Past Winners

DEBORAH JANS (KU Leuven): Family matters: Investigating inflammatory bowel disease aggregation in multiplex families through DNA methylation profiling

Relatives of patients with inflammatory bowel disease (IBD) are at the highest risk of developing IBD. Some families exhibit a notably high prevalence of the disease, with three or more first-degree relatives affected. However, the reasons behind this high occurrence of IBD in these so-called multiplex families remain unclear. Families share genetics but also environmental factors. Epigenetic modifications, such as DNA methylation, are important mediators of gene-environment interactions.

We aim to deepen our understanding of familial IBD by investigating DNA methylation as a reflection of environmental influences in multiplex families.

Specifically, we will perform methylation profiling on peripheral blood samples of individuals of 60 multiplex families, each with a minimum of three affected first-degree relatives, and matched sporadic cases and controls. We will explore the differences in methylation patterns between (familial) cases and controls to look for associated genes, but also to match these differences to known exposure-related methylation signatures. The relative contribution of environment versus genetics might be different between sporadic and familial cases and therefore we will also compare methylation signals both quantitatively as qualitatively between sporadic and familial cases.

This project will provide further insights into the familial aggregation of IBD and how familial IBD cases differ from sporadic ones. Ultimately, understanding the underlying causes of familial aggregation will contribute to a clearer understanding of the pathogenesis of IBD as a whole.

CLÉMENCE VUCKOVIC (Hôpital Erasme): Longitudinal characterization of the gut and oral microbiota in Inflammatory Bowel Disease patients in remission and identification of predictive microbial factors of relapse” – ANTICIPATE

Inflammatory bowel diseases (IBD) are characterized by imbalanced host-local microbiota interactions. While gut microbiota changes are thought to be a trigger in disease activity and despite recent suggestions of oral dysbiosis as pejorative factor associated with disease activity, it has yet not been proven as a pivotal factor influencing disease relapses.

The aim of this research is to longitudinally characterize the oral and gut microbiota in IBD patients in remission and to assess whether their microbiota composition or metabolomic characteristics could predict disease relapse.

This single centre prospective cohort is based on highly selected IBD patients with strict definition of disease remission (n=200). All patients who remain in remission will be followed for 12 months. Patients who experience a flare during follow-up will be managed differently. The composition of the oral and gut microbiota will be determined by 16S rRNA and ITS2 gene sequencings, targeting bacteria and fungi, respectively. Metabolomic studies will be performed on saliva, serum and faeces samples using 1H-NMR with LC-MS as a complementary method. At the end of follow-up, we will examine changes in the microbiota and metabolite composition of patients prior to relapse.

SAEED ABDURAHIMAN (KU Leuven): Deciphering cellular dynamics and the role of microbiota in perianal Crohn's disease: a multiomics approach

JUDITH WELLENS (KU Leuven): The FOAM-study: FOod Additives on the Mucosal barrier

Epidemiological data suggest that lifestyle factors and especially the diet could explain the stunning worldwide increase in IBD incidence. In particular the Western diet is often incriminated. This diet is low in fibres and rich in fat, sugar, processed meat, ultra-processed foods and food additives. Emulsifiers are one category of food additives that has been associated with intestinal inflammation, increased permeability and tumor growth in in vitro and animal models.

In this research project, we hypothesize that some but not all emulsifiers can promote and maintain a pro-inflammatory (gut) environment (i), that this effect can partially be explained by direct interaction of the emulsifier with the gut epithelium, and another part by taxonomic and functional changes in the microbiota (ii), and that the effect is modulated by a genetic predisposition of the host (iii).

To investigate this, we will undertake a 7-week randomized, double-blind placebo-controlled pilot study in 60 healthy volunteers. All participants will be asked to follow an emulsifier-free diet for 6 weeks. After an initial two weeks, subjects will be randomised to one of six groups to receive one of the following food additives: carrageenan, carboxymethylcellulose, Polysorbate-80, lecithin, the clean label alternative Beneo Remy B7 native rice starch, or placebo (no additives) incorporated in 3 brownies daily. Besides collecting detailed nutritional information, blood, stool, and urine samples will be collected at four timepoints.

