Molecular characterization of canine steroid-responsive enteropathy using NanoString transcriptomic analysis

Steroid-responsive enteropathy (SRE) is a chronic enteropathy associated with chronic gastrointestinal inflammation and corticosteroid responsiveness, however, its molecular and immunopathogenic mechanisms remain poorly defined. For this study, we characterized the gene expression profile, cell type profile, and signaling pathway of duodenal biopsies from seven dogs with SRE that had similar immunophenotypic profiles. From 800 genes analyzed, 88 genes were significantly differentially expressed (DEGs) (P-Adj ≤ 0.05), with 76 genes upregulated and 12 genes downregulated. The top 10 upregulated DEGs were PIP, CSF3R, MMP1, EGR1, PRF1, PTGS2, CD274, NKG7, CD8A, and CEBPB and the top ten downregulated DEGs were IL17F, ERBB4, TUBB3, CD1E, BLK, NCAM1, ESR2, IL1RL2, CD1A6, TNFSF11. CD8 T-cells, cytotoxic cells, exhausted CD8 T-cells, macrophages, neutrophils, natural killer CD56dim cells, and T helper 1 (Th-1) cells were increased (P < 0.05) in SRE dogs compared to control dogs. These findings are consistent with immune dysregulation, tissue damage, impaired tissue repair, and chronic inflammation in SRE dogs. Pathway enrichment analysis for upregulated genes identified 20 statistically significant pathways (false discovery rate < 0.05), including cytokine-mediated signaling pathways (interleukin (IL)-15 and IFN- γ), adaptive immune response, and negative regulation of IL-12-mediated signaling pathway. The downregulated gene pathways were tumor necrosis factor receptor binding and regulation of the IL-6 production pathway. Our findings suggest that canine SRE is characterized by Th1-associated and cytotoxic immune responses, accompanied by activation of IL-15-, interferon-γ-, and JAK/STAT-related signaling pathways, indicating a coordinated inflammatory network contributing to chronic intestinal inflammation and impaired mucosal homeostasis.