IBD Research Unit: Projects


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


    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 primarily focused on translational research utilizing patient-derived material for the identification and characterization of novel therapeutic targets for IBD. In a broader context, the group investigates how intestinal inflammation drives extra-intestinal manifestations such behavioral symptoms and Parkinson’s disease.

    Fibrogenesis in IBD:  an untreatable complication in patients with 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). We showed that inhibiting local ROCK is a valuable target to inhibit fibrosis in patients with Crohn’s disease (in collaboration with Amakem Therapeutics). This compound was bought by RedX Pharmaceuticals, and together, we aim to bring this drug to the clinic.

    A major goal in our lab is to identify biomarkers for intestinal fibrosis. In addition, through a national collaboration, we have identified genetic markers that are associated with the early development of fibrosis in these patients. The functional effect of these genetic variants is under investigation, and may provide novel clues into the pathogenesis of fibrosis.

    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. 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. We have recently shown that prolylhydroxylases, the central regulators of the hypoxic response, are differentially expressed in biopsies of patients with IBD. In this project, we are investigating endothelial-specific knockout of prolylhydroxylases in models of colitis, focusing on their effect on blood vessel function.

    Targeting persistent fatigue in patients with IBD

    Persistent fatigue, the feeling of exhaustion and lack of energy, severely impairs the quality of life of patients with chronic IBD. Even during stable remission periods, over 40% of patients still suffer from disabling fatigue. However, this problem is poorly understood and underestimated in clinical practice. Management strategies focusing on fatigue are lacking, and intervention studies are scarce. An important dietary component that may influence fatigue-like symptoms is tryptophan (Trp), because of its role as a precursor for the neurotransmitter serotonin. We have recently initiated a multicenter, placebo-controlled clinical trial designed to evaluate the efficacy of Trp supplementation in quiescent IBD patients (TBM funded). To provide a detailed scientific rationale and a pathophysiological basis to understand fatigue in patients with IBD, the goal is to use animal models to: 1) objectify fatigue as an inherent symptom of chronic gut inflammation and 2) link behavioral changes with an in depth analysis of Trp metabolism at the gut-blood-brain interface. In collaboration with Prof. Roos Vandenbroucke (VIB/UGent)

    Malnutrition and intestinal homeostasis

    Malnutrition is a major leading cause of childhood mortality worldwide. Severe acute malnutrition is categorized into either marasmus or kwashiorkor, the latter being characterized by oedema, fatty liver and higher case fatality rates (20-49%). It however remains unclear what causes a malnourished child to develop kwashiorkor instead of marasmus. Several hypotheses have been proposed in the past, but none have so far been able to fully elucidate the cause of kwashiorkor, limiting the development of effective prevention or treatment strategies.  We aim to unravel the aetiology and pathophysiology of kwashiorkor and we will investigate the potential role of bile acid receptor farnesoid-X receptor signaling in malnutrition, and link this with our previous observation that specific bile acids have a beneficial role in experimental colitis. This project runs in close collaboration with Artsen Zonder Grenzen and the Hospital for Sick Children (SickKids, Toronto, Canada).

    Intestinal inflammation is one of the hallmarks of severe malnutrition, especially kwashiorkor, and has been found to be significantly associated with mortality. Furthermore, these children manifest severe villus blunting, reduced mucus secretion, small intestinal bacterial overgrowth and abnormal bile acid homeostasis. In this study, we will apply the knowledge from IBD research to better understand the pathophysiology and molecular mechanisms underlying intestinal inflammation in kwashiorkor. 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, microbiota changes and inflammation. A pilot clinical trial was initiated using ursodeoxycholic acid to investigate its influence on fecal bile acid composition in patients with IBD. We aim to explore the potential and extend the use of this strategy to alleviate intestinal inflammation in kwashiorkor in hope of decreasing the mortality rates in the affected children.

    Inflammation in the gut and aggregation of alpha-synuclein: a risk factor for Parkinson’s disease?

    Parkinson’s disease (PD) is characterized by the formation of intracellular inclusion bodies that are composed of the misfolded protein alpha-synuclein (α-syn). These aggregates ultimately cause loss of neurons leading to the well-known motor symptoms. Increasing evidence suggests that α-syn containing aggregates first appear in the enteric nervous system with a subsequent spread to the brain via the vagal nerve. Although the evidence for a role of systemic and intestinal inflammation in α-syn aggregation and neurodegeneration is rising, detailed mechanistic insights in how this process occurs and whether it affects α-syn spreading from the gut to the central nervous system is unknown. In addition, the potential central role of the choroid plexus and the cerebrospinal fluid in driving synucleopathy under inflammatory pressure has not been considered. The objectives of this project are to evaluate whether systemic and gastrointestinal inflammation promote α-syn expression and aggregation in the gut and the brain and whether it increases gut-brain transport of α-syn and neurodegeneration. This project runs in close collaboration with Prof. Roos Vandenbroucke (VIB/UGent) and Prof. Patrick Santens (UZ Gent).