Irish research identifies possible therapeutic targets in coeliac disease

Reference: September 2025 | Issue 9 | Vol 11 | Page 50

Scientists have discovered how cells in the small intestine of coeliac patients communicate with one another. The new comprehensive atlas of cells fills gaps in knowledge on how different cells in the intestine act together to drive coeliac disease, potentially opening new avenues for future therapeutic intervention.

The newly published collaborative research from scientists at Children’s Health Ireland (CHI), Johnson & Johnson, and Trinity College Dublin, used single-cell RNA sequencing (scRNA-seq) to create the most detailed map to date of how individual cells behave in the small intestine of people with coeliac disease. They looked at more than 200,000 individual cells from tissue samples of both people with active coeliac disease and healthy individuals (all anonymised).

The research was recently published in the journal Cell Reports. The results showed major differences in the types and activities of cells in gut epithelium and the supporting stroma between people with coeliac disease and those without.

The team created an atlas of cells present in the small intestines of both participant groups, allowing them to characterise how these cells are different in disease by identifying which genes are ‘switched on’ and could be involved in activating pathways which potentially drive the disease. The researchers subsequently identified pathways through which different cells can communicate with each other to drive the tissue damage which is characteristic of coeliac disease.

The research revealed that people with coeliac disease had more stem cells and secretory cells, but fewer cells absorptive enterocytes, reflecting crypt hyperplasia and villus atrophy. Distinct changes in stromal populations correlated with epithelial changes, particularly increased abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts.

Cell-cell interaction analysis proposed a distinct role for fibroblasts in supporting epithelial reprogramming of the increased stem/crypt epithelial fraction in coeliac disease, mediated by myeloid-derived interleukin-1β (IL-1β) and lymphoid-derived interferon γ (IFN-γ). This dataset reveals a role for T-myeloid-stromal-epithelial cell communication in the condition, highlighting key mechanisms of tissue-level cellular dynamics in response to gluten ingestion.

These data reveal a previously undescribed disease-associated stromal-enterocyte-immune interaction and provide a deeper understanding of the cellular networks underlying the mucosal inflammation, while opening the door for new therapies targeting both the myeloid and stromal compartment.

Prof Patrick Walsh, Professor of Clinical Medicine, School of Medicine, Trinity College Dublin, said: “These findings provide a detailed and comprehensive map of the cellular landscape in the inflamed intestine of young coeliac patients and has the potential to inform future directions for researchers working internationally to tackle this disease.”

Prof Seamus Hussey, Consultant in Gastroenterology, Hepatology, Intestinal Failure, and Transplant Medicine at CHI, Crumlin, said: “Every year, 150 to 200 children in Ireland are newly diagnosed with coeliac disease, a condition that currently requires a lifelong gluten-free diet. This groundbreaking research stems from existing strong partnerships between researchers in Trinity and CHI. Illuminating new intricate immune pathways and connections in paediatric coeliac disease marks a pivotal step toward developing novel, immune-based medical treatment options for patients worldwide.”

Darren Ruane, Director of Translational Science and Medicine at Johnson & Johnson, Immunology, said: “This exciting collaboration between Johnson & Johnson and the research teams at Trinity and CHI, has provided significant impact to the coeliac disease field. These efforts have identified novel pathways related to coeliac disease pathogenesis and highlighted the previous unknown role of stromal-immune cellular communication in disease. This research will enable new therapeutic target identification.”

Writing in Cell Reports, the authors point out that the research has some limitations. Despite their ability to recover many crypt-like stem cells, limited expression of markers for the crypt small intestine Paneth cells, such as DEFA5 and DEFA6, was observed within the dataset, suggesting that an epithelium-specific processing step may be required to adequately sample this limited cell type.

Furthermore, despite a myeloid population totalling 4,366 cells, significant patient to patient variation was noted within the myeloid compartment. It should also be noted that samples were cryopreserved prior to scRNA-seq characterisation, which can impact cell recovery.

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