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Reveal the key mediators of inflammation in Crohn's disease undergoing biological treatments

ABSTRACT: Crohn’s disease (CD) is a major subtype of life-long Inflammatory Bowel Disease (IBD) affecting a growing population in United States. To advance the knowledge in pathology, our study investigates into the common inflammatory feature in CD across different inflammation statuses by single-cell transcriptomics. First, we provided a detailed mucosal cellular landscape of terminal ileum (TI) and ascending colon (AC), with endoscopic diagnosis (CD inflamed, adjacent-to-inflamed, non-inflamed and non-IBD control), including a cohort of patients undergoing biological treatments. Differences between regions (TI and AC), and features of mucosal inflammation status in cellular composition are captured within the cellular landscapes. Second, we identified an inflammation cascade that include follicle-associated enterocytes and macrophages via molecules like CCL20 and S100As, as key mediators of CD inflammation. These key mediators serve as hubs in imputed cell-cell interactions under CD inflammation, expanding the interplay network with increasing disease severity. Finally, we demonstrate a scoring method by surveying the mucosa, using GWAS loci, and transcriptome features including differentially expressed genes (DEGs), and genes from a novel singular value decomposition (SVD)-based co-expression network analysis framework. Applying independently to the epithelial and immune lineage, we identify inflammation signatures that reflect disease severity. Furthermore, we report a short, robust list of epithelial and immune transcript makers whose expressions harmonize with endoscopic diagnosis and histological assessment. These markers are merely within known IBD GWAS loci. Collectively, this study narrates a shared inflammation pattern involving cells and cytokines for active CD and present a short list of markers for metrical inflammation assessment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266616 | GEO | 2024/12/16

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in inflamed and non-inflamed colon pinch biopsies from the IBD patients using expression microarrays platform. In this study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In case of inflamed CD and UC (iCD and iUC), we identified 438 and 745 differentially expressed lncRNAs, respectively, while in case of the non-inflamed CD and UC (niCD and niUC), we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (p-value < 0.001, Pearson’s Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed that they are involved in immune response, pro-inflammatory cytokine activity and MHC protein complex. The lncRNA expression profiling in both inflamed and non-inflamed CD and UC, successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggests their potential as biomarkers in IBD. A total of 96 biopsy samples (including 6 samples used as technical replicates) extracted from different colonic locations from 45 patients (CD=13, UC=20, Controls=12) were profiled using Agilent Custom 8x60K format lncRNA expression microarray. In Gencode v15 lncRNA microarray design, each lncRNA transcript is targeted by two probes covering 22,001 lncRNA transcripts corresponding to 12,963 lncRNA genes. In addition, each array contains 17,535 randomly-selected protein-coding targets, of which 15,182 (unique 12,787) correspond to protein-coding genes.