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Single-Cell and Spatial Multi-omics Reveal Interferon Signaling in the Pathogenesis of Perianal Fistulizing Crohn’s Disease

ABSTRACT: Background & Aims: Perianal fistulizing Crohn’s disease (PCD) is a common and debilitating complication with elusive pathophysiology. We examined biopsies from patients with PCD and related conditions using a multi-omics approach. Methods: Patients with PCD (n=24), CD without perianal disease (NPCD, n=10), and idiopathic perianal fistulas (IPF, or cryptoglandular fistulas, n=25) were recruited. Biopsies were taken from fistula tracts, fistula opening, and rectal mucosa during examination under anesthesia or colonoscopy. Single-cell RNA-sequencing (scRNA-seq), mass cytometry (CyTOF), spatial transcriptomics (ST), immunohistochemistry (IHC), and integrated analysis of published datasets were performed. Results: ScRNA-seq, CyTOF, and ST unraveled immune and non-immune cell compartments in PCD and IPF fistula tracts. PCD fistulas showed hyperactivated pathogenic pathways including interferon (IFN)G response, TNF signaling, and IL6-JAK-STAT3 in myeloid cells. Similarly, stromal cells from PCD fistulas exhibited elevated IFNG and TNF response, TNF signaling, and epithelial-mesenchymal transition (EMT). Further analysis revealed cellular modules associated with anti-TNF therapy in PCD patients. In addition to fistula tracts, intestinal cells from PCD patients also expressed greater levels of IFNG-responsive and EMT genes compared to CD patients without perianal disease. In addition, we showed that both fistula tracts and ileal mucosa from PCD patients harbored expanded IFNG+ Th17 cells, which expressed elevated inflammatory mediators. The findings were independently validated using ST and IHC. Conclusion: Multi-omics analysis revealed immune and nonimmune cell landscapes of PCD. and highlights the pathogenic role of hyperactivated IFNG signaling in both fistula tracts and luminal mucosa of patients with PCD. This study identified IFNG as a potential therapeutic target for PCD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277387 | GEO | 2025/06/17

REPOSITORIES: GEO

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Project description:Background: CrohnM-bM-^@M-^Ys disease is presently an incurable inflammatory bowel disease. Fistulae are extensions of the intestinal tract that may form connections with other organs. These are a common complication of CrohnM-bM-^@M-^Ys disease affecting up to 50% of patients with the most common including perianal and rectovaginal fistulae. The dysregulated growth observed in fistulae shares several major characteristics seen in the development of tumours. These similarities include epithelial-to-mesenchymal transition (EMT), invasive cell growth, increased extracellular matrix production and remodelling, up-regulated local expression of growth factors such as IGF-1 and the down-regulation of apoptosis pathways. Although several susceptibility loci have been described within CrohnM-bM-^@M-^Ys disease there is no individual gene or mutation that identifies susceptibility or the subsequent formation of fistulae within all people. Copy-number variation (CNV) is one mechanism that may explain much of this genetic complexity. CNV may be caused by a variety of mechanisms such as cycles of chromosomal breakage/fusion/bridging that are typical within chronically inflamed tissue. Interestingly CNV shows locus-specific mutation rates between individuals higher than that of SNPs and has been associated with complex Mendelian traits including disease susceptibility. In this current study we performed array comparative genomic hybridisation (aCGH) analysis of active fistulae resected from patients as part of a previous surgical intervention. As the control for comparison we employed tissue taken from the same patient within the same surgery at an uninvolved site of the gastrointestinal tract. This matched control was employed to better investigate CNV specific to the fistula tissue of each individual avoiding complications associated with the large number of CNV present within the healthy population. Major question addressed by the work: What are the differences in genetic copy-number within localised intestinal fistula tissue of individuals with CrohnM-bM-^@M-^Ys disease compared to healthy intestinal tissue from the same individual? Samples were selected from patients presenting with CrohnM-bM-^@M-^Ys Disease fistulae at Eastern Health Department of Gastroenterology and Hepatology (Arnold Street, Box Hill, Victoria, Australia). The 8 samples used in this study were formalin-fixed paraffin-embedded (FFPE) specimens following a surgical intervention to remove fistula tissue. To focus on changes within the individual patient we used tissue taken from the same surgery at an uninvolved region of the intestine as the matched control for CNV analysis.

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Single-Cell and Spatial Multi-omics Reveal Interferon Signaling in the Pathogenesis of Perianal Fistulizing Crohn’s Disease

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