The goal of the FOAM study is to elucidate the role of emulsifiers on the intestinal barrier, intestinal and systemic inflammation, and the gut microbiota in healthy volunteers. Doing so, we aim to develop much needed new treatments for our IBD patients and design novel approaches for prevention strategies.

LORENZO GIORIO (KU Leuven): Development of a Gut-On-A-Chip model for pre-clinical testing of drugs for inflammatory bowel disease

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a chronic progressive disorder of the gastrointestinal tract that poses multiple challenges to treatment development due to its multifactorial character. A valid ex vivo research model that properly mimics the in vivo situation is lacking, and pivotal to understand disease driving mechanisms and evaluate preclinical compounds. Intestinal organoids already constitute a very promising tool to model IBD and screen drugs in development, due to their ability to maintain site-specific and patient-specific characteristics, as opposed to cancer-derived cell lines. However, to successfully mimic and evaluate disease mechanisms, other characteristics have to be taken into account. Gut-on-a-chip constitute a possible solution to this problem, and are microfluidic devices lined with living cells that can recapitulate organ-level physiology and pathophysiology with high fidelity. Seeding chips with IBD patient-derived intestinal organoids, endothelial cells and immune cells will strongly increase the ability to pre-clinically predict the efficacy of drugs. The overall aim of this project is to develop a gut-on-a-chip pre-clinical model, in collaboration with industrial partners. This model will further unravel IBD disease mechanisms and improve pre-clinical screening of potential therapeutic compounds, which will ultimately help predict therapeutic efficacy on an individual patient level.

JADE CELIS (UZ Gent) : Functional genetics study of fibrostenosis in patients with Crohn's disease

Background: Genetics has been shown to direct wound healing responses toward healing or progressive fibrosis in liver and lung disease. Attempts to identify genetic markers for fibrostenotic Crohn’s disease however are hampered by difficulties to uniformly define fibrostenosis. We recently conducted a case-control genetic association study by in-depth phenotyping of patients from three Belgian IBD centers, through which we identified suggestive associations.

Aims: We aim to complete the genetic association study by including a validation cohort, identify mutations in candidate genes in replicated loci, and functionally study two prioritized genes (and potential mutations) ex vivo and in vivo.

Methods: A retrospective case-control association study was performed by applying strict inclusion criteria, in which cases were defined by the occurrence of (sub)obstruction in the first five years following diagnosis (N=56), and the control group comprised CD patients who had inflammatory disease without fistula formation or fibrostenosis for at least 10 years. Inclusion for the replication cohort is ongoing and currently contains 122 cases and 187 controls. Immunochip data were subjected to association analysis. Upon validation of associated single nucleotide polymorphisms (SNPs), we will use Illumina NextSeq or Illumina HiSeq to perform targeted sequencing of the regions surrounding the top associated SNPs to determine the presence of protein-coding (missense) mutations or mutations in UTRs which may have a functional effect. Functional analysis of prioritized genes (and potential mutations) will be investigated through culture of primary fibrocytes of CD patients and conditional knockout of genes in fibroblasts in mice.

Anticipated impact: Identifying specific genetic markers associated with the risk for fibrosis development and the concomitant functional study of genetic variants will improve the mechanistic understanding of fibrostenosis. In addition, findings may lead to novel and druggable targets, as has been shown for other fibrotic disease.

The first part of the grant was awarded thanks to a legacy received through the King Boudewijn foundation.

