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ObjectiveIron deficiency is a common complication in patients with IBD and oral iron therapy is suggested to exacerbate IBD symptoms. We performed an open-labelled clinical trial to compare the effects of per oral (PO) versus intravenous (IV) iron replacement therapy (IRT).DesignThe study population included patients with Crohn's disease (CD; N=31), UC (N=22) and control subjects with iron deficiency (non-inflamed, NI=19). After randomisation, participants received iron sulfate (PO) or iron sucrose (IV) over 3 months. Clinical parameters, faecal bacterial communities and metabolomes were assessed before and after intervention.ResultsBoth PO and IV treatments ameliorated iron deficiency, but higher ferritin levels were observed with IV. Changes in disease activity were independent of iron treatment types. Faecal samples in IBD were characterised by marked interindividual differences, lower phylotype richness and proportions of Clostridiales. Metabolite analysis also showed separation of both UC and CD from control anaemic participants. Major shifts in bacterial diversity occurred in approximately half of all participants after IRT, but patients with CD were most susceptible. Despite individual-specific changes in phylotypes due to IRT, PO treatment was associated with decreased abundances of operational taxonomic units assigned to the species Faecalibacterium prausnitzii, Ruminococcus bromii, Dorea sp. and Collinsella aerofaciens. Clear IV-specific and PO-specific fingerprints were evident at the level of metabolomes, with changes affecting cholesterol-derived host substrates.ConclusionsShifts in gut bacterial diversity and composition associated with iron treatment are pronounced in IBD participants. Despite similar clinical outcome, oral administration differentially affects bacterial phylotypes and faecal metabolites compared with IV therapy.Trial registration numberclinicaltrial.gov (NCT01067547).

ObjectiveThis phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD).DesignEligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.ResultsIn all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.ConclusionsClinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells.Trial registration numberNCT01276509; Results.

AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

Abstract Background CALM was a randomized phase 3 trial in patients with Crohn’s disease (CD) that demonstrated improved endoscopic outcomes when treatment was escalated based on cutoffs for inflammatory biomarkers, fecal calprotectin (FC), C-reactive protein (CRP), and CD Activity Index (CDAI) remission vs CDAI response alone. The purpose of this post hoc analysis of CALM was to identify drivers of treatment escalation and evaluate the association between biomarker cutoff concentrations and endoscopic end points. Methods The proportion of patients achieving CD Endoscopic Index of Severity (CDEIS) <4 and no deep ulcers 48 weeks after randomization was evaluated according to CRP <5 mg/L or ≥5 mg/L and FC <250 μg/g or ≥250 μg/g. Subgroup analyses were performed according to disease location, and sensitivity analyses were conducted in patients with elevated CRP and/or FC at baseline. The association between endoscopic end points and biomarker cutoffs was performed using χ 2 test. Results The proportion of patients who achieved the primary end point CDEIS <4 and no deep ulcers was significantly greater for those with FC <250 µg/g (74%; P < 0.001), with an additive effect for CRP <5 mg/L. The association of FC <250 µg/g with improved endoscopic outcomes was independent of disease location, although the greatest association was observed for ileocolonic disease. Fecal calprotectin <250 µg/g, CRP <5 mg/L, and CDAI <150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS <4 and no deep ulcers 48 weeks after randomization. Conclusion This post hoc analysis of CALM demonstrated that a cutoff of FC <250 µg/g is a useful surrogate marker for mucosal healing in CD. A post hoc analysis of a phase 3 trial in Crohn’s disease showed that a fecal calprotectin cutoff of <250 μg/g accurately classified mucosal healing at week 48 after randomization in a majority of patients.

BACKGROUND/OBJECTIVES: Enteral feeding will induce remission in as many as 80–90% of compliant patients with active Crohn’s disease (CD), but its method of action remains uncertain. This study was designed to examine its effects on the colonic microbiome. METHODS/SUBJECTS: Healthy volunteers and patients with CD followed a regimen confined to enteral feeds alone for 1 or 2 weeks, respectively. Chemicals excreted on breath or in faeces were characterised at the start and at the end of the feeding period by gas chromatography/mass spectrometry. RESULTS: One week of feeding in healthy volunteers caused significant changes in stool colour and deterioration in breath odour, together with increased excretion of phenol and indoles on the breath. Feeding for 2 weeks in patients with CD produced significant improvements in symptoms and a decrease in the concentration of C-reactive protein. The faecal concentrations of microbial products, including short-chain fatty acids (SCFAs), and potentially toxic substances, including 1-propanol, 1-butanol and the methyl and ethyl esters of SCFAs, showed significant falls. CONCLUSIONS: A significant change occurs in the production of microbial metabolites after enteral feeding in both healthy volunteers and patients with CD. Many of those detected in CD are toxic and may feasibly lead to the immunological attack on the gut microbiota, which is characteristic of inflammatory bowel disease. The reduction in the production of such metabolites after enteral feeding may be the reason for its effectiveness in CD.

Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD. Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data. When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied α4β7 integrin-MADCAM1 axis. Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-α therapy goes through downregulation of certain adhesion molecules.

