EDIOM · Elucidating drivers of human Inflammatory Bowel Disease by next-generation organoid modeling

Elucidating drivers of human Inflammatory Bowel Disease by next-generation organoid modeling

Inflammatory Bowel Disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic condition in which the immune system mistakenly attacks the intestine. The resulting inflammation causes recurring symptoms and long-term tissue damage, and many patients require lifelong treatment. Although several anti-inflammatory and immunosuppressive medicines are available, a substantial proportion of people do not respond well or lose response over time. This reflects a core challenge: IBD is biologically diverse, and multiple inflammatory pathways can be active in different patients and at different stages of disease. The project was motivated by the need for a human-tissue–based understanding of these pathways, because animal models and simplified cell cultures cannot fully capture the complexity of the human gut immune system. In particular, CD4⁺ “helper” T cells are central coordinators of immunity and are strongly implicated in IBD, including responses to harmless gut microbes (the commensal microbiota). Yet it has remained unclear how inflammatory helper T-cell programs, tissue-resident states, and regulatory programs coexist, change during disease activity, and interact with other immune and non-immune cells within the intestinal environment. The overall objective was therefore to identify, and then experimentally test, the key cellular networks and cell-to-cell communication pathways that drive human intestinal inflammation. To achieve this, the project combined three elements into a single workflow: immune-competent “mini-gut” organoids grown from patient biopsies (air–liquid interface cultures) that preserve multiple tissue compartments, high-dimensional immune profiling to capture many features of T-cell state in one experiment (including a 37-marker spectral flow cytometry assay), and spatial plus computational approaches to place immune states in their tissue context and integrate cellular, protein and spatial measurements into disease-associated interaction networks. Overall objectives: 1) Build and validate immune-competent patient-derived intestinal organoids as an ex vivo model for IBD. 2) Profile CD4⁺ T helper cell programs in gut tissue at high resolution, including functional outputs and the capacity to shift between inflammatory and regulatory states (“plasticity”). 3) Add spatial context to determine where disease-linked immune states arise and which cell types interact most frequently within inflamed tissue. 4) Integrate cellular, protein and spatial measurements with computational modelling to identify disease-enriched cellular networks and actionable cell-to-cell signalling pathways. 5) Functionally test top candidate drivers in organoids (by targeted perturbation) to distinguish association from mechanism, prioritise therapeutic targets, and define measurable biomarkers of disease-relevant immune states. Pathway to impact: by connecting realistic human tissue models with multi-modal readouts and data integration, the project aims to deliver a practical pipeline for identifying causal drivers of inflammation, selecting druggable targets, and developing biomarkers that can help stratify patients and support more targeted, durable treatment strategies; ultimately reducing the burden of IBD on patients and healthcare systems.

Data: CORDIS, © European Union