IBD Research Unit: Projects

Biobank

    The lab collects biospecimens from IBD patients for biomedical research purposes, including:

    Service

    The lab provides services to test novel therapeutics for IBD in a pre-clinical platform including:

    • animal models in mice: acute and chronic DSS-induced colitis, acute and chronic TNBS-induced colitis, adoptive T cell transfer-induced colitis; with additional focus on the development of intestinal fibrosis
    • ex vivo human biopsy cultures

    Fundamental Research

    The IBD Research Unit is a prototypical translational research group utilizing patient-derived material and in vitro models for validation in appropriate animal models. Research is focused on intestinal innate immunity and fibroblast function in IBD pathogenesis.

    Identification of susceptibility genes for inflammatory bowel diseases (IBD) and Spondyloarthropathy (SpA)

    Our department is a participant of the International IBD Genetics Consortium, a network of researchers working on the genetics of IBD. This collaboration has resulted in three large scale genome-wide association studies of both CD and UC in which multiple genomic loci implicated in these diseases have been identified. At the end of 2012, >160 replicated loci were found, and the genes within these loci have led to the discovery of new pathways involved in chronic gut inflammation (Jostin et al 2012). We analyzed the overlap between susceptibility loci in CD and SpA and found a significant and new association with a SNP in a locus closely linked to ORMDL3, a gene that plays a role in endoplasmic reticulum (ER) stress and is also associated with susceptibility to asthma (Laukens et al 2010). These GWAS data are further explored focusing on their association with specific disease phenotypes such as fibrostenosing disease.

    The role of Rho kinase inhibitors in IBD

    A promising target for IBD is Rho kinase (ROCK), a pleiotropic kinase that is overactive in IBD tissues and is involved in a number of physiological and pathological processes of inflammation (e.g. cytokine production, angiogenesis) and gut homeostasis (fibrosis, loss of barrier function, adaptation to hypoxia). However, precaution is warranted as ROCK inhibition is known to cause serious systemic side-effects. In this research project the emphasize is on examining the effects of locally administered ROCK inhibitors in different mouse models of colitis in order to provide a proof of concept that ROCK inhibition by rectal administration is feasible and is able to relieve symptoms associated with murine colitis. Mechanistically, the specific focus of attention is their effect on intestinal inflammation, epithelial barrier function and fibrosis.

    The role of bile salts in IBD

    Bile acids are important regulators of epithelial cell viability in the gastrointestinal lumen. A correlation between fecal bile acid dysmetabolism and dysbiosis has recently been shown in stool samples of patients with IBD. Promising results were obtained using the secondary bile acid tauroursodeoxycholic acid (TUDCA) in acute colitis in mice, inhibiting intestinal epithelial apoptosis and significantly altering fecal bile acid composition. The use of specific combinations of  bile acids as a novel therapeutic is under investigation in various acute and chronic IBD models, focusing on their effect on total bile acid composition and microbiota changes. A pilot clinical trial was initiated using ursodeoxycholic acid to investigate its influence on fecal bile acid composition in patients with IBD.

    The role of metallothioneins as danger signals in IBD

    Metallothioneins are zinc-binding acute stress proteins with immunomodulating functions. We have recently shown that these proteins are released from intestinal epithelial cells upon cell death, and confer chemotactic properties toward leukocytes in vitro and during colitis in vivo (Devisscher et al 2013). As such,  they can be classified as newly identified danger signals in the gut. Interestingly, blocking the function of metallothioneins by the use of monoclonal antibodies confers protection to both acute and chronic colitis and is the subject of a national patent filing (WO2013007678). Their role as immunomodulating proteins is explored, for example in driving macrophage differentiation.

    The role of endothelial dysfuncion in gut inflammation

    Intestinal endothelial dysfunction may represent an important hallmark of IBD (Hindryckx et al 2010). We have recently shown that prolylhydroxylases, the central regulators of the hypoxic response, are differentially expressed in biopsies of patients with IBD (Van Welden et al 2013). In this project, we are investigating endothelial-specific knockout of prolylhydroxylases in models of colitis, focusing on their effect on blood vessel function.