Sare Verstockt

Genetic and Transcriptomic Bases of Intestinal Epithelial Barrier Dysfunction in Inflammatory Bowel Disease

Background: Intestinal barrier defects are common in patients with inflammatory bowel disease (IBD). To identify which components could underlie these changes, we performed an in-depth analysis of epithelial barrier genes in IBD. Methods: A set of 128 intestinal barrier genes was selected. Polygenic risk scores were generated based on selected barrier gene variants that were associated with Crohns disease (CD) or ulcerative colitis (UC) in our study. Gene expression was analyzed using microarray and quantitative reverse transcription polymerase chain reaction. Influence of barrier gene variants on expression was studied by cis-expression quantitative trait loci mapping and comparing patients with low- and high-risk scores. Results: Barrier risk scores were significantly higher in patients with IBD than controls. At single-gene level, the associated barrier single-nucleotide polymorphisms were most significantly enriched in PTGER4 for CD and HNF4A for UC. As a group, the regulating proteins were most enriched for CD and UC. Expression analysis showed that many epithelial barrier genes were significantly dysregulated in active CD and UC, with overrepresentation of mucus layer genes. In uninflamed CD ileum and IBD colon, most barrier gene levels restored to normal, except for MUC1 and MUC4 that remained persistently increased compared with controls. Expression levels did not depend on cis-regulatory variants nor combined genetic risk. Conclusions: We found genetic and transcriptomic dysregulations of key epithelial barrier genes and components in IBD. Of these, we believe that mucus genes, in particular MUC1 and MUC4, play an essential role in the pathogenesis of IBD and could represent interesting targets for treatment.

Genetic Influences on the Development of Fibrosis in Inflammatory Bowel Disease

Intestinal fibrosis is a common complication in inflammatory bowel disease. These fibrotic processes develop in genetically susceptible individuals, influenced by an interplay with environmental, immunological and disease-related factors. A deeper understanding of the genetic factors driving fibrogenesis might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapies. Here we review the genetic factors that have been associated with the development of fibrosis in patients with both Crohn’s disease and ulcerative colitis, as well as their potential pathophysiological mechanism(s).

TREM-1, the ideal predictive biomarker for endoscopic healing in anti-TNF-treated Crohn’s disease patients?

We read with great interest the study by Gaujoux et al , who described a whole blood marker for anti-tumour necrosis factor (TNF) responsiveness in patients with Crohn’s disease (CD). The availability of anti-TNF agents dramatically changed therapeutic strategies for patients with CD. However, an overall non-response rate of 30% has been observed, and, together with the approval of new classes of biological agents with a different mode of action, clearly indicates the need for predictive biomarkers. Gaujoux et al identified triggering receptor expressed on myeloid cells 1 ( TREM1) expression in whole blood as a biomarker for anti-TNF (non)response (higher expression in responders).1 In inflamed colonic tissue, TREM1 expression is also decreased in future infliximab responders.1 2 TREM-1 is known to amplify inflammation, whereas TREM-1 inhibition in vivo attenuates colitis by modulating autophagy and endoplasmic reticulum (ER) stress.3 We first measured serum TREM-1 (sTREM-1) (Human sTREM-1 ELISA (HK348), Hycult Biotech, Uden, the Netherlands) in 85 patients with CD with active disease prior to anti-TNF therapy (table 1). To reduce the risk of including treatment failures secondary to immunogenicity (and not drug mechanistic failure) or non-drug-related healers, all included patients had to have a good drug exposure, defined as a maintenance trough level >3.0 µg/mL for infliximab or >5.0 µg/mL for adalimumab. Interestingly, patients who achieved mucosal healing (complete absence of ulcerations and erosions4) after 6 months of anti-TNF therapy (adalimumab and infliximab) had significantly lower baseline sTREM-1 levels compared with non-responders (50.8 pg/mL …

P067 Molecular profiling of early Crohn's disease reveals a prominent role for WNT5A.

[Verstockt, S.; Cleynen, I.] Katholieke Univ Leuven, Dept Human Genet, Leuven, Belgium. [Van der Goten, J.; Vancamelbeke, M.; Verstockt, B.; Rutgeerts, P.; Ferrante, M.; Vermeire, S.; Arijs, I.] Katholieke Univ Leuven, Dept Clin & Expt Med, Translat Res Ctr Gastrointestinal Disorders, Leuven, Belgium. [Van Lommel, L.; Schuit, F.] Katholieke Univ Leuven, Dept Cellular & Mol Med, Gene Express Unit, Leuven, Belgium. [Arijs, I.] Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium. [Arijs, I.] Jessa Hosp, Hasselt, Belgium.

TNF-driven pathways are increased at baseline in Crohn’s disease patients not responding to infliximab

[Verstockt, B.; Arijs, I.; de Bruyn, M.; Van Assche, G.; Vermeire, S.; Ferrante, M.] Katholieke Univ Leuven, Dept Clin & Expt Med, TARGID IBD, Leuven, Belgium. [Verstockt, B.] Univ Cambridge, Sch Clin Med, Dept Med, Biomed Campus, Cambridge, England. [Verstockt, B.] Cambridge Inst Med Res, Cambridge, England. [Arijs, I.] Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium. [Arijs, I.] Jessa Hosp, Hasselt, Belgium. [de Bruyn, M.] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Leuven, Belgium. [Verstockt, S.] Katholieke Univ Leuven, Lab Complex Genet, Dept Human Genet, Leuven, Belgium. [Van Assche, G.; Vermeire, S.; Ferrante, M.] Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium. [Breynaert, C.] Katholieke Univ Leuven, Clin Immunol Lab, Dept Microbiol & Immunol, Leuven, Belgium.