Brecht Hens (VUB, UZ Brussel)

Improved detection of dysplasia and colorectal carcinoma in inflammatory bowel disease 

Patients with colonic inflammatory bowel disease (IBD) are at increased risk for the development of colorectal cancer (CRC), accounting for 10% of the mortality in IBD. It is unclear how novel treatments may have an impact on cancer risk. European guidelines recommend endoscopic surveillance of patients with IBD based on individual risk profile and disease duration, which, however, is flawed due to a lack of standardisation and the difficult discrimination between inflammatory and neoplastic changes in chronically active colitis. Early dysplastic lesions are often flat and subtle and hence difficult to detect, contributing to the higher rate of CRC diagnosed within 3-5 years after colonoscopy in patients with IBD compared to non-IBD patients. An estimated 50% of CAC are considered so-called interval carcinomas.

This large number of colonoscopies pose a significant strain on IBD-patients and -clinics, but currently constitute the sole screening method for CAC. In contrast, screening for CRC in the general population is optimized by using non-invasive faecal blood testing to identify high-risk individuals, limiting colonoscopies mainly to patients with an abnormal stool test result. 

The main objectives of this joint research project with Amsterdam UMC are 1) to develop biomarkers for early detection of colorectal dysplasia and carcinoma in order to non-invasively identify individuals at high risk, and 2) to develop an AI algorithm for endoscopic identification of dysplastic colorectal lesions to improve colonoscopic accuracy and yield. These techniques might ultimately reduce the need of frequent surveillance colonoscopies and ameliorate the detection of early dysplasia, resulting in improved patient outcome and quality of life

Ine De Greef (KU Leuven)

Identification of mesentric triggers of early post-operative Crohn's recurrence

The chronic uncontrolled inflammation in Crohn’s disease may lead to tissue remodelling and fibrosis, and is the main reason why more than 50% of Crohn’s disease patients will ever need surgery, of which 70% will develop new lesions in the intestine as early as weeks to months after surgery. The triggers that play a role in this post-operative recurrence are not yet completely unravelled. At the external side of the small intestine, the phenomenon “creeping fat” is observed, which is mesenteric fat – a structure that connects the intestines and holds them in place - migrating to the sites of intestinal inflammation. This is solely seen in Crohn’s disease, but whether creeping fat has a pathological or protective role is still not clear. 

In this project, state-of-the-art technologies will be used to characterize the cellular and molecular composition of creeping fat, and link these new insights to the post-operative outcome 6 months after surgery. The results of this study will lead to (1) a better understanding of the underlying disease biology and etiology; (2) identification of pointers for new therapies or repurposing of existing drugs; (3) identification of predictive markers for post-operative Crohn’s disease recurrence so that medical treatment can be initiated quickly in order to prevent Crohn’s lesions to recur after surgery

Matthias Lenfant (KU Leuven)

Role of histological remission and mucosal healing as new targets for IBD

Crohn’s disease (CD) and ulcerative colitis(UC) are chronic inflammatory bowel diseases (IBD). A better understanding of disease course and the introduction of biologics has led to a shift from conventional symptom control to a treat-to-target approach. The most recent STRIDE-II consensus established endoscopic remission in addition to steroid-free clinical remission as suitable targets based on current evidence.

Histopathology has an important role in IBD management with regards to (1) diagnosis, (2) assessing disease severity, (3) evaluation of complications, and (4) evaluation of treatment response. Endoscopic and histological healing are not synonymous: histological evaluation of IBD patients has demonstrated the presence of histological signs of disease activity regardless of clinical and endoscopic remission.

Histologic remission may be a better predictor of the clinical course. In UC, histologic remission has been associated with a reduced risk of clinical relapse, corticosteroid use, hospitalization, and colorectal carcinoma. The data in CD are scarcer though some studies suggest a reduced risk of therapy failure, drug escalation and corticosteroid use in the presence of histologic remission.

The depth of healing necessary for long-term remission remains unclear, and it is uncertain if this should be evaluated by endoscopy, by histology, or both. Incorporating molecular profiling of IBD patients using transcriptomic analyses may further improve understanding and classification of deep remission.

