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 will be awarded thanks to a legacy received through the King Boudewijn foundation.
