Maaike Vancamelbeke

The intestinal barrier: a fundamental role in health and disease

ABSTRACT Introduction: The gastrointestinal mucosa constitutes a critical barrier where millions of microbes and environmental antigens come in close contact with the host immune system. Intestinal barrier defects have been associated with a broad range of diseases and therefore denote a new therapeutic target. Areas covered: This review is based on an extensive literature search in PubMed of how the intestinal barrier contributes to health and as a trigger for disease. It discusses the anatomy of the intestinal barrier and explains the available methods to evaluate its function. Also reviewed is the importance of diet and lifestyle factors on intestinal barrier function, and three prototypes of chronic diseases (inflammatory bowel disease, celiac disease and nonalcoholic fatty liver disease) that have been linked to barrier defects are discussed. Expert commentary: The intestinal barrier has been investigated by various methods, but correlation of results across studies is difficult, representing a major shortcoming in the field. New upcoming techniques and research on the effect of barrier-restoring therapeutics may improve our current understanding of the gut barrier, and provide a step forward towards personalised medicine.

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.

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.