Background Increased intestinal permeability (IP) has been implicated in the etiopathogenesis, disease activity and relapse of Crohn’s disease (CD). Glutamine, the major fuel for the enterocytes, may improve IP. Aim We evaluated the effect of oral glutamine on IP and intestinal morphology in patients with CD. Methods In a randomized controlled trial, consecutive patients with CD in remission phase with an abnormal IP were randomized to a glutamine group (GG) or active control group (ACG) and were given oral glutamine or whey protein, respectively, as 0.5 g/kg ideal body weight/day for 2 months. IP was assessed by the lactulose mannitol excretion ratio (LMR) in urine, and morphometry was performed by computerized image analysis system. Results Patients (age 34.5 ± 10.5 years; 20 males) were assigned to the GG ( n  = 15) or ACG ( n  = 15). Fourteen patients in each group completed the trial. The LMR [median (range)] in GG and ACG at 2 months was 0.029 (0.006–0.090) and 0.033 (0.009–0.077), respectively, with P  = 0.6133. IP normalized in 8 (57.1%) patients in each group ( P  = 1.000). The villous crypt ratio (VCR) [mean (SD)] in GG and ACG at 2 months was 2.68 (1.02) and 2.49 (0.67), respectively, ( P  = 0.347). At the end of 2 months LMR improved significantly in GG from 0.071 (0.041–0.254) to 0.029 (0.006–0.090) ( P  = 0.0012) and in ACG from 0.067 (0.040–0.136) to 0.033 (0.009–0.077) ( P  = 0.0063). VCR improved in the GG from 2.33 (0.77) to 2.68 (1.02) ( P  = 0.001), and in ACG from 2.26 (0.57) to 2.49 (0.67) ( P  = 0.009). Conclusions Intestinal permeability and morphology improved significantly in both glutamine and ACG.

PurposeMany patients with Crohn’s disease (CD) and ulcerative colitis (UC) who have a high 6-methylmercaptopurine/6-thioguanine (6-MMP/6-TGN) ratio receive allopurinol 100 mg in addition to thiopurines to optimize metabolite concentrations. However, some patients do not tolerate allopurinol at this dosage.The aim of this study was to determine the intra-patient effect of reducing the allopurinol dosage from 100 to 50 mg, in terms of metabolite concentrations, enzyme activities, efficacy, and tolerability.MethodsA prospective non-inferiority one-way crossover study was performed. CD and UC patients with stable disease using a thiopurine and allopurinol 100 mg were switched to 50 mg for 1 month. Primary outcomes were thiopurine metabolite concentrations. Secondary outcomes were enzyme activities of xanthine oxidase, thiopurine methyltransferase and hypoxanthine-guanine phosphoribosyltransferase, disease activity, and tolerability.ResultsTwenty-two patients were included. Treatment with allopurinol 50 mg compared with 100 mg resulted in a significant decrease in mean 6-TGN levels (761 to 625 pmol/8 × 108 RBC; p = 0.005) and a significant increase in mean 6-MMP levels (451 to 665 pmol/8 × 108 RBC; p = 0.01). However, the mean metabolite concentrations were still therapeutic. Enzyme activities, disease activity scores, and patient experiences did not alter significantly. Generally, UC patients were more positive about their improved treatment than CD patients.ConclusionCombination therapy with 50 mg allopurinol led to a decrease of 6-TGN levels compared with 100 mg allopurinol. Disease activity, side effects, and patient experience, however, were similar between allopurinol 100 and 50 mg. UC patients seem to benefit and prefer lower doses whereas the contrary is seen in CD patients.Trial registrationEudraCT trial registry - number 2016-001638-84

Background: Interleukin 10 (IL-10) exerts anti-inflammatory actions by counteracting many biological effects of interferon γ (IFN-γ). Aims: To investigate this in humans, we studied the effects of human recombinant IL-10 administration on IFN-γ production by patient leucocytes. Furthermore, we assessed the IFN-γ inducible molecule neopterin and nitrite/nitrate serum levels, which are indicative of endogenous nitric oxide formation. Methods: As part of two placebo controlled double blind studies, we analysed patients with chronic active Crohn's disease (CACD) who received either subcutaneous recombinant human IL-10 (n=44) or placebo (n=10) daily for 28 days, and patients with mild to moderate Crohn's disease (MCD) treated with either subcutaneous IL-10 (n=52) or placebo (n=16) daily for 28 days. Neopterin and nitrite/nitrate concentrations were measured in serum, and ex vivo IFN-γ formation by lipopolysaccharide or phytohaemagglutinin (PHA) stimulated whole blood cells were investigated before, during, and after IL-10 therapy. Results: In patients with CACD, the highest dose of 20 μg/kg IL-10 caused a significant increase in serum neopterin on days +15 and +29 of therapy compared with pretreatment levels. No changes were observed for nitrite/nitrate levels under either condition. In MCD, treatment with 20 μg/kg IL-10 resulted in a significant increase in PHA induced IFN-γ production. Conclusions: High doses of IL-10 upregulate the production of IFN-γ and neopterin. This phenomenon may be responsible for the lack of efficacy of high doses of IL-10 in the treatment of CACD and MCD.

BackgroundCrohn’s disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined.MethodsPeptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Anti-inflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice.ResultsThe seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-κB pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice.ConclusionsA 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.