DOP40 Inflammatory Bowel Disease single cell atlas construction to enable cell type-specific target identification

Abstract

Abstract Background Advances in single-cell technologies enable the unbiased study of cellular heterogeneity. Recently, single-cell RNA sequencing (scRNA-seq) has been utilised on intestinal and blood samples from patients with inflammatory bowel disease (IBD) and healthy individuals, often in conjunction with cell surface proteome and TCR repertoire analyses. These individual studies revealed novel cell subpopulations of immune, mesenchymal, and epithelial cells in UC and CD, but are not sufficiently powered to consistently identify granular cell subsets or establish their association with disease status and response to treatment. Integration of these studies into a unified IBD single-cell atlas would provide a more robust data foundation for therapeutic target discovery. Here, we constructed a comprehensive, multi-modal single-cell atlas of human IBD tissue, combining a large breadth of meta-analysis with the depth of single-cell resolution. Methods Raw data from 20 public datasets were curated and reprocessed to generate a harmonised data foundation to support downstream discovery efforts. Low-quality cells and doublets were removed using thresholds for gene number, gene count, and percentage of counts originating from mitochondrial genes, and the resulting data were normalised and adjusted for batch effects. Published clinical metadata from each study were re-annotated with controlled vocabularies. Associations between clinical metadata and cellular/molecular features were discovered using computational and ML approaches. Results We generated a large-scale integrated single-cell atlas for IBD comprising >500 tissue samples from >200 IBD patients and relevant controls, with harmonised clinical metadata including treatment history and response. This tissue atlas comprises >990k high-quality cells with granular annotations of 129 cell types/states. IBD inflammation and non-response to anti-TNF treatment were associated with unique transcriptional signatures in specific mononuclear phagocyte, CD4 T cell, and fibroblast subpopulations. Further prioritisation and validation of genes comprising these signatures may yield future therapeutic targets for IBD. Conclusion This atlas integrates single-cell data across the largest available collection of IBD patient-derived tissue samples. Leveraging high-resolution cell type annotations and harmonised clinical metadata, meta-analyses of this data foundation will broaden the understanding of IBD biology to identify novel targets and pathways for drug discovery.