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Single Cell RNA Sequencing Unveils Distinct Cellular Dynamics in Celiac Disease Duodenal Biopsies

ABSTRACT: Celiac disease (CeD) is the most common autoimmune disorder in the U.S., affecting at least 1% of the population. The ingestion of gluten-containing proteins triggers an adaptive immune response, causing intestinal damage and leading to both gastrointestinal and systemic symptoms. Despite a strong genetic predisposition, the mechanistic understanding of CeD remains limited. The lack of approved therapy, other than dietary avoidance of gluten which is difficult and often unsuccessful, underscores the need to identify new mechanisms that can provide insights for developing therapeutics. To gain an unbiased view of the transcriptional landscape of the duodenum, we compared duodenal biopsies showing active CeD to normal controls using single-cell RNA sequencing. We analyzed fresh research biopsies from 4 patients with active CeD, confirmed by diagnostic biopsies from the same endoscopy, as well as 2 healthy control biopsies without specific pathological changes. Our analysis captured every major intestinal mucosal cell type including all subsets of immune cells, epithelial cells and stromal cells. Among these, enterocytes and activated T cells exhibited the most significant differences between CeD biopsies and controls. In CeD biopsies, CD8+TCR αβ and TCR γδ T cells were the primary producers of IFNG, a feature that was largely absent in the control biopsies. Moreover, enterocytes that express villous defining marker APOA4+ showed elevated levels of IFNGR1, suggesting an increased responsiveness to IFNγ produced by CeD T cells. We assessed effects of IFNγ on potential target molecules expressed on enterocytes that could activate and trigger killing by CTL. Bioinformatic ligand receptor analyses showed frequent interactions between intraepithelial CTLs and enterocyte HLA-E or HLA-B, suggesting that IFNγ production by the CTLs likely promotes further CTL recruitment and antigen-dependent killing of the villous epithelium.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315138 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Coeliac Disease (CeD) is a chronic autoimmune disorder affecting 0.5-1% of the general population with a wide geographical distribution. Despite recent efforts to deeply phenotype gluten-specific immune activation at the single cell level, recent clinical studies targeting gluten degradation and other immune tolerance mechanisms have been unsuccessful. To this end, a deeper understanding of immune and non-immune cellular dynamics and interactions are required to characterize tissue-specific mechanisms responsible for CeD pathogenesis, repair, and resolution. Here, we assembled the most comprehensive scRNAseq dataset in Coeliac Disease to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. Compared to control duodenum, CeD was characterized by single cell differential changes in abundance, gene expression and cell-cell interactions across cellular compartments. In the immune compartments, CeD samples showed expected increases in plasma cell abundance and shifts toward type 1 effector biology (e.g., increase in cycling CD8pos, γδ T cells and IFNG transcriptional shifts) and Tfh-related biology (e.g., increases in IL21 signaling to effector T cells). In addition, activated myeloid subsets, including DC2 and monocytes, were increased in disease and were characterized by increased pro-inflammatory pathway expression, including IL-1β. Non-immune compartments showed increased stem/crypt and secretory enterocytes in CeD samples with a decrease in absorptive enterocytes, reflecting the villus atrophy and crypt hyperplasia hallmarks of CeD epithelial dysfunction. Accompanying the epithelial changes, distinct changes in stromal populations were identified, particularly with increases in abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis across multiple cellular compartments proposed a distinct increased role of fibroblasts to support the epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived IL-1β signal and lymphoid-derived IFN-γ. This dataset reveals a previously unknown role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.

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Single Cell RNA Sequencing Unveils Distinct Cellular Dynamics in Celiac Disease Duodenal Biopsies

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