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

Area of Science:

• Gastroenterology and Immunology
• Single-cell genomics
• Autoimmune disorders

Background:

• Celiac disease (CeD) is a prevalent autoimmune disorder affecting the small intestine.
• Understanding the cellular dynamics in CeD is crucial for developing targeted therapies.

Purpose of the Study:

• To create the most comprehensive single-cell RNA sequencing (scRNA-seq) dataset in CeD to date.
• To characterize cellular and interactional changes in the duodenal tissue of CeD patients compared to controls.

Main Methods:

• Collected 203,555 cells from 21 active CeD and 11 control duodenal samples.
• Utilized scRNA-seq to analyze differential gene expression, cell abundance, and cell-cell interactions.
• Investigated fibroblast, myeloid, and lymphoid cell contributions to epithelial changes.

Main Results:

• Identified significant single-cell differential changes in cell abundance and gene expression in CeD.
• Observed increased stem/crypt and secretory epithelial cells, with decreased absorptive enterocytes, indicating crypt hyperplasia and villus atrophy.
• Found increased abundance and activity of NRG1 and SMOC2 fibroblasts, supporting epithelial reprogramming.

Conclusions:

• CeD involves complex T-myeloid-stromal-epithelial cell communication.
• Fibroblast-mediated support of epithelial reprogramming, influenced by IL-1β and IFN-γ, is a key mechanism in CeD.
• This dataset provides insights into tissue-level cellular dynamics in response to gluten.