraCT no.2013-000971-34.

Background: The health-related quality of life (HrQoL) can be substantially affected in patients with recurrent Clostridioides difficile infection (rCDI) but the impact of effective treatment of the infection remains unclear. This study aimed to evaluate the HrQoL in patients with rCDI and estimate the gain in HrQoL associated with effective treatment of rCDI. Methods: Patients’ HrQoL was estimated based on EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) questionnaires obtained from a Danish randomised controlled trial (RCT). In the RCT, 64 patients with rCDI were randomised to receive either vancomycin (n = 16), fidaxomicin (n = 24) or faecal microbiota transplantation (FMT) preceded by vancomycin (n = 24). The primary outcome in the RCT was rCDI resolution. Patients were closely monitored during the RCT, and rescue FMT was offered to those who failed their primary treatment. Patients’ HrQoL was measured at baseline and at 8- and 26-weeks follow-up. Linear regression analyses conditional on the differences between baseline and follow-up measurements were used to assess statistical significance (p < 0.05). Results: Within 26 weeks of follow-up, 13 (81%) patients treated with vancomycin, 12 (50%) patients treated with fidaxomicin, and 3 (13%) patients treated with FMT had a subsequent recurrence and received a rescue FMT. The average HrQoL for untreated patients with rCDI was 0.675. After receiving effective treatment, this value increased by 0.139 to 0.813 (p < 0.001) at week 8 and by 0.098 to 0.773 (p = 0.003) at week 26 of follow-up compared with baseline. Conclusion: The HrQoL was adversely affected in patients with an active episode of rCDI but increased substantially after receiving an effective treatment algorithm in which rescue FMT was provided in case of a primary treatment failure. Trial registration: The RCT was preregistered at EudraCT (j.no. 2015-003004-24, https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003004-24/results) and at ClinicalTrials.gov (study identifier NCT02743234, https://clinicaltrials.gov/ct2/show/NCT02743234).

Background: Seven weeks of high-dose vitamin D treatment decreases intestinal IL17A and IFN-γ mRNA expression in active Crohn’s disease (CD). In this follow-up study, we investigated whether seven-week vitamin D treatment affected the infliximab response in the following 45 weeks compared to placebo. Methods: CD patients (n = 40) were initially randomised into four groups: infliximab + vitamin-D; infliximab + placebo-vitamin-D; placebo-infliximab + vitamin-D; and placebo-infliximab + placebo-vitamin-D. Infliximab (5 mg/kg) or placebo-infliximab was administered at weeks 0, 2 and 6. Vitamin D (5 mg bolus followed by 0.5 mg/day for 7 weeks) or placebo-vitamin D was handed out. After the 7-week vitamin D period, all patients received infliximab during follow-up. Results are reported for Group D+ (infliximab + vitamin-D and placebo-infliximab + vitamin-D) and Group D- (infliximab + placebo-vitamin-D and placebo-infliximab + placebo-vitamin-D). Results: Group D- patients had greater needs for infliximab dose escalation during follow-up compared to group D+ (p = 0.05). Group D+ had lower median calprotectin levels week 15 (p = 0.02) and week 23 (p = 0.04) compared to group D-. Throughout follow-up, group D+ had 2.2 times (95% CI: 1.1–4.3) (p = 0.02) lower median CRP levels compared with group D-. Conclusions: Seven weeks high-dose vitamin D treatment reduces the need for later infliximab dose-escalation and reduces inflammatory markers. EudraCT no. 2013-000971-34.