Immune signaling mediates stromal changes to support epithelial reprogramming in celiac duodenum.

Celiac disease is a chronic autoimmune disorder affecting 0.5%-1% of the population. Here, we assembled the most comprehensive single-cell RNA sequencing (scRNA-seq) dataset in celiac disease (CeD) to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. CeD was characterized by single-cell differential changes in abundance, gene expression, and cell-cell interactions across cellular compartments versus control. Epithelial changes included increased stem/crypt and secretory epithelial cells in CeD and decreased 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 increased role of fibroblasts to support epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, 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 CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.