Intestinal epithelial cell stress modulates enteric fibroblastic and neuronal profiles in Inflammatory Bowel Disease

C. Escudero-Hernández © C. Escudero-Hernández

Background & aim of research

This project aimed to understand the effects that crucial IBD epithelial stress factors (i.e. ATG16L1 and XBP1 impairments) might have in enteric fibroblasts and neurons.

Gabriele Dragoni © ECCO

After repeated postponements due to travel restrictions to Japan, I was able to carry out enteroscopy training at the Tokyo Medical and Dental University (TMDU) Hospital between September and October 2022.

Induction of circadian microbial function in chronic intestinal inflammation

Silke Kiessling © Silke Kiessling

Background & aim of research

Impaired clock gene expression has been observed in biopsies from patients with Inflammatory Bowel Disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The intestinal clock balances gastrointestinal homeostasis by regulating the microbiome. We aimed to characterise intestinal immune functions in mice lacking the intestinal clock and in IBD-relevant mouse models under different feeding conditions in order to assess the functional impact of the intestinal clock in the development of gastrointestinal inflammation.

Investigating the genetics of IBD multiplex families

Ho-Su Lee © Ho-Su Lee

Background & aim of research

This research aimed to investigate the genetic architecture of Inflammatory Bowel Disease (IBD) multiplex families (including at least three affected first-degree relatives), and to identify the underlying genetic factors that contribute to the familial aggregation of IBD.

Role of DNA methYlation and geNe expression alterations in development of eArly-onset priMary sclerosIng cholangitis in ulCerative colitis – DYNAMIC

Sudipto Das © Sudipto Das

Background & aim of research

Primary Sclerosing Cholangitis (PSC) is a progressive choleostatic disease and up to 80% of patients also have Ulcerative Colitis (PSC-UC). This presents a clinical challenge owing to the diagnostic difficulty and the increased risk for development of cancer. The aim of this study was to identify the transcriptomic and epigenetic alterations regulating the phenotype of this disease.

The role of autophagy in limiting IBD-associated AIEC-induced intestinal inflammation

Shai Bel © Shai Bel

Background & aim of research

While the aetiology underlying the development of Inflammatory Bowel Diseases (IBD) is unclear, evidence points to an interaction between host genetics, such as mutations in autophagy genes, and environmental factors, such as bacterial infections. Multiple studies have identified an adherent-invasive Escherichia coli pathotype (AIEC) only in patients with IBD. It is thought that AIEC exploits the intestinal inflammation in patients with IBD to attach to intestinal epithelial cells, intensifying the pre-existing inflammation. Studies in vitro have shown that functional autophagy is crucial to eliminate AIEC infection. Here, we aimed to identify how autophagy protects the host from AIEC-associated pathologies in vivo.

Marc Ferrante © ECCO

Yves Panis © ECCO

Pauline Rivière © Pauline Rivière

For two years, a group of 25 IBD specialists, including gastroenterologists, surgeons and scientists, have been working to build a research framework for postoperative recurrence (POR) in patients with Crohn’s Disease. Even though more biological therapies are now available, ileocaecal resection is still a frequent event and POR management remains a challenge for both patients and IBD specialists.

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.