Circulating tumour DNA and artificial intelligence as screening tools for dysplasia in Inflammatory Bowel Disease

Brecht Hens © Brecht Hens

Background & aim of research

Patients with colonic Inflammatory Bowel Disease (IBD) are at increased risk for the development of colorectal cancer. Surveillance colonoscopy is therefore advised, starting at 8 years after initial diagnosis of IBD and then repeated every 1–5 years based on the individual risk profile. However, screening based solely on colonoscopy is flawed as interval carcinomas still account for around 40%–50% of all colitis-associated carcinomas (CAC). In sporadic colorectal cancer, both liquid biopsies and artificial intelligence (AI) have proved to be feasible and to yield promising results. Patients with IBD were systemically excluded from these trials.

The aim of this research project is to improve the early detection of IBD-associated dysplasia by (1) developing non-invasive biomarkers using blood and/or stool samples to identify high-risk individuals and (2) developing a machine learning algorithm to aid in the detection of neoplastic lesions during colonoscopy.

Unraveling the role of fibroblast subsets in fibrostenotic Crohn’s disease

Andrea van der Meulen-de Jong, Marieke Barnhoorn, Luuk Hawinkels, Gianluca Matteoli © Marieke Barnhoorn

Objectives

Fibrosis occurs in most Crohn’s Disease (CD) patients, although it only becomes clinically apparent in those who develop stenotic disease. Fibroblasts are considered the main cell type contributing to fibrosis by production and remodelling of the extracellular matrix. Recently, changes have been shown in the relative abundance of different fibroblast subsets in the inflamed intestine of IBD patients. However, the abundance of fibroblast subsets and their spatial localisation in fibrostenotic IBD tissue are currently unknown. The overall aim of this project is to unravel the role of fibroblast subsets in the pathogenesis of fibrostenotic CD and to identify novel therapeutic targets.

As a first objective, we will map the differences in abundance and spatial distribution of fibroblast subsets in patients with inflammatory and stenotic CD using a unique 40-marker fibroblast Imaging Mass Cytometry (IMC) antibody panel. Thereafter, as a second objective, we will investigate (pathogenic) fibroblast subsets derived from fibrostenotic lesions in CD patients using a fibroblast-rich, three-dimensional organoid-based model. Lastly, we will assess in CD patients the effects of Janus kinase (JAK) inhibition on the relative abundance of identified fibroblast subsets.

Decoding molecular mechanisms and druggable targets of VEO-IBD by multimodal single-cell profiling

Daniel Kotlarz © Daniel Kotlarz

Objectives

The pathogenesis and course of Inflammatory Bowel Disease (IBD) are heterogeneous and have striking age-dependent characteristics. In particular, children with very early-onset IBD (VEO-IBD) show a higher incidence of unclassified IBD and develop courses different from adult-onset forms. VEO-IBD is a rare condition, but the incidence is increasing globally at an alarming pace. Notably, VEO-IBD patients often fail to respond to conventional therapies and show life-threatening conditions.

In paradigmatic studies, we have previously reported IL-10R deficiencies as a monogenic cause in children with intractable VEO-IBD. Based on knowledge of the molecular disease mechanisms, IL-10R-deficient patients could be cured by allogeneic haematopoietic stem cell transplantation. This prime example of translational research has shifted paradigms by demonstrating the relevance of genetics for the treatment of VEO-IBD patients. Our genetic screen of one of the largest international VEO-IBD cohorts has revealed disease-causing mutations in approximately 20% of analysed patients (>60 genetic entities) and suggested optimised treatment for a significant number of children. However, most VEO IBD patients still lack definitive diagnosis and the disease mechanisms remain largely elusive.

Travel awards ECCO'23 © ECCO

This year, available funding for ECCO Fellowships and Grants Programme (F&G) increased to 1.9 Million Euros for this year’s Call 2023 (to be awarded ECCO’24), this is the largest funding volume to date. With diverse funding streams for innovative research and international collaborations such as the Pioneer Award and the new Global Grant as well as those specifically for early career scientists, Dieticians and Nurses, the ECCO F&G Programme has really grown in the last five years.

Identifying biomarkers prior to IBD diagnosis from the Prospective Urban Rural Epidemiology Study (PURE-IBD)

Neeraj Narula © Neeraj Narula

Background & aim of research

The primary objective of this study is to identify novel serum biomarkers prior to IBD onset that may mediate IBD risk in PURE.

