New insights into perianal fistulising CD pathogenesis may lead to new therapies

Perianal fistulising Crohn’s disease (CD) was associated with increased interferon (IFN)-γ expression and response in fistula tracts and luminal mucosa, probably driven by IFN-γ and Th17 cells. Also, heightened IFN-γ and tumour necrosis factor (TNF)-α signalling may promote epithelial-mesenchymal transition in perianal CD.

“Perianal fistulising CD has different mucosal cell responses compared with idiopathic perianal fistulas or CD without perianal disease,” explained Dr Siyan Cao (Washington University, MO, USA) [1]. “Some pathogenic pathways may become therapeutic targets for perianal CD.”

The study collected biopsies from the rectum, fistula tracts, and fistula openings of patients with perianal CD, idiopathic fistulas, and CD without perianal disease. Using single-cell RNA sequencing, the investigators aimed to examine the pathogenesis of perianal CD and identify potential therapeutic targets for this disease.

The study revealed several key findings. Perianal CD was associated with enhanced IFN-γ and TNF-α responses in fistula tracts and luminal mucosa of the rectum, colon, and terminal ileum. Additionally, rectal epithelial cells expressed elevated IFN-γ responsive genes in patients with active perianal CD. It was also found that the increased IFN-γ and TNF-α response may drive epithelial-mesenchymal transitioning in perianal CD. Th17 cells were found to express heightened IFN-γ levels in perianal CD fistulas, while immunohistochemistry showed upregulated IFN-γ and p-STAT1 in perianal CD fistula tracts.

“We are currently working on expanding our research and considering testing IFN-γ antagonists in animal models of perianal CD,” Dr Cao concluded.

1. 
   
   1. Cao S, et al. Pathogenesis and therapeutic targets of perianal fistulizing Crohn’s disease by multi-omics analysis. LB08, UEG Week 2024, 12–15 October, Vienna, Austria.

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Posted on 28 November 2024