Elevated Poster Presentation International Celiac Disease Symposium 2026

From Stress to Regeneration: Single-Cell Multiomics Reveals Epithelial Reprogramming in Refractory Coeliac Disease (141993)

Fabio Luciani 1 2 , Mandeep Singh 3 , Michael Li 3 , Arman Safavi 3 , Chris Goodnow 4 , Luca Elli 5 , Antonio Di Sabatino 6 , Marco Lenti 6 , Matt Field 7 , Andrew Calcino 7 , Scott Read 8 , Golo Ahlenstiel 8 , Martina Bonomi 2
  1. Immunogenomics and AI, Westmead Institute for Medical Research, Sydney, NSW, Australia
  2. University of New South Wales, Sydney, NSW, Australia
  3. Westmead Institute for Medical Research, Sydney, NSW, Australia
  4. Immunogenomics, Garvan Institute for Medical Research , Sydney, NSW, Australia
  5. Gastroenterology, University of Milan, Milano, Lombardia, Italy
  6. Internal Medicine, Policlinico San Matteo, Pavia, Lombardia, Italy
  7. James Cook University , Cairns, QLD, Australia
  8. Gastroenterology, Western Sydney University, Sydney, NSW, Australia

Background: Coeliac disease (CeD) is characterised by chronic intestinal inflammation and epithelial injury, yet how epithelial cell populations adapt during disease progression remains poorly understood. While immune-mediated mechanisms have been extensively studied, the contribution of epithelial remodelling to persistent tissue damage and refractory disease is less clear.

Methods: We performed single-cell multiomic profiling of duodenal biopsies from healthy controls, active CeD (ACD) and refractory coeliac disease type 1 (RCD1) and Type II (RCD2). Epithelial cells were subclustered and analysed using differential abundance, differential gene expression, pathway enrichment and pseudotime trajectory analysis.

Results: Single-cell analysis identified distinct epithelial populations, including enterocytes, transit-amplifying (TA) cells, enteroendocrine cells (EECs), tuft cells and epithelial stem cells. Disease progression was associated with a continuum of epithelial remodelling. Enterocytes transitioned from absorptive programs in healthy tissue towards stress-associated states in ACD and regenerative, immune-visible states in RCD1 characterised by HLA-E, REG1A and REG3A expression. Importantly, disease-associated transcriptional changes were already evident within TA populations, which acquired injury-repair, inflammatory and antigen-presentation programs prior to differentiation into mature epithelial lineages. Pseudotime analysis supported the presence of a remodelled crypt-villus differentiation axis in RCD1. Among specialised epithelial subsets, EECs and tuft cells demonstrated marked expansion and transcriptional reprogramming. RCD1 EECs upregulated pathways involved in vesicular trafficking, endocrine function and sensory signalling, including pain-associated ion channels, suggesting enhanced epithelial-neuronal crosstalk. Tuft cells exhibited altered secretory and innate immune programs consistent with tissue remodelling and repair.

Conclusions: These findings reveal that chronic inflammation in coeliac disease drives progressive epithelial remodelling beginning at the progenitor stage and culminating in specialised regenerative and sensory epithelial states. Epithelial reprogramming may represent a central feature of RCD1 pathogenesis and a potential therapeutic target.