Hepcidin and iron status in patients with inflammatory bowel disease undergoing induction therapy with vedolizumab or infliximab

Lay Summary: Absolute iron deficiency is the primary determinant of hepcidin levels, even in an inflammatory state. Induction therapy can decrease hepcidin levels, which might improve iron bioavailability. Hence, hepcidin is a potential diagnostic iron deficiency biomarker that could assist therapeutic decision making. Background: Hepcidin, the systemic iron regulator, could be critical in differentiating iron deficiency (ID) from functional iron restriction in inflammatory bowel disease (IBD). We assessed hepcidin as a diagnostic ID marker and explored the relationship between hepcidin and its regulators in patients with IBD undergoing induction therapy with infliximab (IFX) or vedolizumab (VEDO). Methods: Patients with active IBD receiving induction therapy with IFX or VEDO were included. Serum samples at baseline and after 6 weeks of induction therapy were analyzed for hepcidin, inflammation- and hypoxia-associated cytokines, and oxidative stress. Data were analyzed by stratifying based on the response at week 14. Results were compared with samples from age- and sex-matched healthy control subjects. Results: Patients receiving induction therapy with IFX (n = 71) or VEDO (n = 51) and healthy control subjects (n = 50) were included. At baseline, hepcidin correlated positively with ferritin and negatively with soluble transferrin receptor/log ferritin index (P Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Circulating miRNAs as potential biomarkers for celiac disease development

Background & AimsCeliac disease (CeD), an immune-mediated disease with enteropathy triggered by gluten, affects ~1% of the general European population. Currently, there are no biomarkers to predict CeD development. MicroRNAs (miRNAs) are short RNAs involved in post-transcriptional gene regulation, and certain disease- and stage-specific miRNA profiles have been found previously. We aimed to investigate whether circulating miRNAs can predict the development of CeD. MethodsUsing next-generation miRNA-sequencing, we determined miRNAs in >200 serum samples from 53 participants of the PreventCD study, of whom 33 developed CeD during follow-up. Following study inclusion at 3 months of age, samples were drawn at predefined ages, diagnosis (first anti-transglutaminase antibody (TGA) positivity or diagnostic biopsy) and after the start of a gluten-free diet (GFD). This allowed identification of circulating miRNAs that are deregulated before TGA positivity. For validation of the biomarkers for CeD and GFD response, two additional cohorts were included in subsequent meta-analyses. Additionally, miRNAs were measured in duodenal biopsies in a case-control cohort. Results53 circulating miRNAs were increased (27) or decreased (26) in CeD versus controls. We assessed specific trends in these individual miRNAs in the PreventCD cohort by grouping the pre-diagnostic samples of the CeD patients (all had negative TGA) by how close to seroconversion (first sample positive TGA) the samples were taken. 8/53 miRNAs differed significantly between controls and samples taken <1 year before TGA positivity: miR-21-3p, miR-374a-5p, 144-3p, miR-500a-3p, miR-486-3p let-7d-3p, let-7e-5p and miR-3605-3p. 6/26 downregulated miRNAs reconstituted upon GFD, including miR-150-5p/-3p, whereas no upregulated miRNAs were downregulated upon GFD. 15/53 biomarker candidates also differed between CeD biopsies and controls, with a concordant direction, indicating that these circulating miRNAs might originate from the intestine. ConclusionsWe identified 53 circulating miRNAs that are potential early biomarkers for CeD, of which several can be detected more than a year before TGA positivity and some start to normalize upon GFD.Transplantation and immunomodulatio

Exposure to thioguanine during 117 pregnancies in women with inflammatory bowel disease

Background: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. Methods: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. Results: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. Conclusion: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