The general objective of this research project is to gain further insight into the role of histological remission and mucosal healing in CD and UC using a combination of classical H&E  histological analyses combined with molecular transcriptomic RNA-Seq approaches. Furthermore, we hope to identify molecular differences in patients with quiescent disease, which could identify a patient subgroup at risk of recurrence and help optimize treatment strategies in the future.

The first part of the grant was awarded thanks to a legacy received through the King Boudewijn foundation.

Inge Jacobs (KU Leuven)

The role of eosinophils in intestinal inflammation and fibrosis

Laure Maes (U Gent)

Establishing a multi-organ microphysiological system to advance gut-brain communication research and development

Sara Deleu (KU Leuven)

Explaining the sharp demarcation in UC patients and identifying potential new therapeutic targets

The first part of the grant was awarded thanks to a legacy received through the King Boudewijn foundation.

Sophie Vieujean (Translational Gastroenterology, CHU, Liège GIGA-Research) 

Involvement of intestinal epithelium in fibrosis initiation and worsening in Crohn’s disease

Sophie Van Welden (U Gent)

Prolyl hydroxylase 1, a promising therapeutic target for colitis-associated cancer

Liselotte Fierens  (KU Leuven)

Quality of care for patients with Inflammatory bowel diseases

Kathleen Machiels and Clara Caenepeel (KU Leuven)

Predictive potential and role of microbiota in the efficacy of biological treatment and development of paradoxical adverse events in patients with inflammatory bowel disease

Ho-Su Lee (KU Leuven)

Familial aggregation in Inflammatory Bowel Disease: a next-generation sequencing study

Marie Truyens (U Gent)

The etiopathogenesis of persistent fatigue in patients with inflammatory bowel disease

Publication reference: Effect of 5-hydroxytryptophan on fatigue in quiescent inflammatory bowel disease: a randomized controlled trial - Gastroenterology (gastrojournal.org)

Kaline Arnauts  (KU Leuven)

The effect of microbiota on intestinal epithelial cells in ulcerative colitis

Simon Bos (U Gent)

Early detection and longitudinal monitoring of intestinal fibrosis in patients with crohn’s disease

Lucas Wauters (KU Leuven)

Unravelling the small bowel microbiome in Crohn’s disease

Sare Verstockt   (KU Leuven)

Molecular profiling of early events in IBD pathogenesis to find markers for early diagnosis

Wiebe Van Hove / Magalie de Bruyn  (KU Leuven)                  

Primary intestinal epithelial cells: a personalized tool for functional characterization of IBD-associated pathways

Cara De Galan (U Gent)

Predictive factors for the clinical response to vedolizumab

Joao Sabino (Leuven)
Food influence on the Intestinal microbioTa trial (FIT trial)
 
Claire Liefferinckx (Bruxelles)
Identification of Genetic variants regulating gEne hubs in the cOntrol of specific and genericmodules across context-dependent activation of Immune Cells in healthy subjects: Understandingthe genetic architecture Of Disease sEverity in IBD (GEOCODE IBD project)
 
Bram Verstockt (Leuven)
Predicting outcome of inflammatory bowel diseases: creating opportunities for personalized medicine

Hindryckx Pieter  (UGent)
The contribution of hypoxia to the pathogenesis and the course of inflammatory bowel disease: defining the window for therapeutic intervention
 
Vancamelbeke Maaike (KU Leuven)
The Role of the Intestinal Epithelial Barrier in the Pathophysiology of Inflammatory Bowel Diseases

Ingrid Arijs (Leuven)
Study of the effect of vedolizumab therapy on colonic mucosal gene expression in patients with ulcerative colitis

Manuel Nobel (Leuven)
Intestinal stem cells - microbiota interactions in inflammatory bowel diseases

Debby Laukens (Gent)
The therapeutic use of anti-metallothionein antibodies in IBD: bench-to-bedside

Dominiek Staelens and Kris Nys (Leuven)
Crohn's susceptibility genes in innate immunity, ER stress and autophagy: from genetics to personalized medicine