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Abstract Disrupted host-microbe interactions at the mucosal level are key to the pathophysiology of IBD. This study aimed to comprehensively examine crosstalk between mucosal gene expression and microbiota in patients with IBD. To study tissue-specific interactions, we perform transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 697 intestinal biopsies (645 derived from 335 patients with IBD and 52 from 16 non-IBD controls). Mucosal gene expression patterns in IBD are mainly determined by tissue location and inflammation, whereas the mucosal microbiota composition shows a high degree of individual specificity. Analysis of transcript-bacteria interactions identifies six distinct groups of inflammation-related pathways that are associated with intestinal microbiota (adjusted P

Abstract Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index

BackgroundAnti-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 methodsPrimary 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.ResultsOut 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.ConclusionsWe 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.

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Aim: To validate the Montreal classification system for Crohn's disease (CD) and ulcerative colitis (UC) within the Netherlands., Methods: A selection of 20 de-identified medical records with an appropriate representation of the inflammatory bowel disease (IBD) sub phenotypes were scored by 30 observers with different professions (gastroenterologist specialist in IBD, gastroenterologist in training and IBD-nurses) and experience level with IBD patient care. Patients were classified according to the Montreal classification. In addition, participants were asked to score extra-intestinal manifestations (EIM) and disease severity in CD based on their clinical judgment. The inter-observer agreement was calculated by percentages of correct answers (answers identical to the "expert evaluation") and Fleiss-kappa (κ). Kappa cut-offs: < 0.4-poor; 0.41-0.6-moderate; 0.61-0.8-good; > 0.8 excellent., Results: The inter-observer agreement was excellent for diagnosis (κ = 0.96), perianal disease (κ = 0.92) and disease location in CD (κ = 0.82) and good for age of onset (κ = 0.67), upper gastrointestinal disease (κ = 0.62), disease behaviour in CD (κ = 0.79) and disease extent in UC (κ = 0.65). Disease severity in UC was scored poor (κ = 0.23). The additional items resulted in a good inter-observer agreement for EIM (κ = 0.68) and a moderate agreement for disease severity in CD (κ = 0.44). Percentages of correct answers over all Montreal items give a good reflection of the inter-observer agreement (> 80%), except for disease severity (48%-74%). IBD-nurses were significantly worse in scoring upper gastrointestinal disease in CD compared to gastroenterologists (P = 0.008) and gastroenterologists in training (P = 0.040). Observers with less than 10 years of experience were significantly better at scoring UC severity than observers with 10-20 years (P = 0.003) and more than 20 years (P = 0.003) of experience with IBD patient care. Observers with 10-20 years of experience with IBD patient care were significantly better at scoring upper gastrointestinal disease in CD than observers with less than 10 years (P = 0.007) and more than 20 years (P = 0.007) of experience with IBD patient care., Conclusion: We found a good to excellent inter-observer agreement for all Montreal items except for disease severity in UC (poor).