HNF4alpha and CDH1 are associated with ulcerative colitis in a Dutch cohort

Item does not contain fulltextBACKGROUND: Inflammatory bowel diseases (IBDs), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are complex disorders with multiple genes contributing to disease pathogenesis. A recent genome-wide association scan identified three novel susceptibility loci for UC: HNF4alpha, CDH1, and LAMB1. We performed an analysis of these three loci in an independent cohort. METHODS: In all, 821 UC patients and 1260 healthy controls of central European Caucasian descent were genotyped for single nucleotide polymorphisms (SNPs): rs6017342 (HNF4alpha), rs1728785 (CDH1), and rs6949033 (LAMB1). Differences in allele and genotype distribution in cases and controls were tested for significance with the chi(2) test. RESULTS: Allelic association analysis showed that SNP rs6017342 in the HNF4alpha locus was strongly associated with UC (P = 1,04 x 10(-11) , odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.37-1.77) and SNP rs1728785 (CDH1) was associated with P = 0.01 (OR = 1.23, 95% CI = 1.05-1.44). SNP rs6949033 in LAMB1 was not associated in our cohort (P = 0.12, OR = 1.11, 95% CI = 0.97-1.26). We found an association for SNP rs6949033 (LAMB1) for disease limited to the rectum (P = 0.02). However, this association was lost after correcting for multiple testing. No further specific subphenotype associations were identified. CONCLUSIONS: This is the first independent study to replicate the HNF4alpha and CDH1 loci as susceptibility loci for UC. The main candidate genes in these risk loci play important roles in the maintenance of the integrity of the epithelial barrier, highlighting the importance of the mucosal barrier function for UC pathogenesis

Impact of a future H2 transportation on atmospheric pollution in Europe

Hydrogen (H2) is being explored as a fuel for passenger vehicles; it can be used in fuel cells to power electric motors or burned in internal combustion engines. In order to evaluate the potential influence of a future H2-based road transportation on the regional air quality in Europe, we implemented H2 in the atmospheric transport and chemistry model LOTOS-EUROS. We simulated the present and future (2020) air quality, using emission scenarios with different proportions of H2 vehicles and different H2 leakage rates. The reference future scenario does not include H2 vehicles, and assumes that all present and planned European regulations for emissions are fully implemented. We find that, in general, the air quality in 2020 is significantly improved compared to the current situation in all scenarios, with and without H2 cars. In the future scenario without H2 cars, the pollution is reduced due to the strict European regulations: annually averaged CO, NOx and PM2.5 over the model domain decrease by 15%, 30% and 20% respectively. The additional improvement brought by replacing 50% or 100% of traditionally-fueled vehicles by H2 vehicles is smaller in absolute terms. If 50% of vehicles are using H2, the CO, NOx and PM2.5 decrease by 1%, 10% and 1% respectively, compared to the future scenario without H2 cars. When all vehicles run on H2, then additional decreases in CO, NOx and PM2.5 are 5%, 40%, and 5% relative to the no-H2 cars future scenario. Our study shows that H2 vehicles may be an effective pathway to fulfill the strict future EU air quality regulations.O3 has a more complicated behavior - its annual average decreases in background areas, but increases in the high-NOx area in western Europe, with the decrease in NOx. A more detailed analysis shows that the population exposure to high O3 levels decreases nevertheless. In all future scenarios, traffic emissions account for only a small proportion of the total anthropogenic emissions, thus it becomes more important to better regulate emissions of non-traffic sectors. Although atmospheric H2 increases significantly in the high-leakage scenarios considered, the additional H2 added into the atmosphere does not have a significant effect on the ground level air pollution in Europe

Impact of a future H2 transportation on atmospheric pollution in Europe

<p><strong>Highlights</strong></p> <p>•European air quality improves in the future due to emission regulations.</p> <p>•When road traffic is converted to H2, air quality improves further.</p> <p>•H2 leaked into the atmosphere does not have a large negative impact on air quality.</p

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

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.Molecular Technology and Informatics for Personalised Medicine and Healt

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

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 mu g/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.Cellular mechanisms in basic and clinical gastroenterology and hepatolog