Understanding inflammatory bowel disease pathogenesis

At the Centre for Children’s Gut Health, our research challenges conventional paradigms of IBD pathogenesis by integrating high-resolution molecular profiling, cutting-edge human organoid technology, and AI-assisted data science.

Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, are complex, chronic disorders of the gastrointestinal tract driven by a convergence of genetic, environmental, microbial, and immunological factors. However, prevailing models — often rooted in animal studies and limited cross-sectional data — fail to account for the cellular and molecular heterogeneity seen in patients, particularly children.

Our team leads a global translational research programme (ORBIT-IBD), which is constructing the world’s largest biobank of patient-derived intestinal epithelial organoids (IEOs) alongside a longitudinal clinical cohort across Europe and Asia. By integrating single-cell epigenomics, spatial transcriptomics, and somatic mutational profiling directly in human-derived tissue, we aim to:

• Reveal novel disease-driving mechanisms such as intestinal epithelial DNA methylation signatures that shape mucosal immunity and barrier function (Dennison al., Gut, 2024).
• Characterise somatic mutation dynamics within intestinal stem cells across age and disease stages (Lee-Six et al., Nature, 2019).
• Interrogate environmental influences (e.g. diet, treatment, microbial exposures) on the intestinal epigenome, using longitudinal data from children and adolescents with newly diagnosed IBD.
• Enable precision medicine, using machine learning models to predict disease progression and therapy response.

Unlike traditional approaches that focus primarily on immune dysfunction, our research places the intestinal epithelium at the centre of IBD pathogenesis, supported by mechanistic data and functional validation through CRISPR-based perturbation screens and co-culture systems with immune and mesenchymal cells.

We believe that only by studying human tissue, in relevant models and over time, can we uncover the true mechanisms underpinning IBD and move toward tailored, effective treatments for children and young people living with these life-altering conditions.

References:

• Howell KJ, Kraiczy J, Nayak KM, et al.
  DNA methylation and transcription patterns in intestinal epithelial cells from pediatric patients with inflammatory bowel diseases differentiate disease subtypes and associate with outcome.
  Gastroenterology 2018; 154(3):585–598.
  https://doi.org/10.1053/j.gastro.2017.10.007
• Dennison TW, Edgar RD, Payne F, et al.
  Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease.
  Gut 2024; 73(9):1464–1477.