Deciphering of composition and characteristics of intra- and peritumoral immune cells in human IBD-associated dysplasia and cancer using novel spatial profiling techniques

Sofía Frigerio © Sofía Frigerio

Background & aim of research

Chronic colonic inflammation in patients with Inflammatory Bowel Disease increases the risk of colitis-associated cancer (CAC). Although mouse studies have been instrumental in understanding CAC development, the immune cell composition and the role of these immune cells in human CAC are largely unknown.

In this study, we aim to decipher the composition and characteristics of immune cells in close proximity to dysplastic pre-cancerous lesions and cancers in IBD patients, and to decipher possible interactions between epithelial cells and the underlying immune cell populations in these regions, using novel spatial profiling techniques.

Delineating an uptake-independent function of SR-BI in Paneth cells in metabolic gut inflammation

Felix Grabherr © Felix Grabherr

Background & aim of research

Dietary lipids are associated with risk of developing Inflammatory Bowel Disease (IBD). Activity of glutathione peroxidase 4 (GPX4), an anti-oxidative selenoenzyme, is impaired in intestinal epithelial cells (IECs) from patients with ileal Crohn’s Disease (CD). GPX4 controls intestinal inflammation triggered by dietary polyunsaturated fatty acids (PUFAs) and dietary PUFA uptake is associated with CD flares. SR-BI (encoded by Scarb1) is a membrane-bound receptor, mainly reported to be involved in the uptake of cholesterol, and cholesterol uptake has been described to play a role in ferroptosis induction, a cell death pathway which is regulated by GPX4. Paneth cells (PCs), specialised IECs within the small intestine, have been described to be the origin of intestinal inflammation. Preliminary data indicate that PCs sense and translate dietary PUFA stress into intestinal inflammation. 

Identification of gut microbial strains contributing to chronic inflammation in human and mice

Bahtiyar Yilmaz © Bahtiyar Yilmaz

Background & aim of research

The relationship between host and microbiota can turn negative, leading to changes in microbial composition and metabolism that result in diseases such as Inflammatory Bowel Disease (IBD). Enteropathogenic strains increase due to the presence of reactive oxygen species in an altered metabolic environment. This study aims to understand how an IBD microbiota carrying an oxidative stress signature adapts over time and how these strains contribute to the disease's trajectory and fluctuations of oxidative stress in the outer mucus layer.

Aim 1: To isolate and characterise the capacity of freshly isolated human small and large intestinal microbial members contributing to oxidative stress.

Aim 2: To colonise germ-free or defined microbiota colonised mice with isolated bacterial strains to test their contributions and resilience to inflammation/oxidative stress in the mouse intestines.

Establishment of a multi-organ-on-chip model to advance gut-brain communication research and developmentrt

Laure Maes © Laure Maes

Background & aim of research

Persistent fatigue severely affects the quality of life of IBD patients and reduces their ability to work. Although IBD patients, even when in clinical remission, report fatigue as one of the most disabling symptoms of their chronic disease, disease management is often only focused on attenuating gastrointestinal symptoms. In order to develop effective therapeutic interventions, a better understanding of what is causing IBD-associated fatigue is required. Therefore, the goal of this project is to develop a human gut-blood-brain in vitro model to explore the impact of active and extinguished gut inflammation on brain and brain barrier function.

Ascertaining the role of the appendix in inflammatory bowel disease in a population-based cohort

Manasi Agrawal © Manasi Agrawal

Background & aim of research

Appendectomy at age <20 years for appendicitis or mesenteric lymphadenitis has been associated with a lower risk of Ulcerative Colitis (UC), but this association has not been detected when appendectomy is performed at an older age or for non-specific abdominal pain. Similar findings have been reported upon combining data from Swedish and Danish registers.  However, in a Danish cohort study of familial units, individuals who had first-degree relatives with appendicitis, but no personal history of appendicitis, at age <20 years also had a lower risk of UC. This risk was even lower in those with a family history of UC. 

Interventional studies on elective appendectomy for UC therapy are underway. The impact of appendiceal inflammation on UC outcomes, including cancer, are not well understood. 

The overall aim of this study is to understand the role of the appendix (appendicitis and appendectomy) in IBD risk and IBD outcomes.