UNRAVELLING A HIDDEN SUBTYPE: MULTIOMICS REVEAL PSORIASIS-LIKE SIGNATURE WITH SURGICAL RELEVANCE IN A SUBSET OF PERIANAL FISTULIZING CROHN’S DISEASE
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Background and aims
Perianal fistulizing Crohn’s disease (pCD) affects 20% of patients with Crohn’s disease (CD) and severely impacts quality of life. Current therapies fail to provide sustained relief, and the molecular underpinnings of pCD remain poorly understood. This study aimed to elucidate the molecular landscape of perianal fistulas through multiomic profiling.
Methods
Paired fistula-tract and adjacent rectal mucosal biopsies were collected from 63 patients (48 with pCD, 15 with cryptoglandular fistula [CPTGL]). Longitudinal sampling generated 101 unique molecular profiles, comprising of both RNA sequencing (RNA-seq) and 16S rRNA sequencing from both tissue sites, followed by integrative multiomics and gene network analyses.
Results
Unsupervised clustering revealed three patient clusters primarily defined by host gene expression, with minimal contribution from microbial profiles. Fistulae in clusters 1 and 2 showed strong immune activation and epithelial–mesenchymal transition (EMT). In contrast, cluster 3 fistulae displayed keratinization and metabolic reprogramming resembling psoriatic skin, together with reduced JAK–STAT signalling. Cluster 3 was enriched for patients classified as TOpClass:2a, who are more suitable for surgical repair (p = 0.02). Conversely, cluster 2, characterized by rectal keratinization and EMT in both fistula and rectum, showed the highest MRI inflammatory-mass score (p = 0.02) and a greater risk of subsequent ileostomy (Kaplan–Meier; p = 0.008). An independent RNAseq dataset validated the keratinization signature in a subset of pCD fistulae.
Conclusion
Integrated multiomic analysis identified distinct molecular subtypes of pCD with surgical and therapeutic relevance. These findings refine the molecular understanding of pCD and support a precision medicine approach.
What You Need to Know?
BACKGROUND AND CONTEXT
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Perianal fistulas affect 1 in 5 Crohn’s disease patients and have a severe negative impact on the quality of life of the patients.
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Most advanced IBD therapies are not efficacious for perianal Crohn’s disease.
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Surgical repair is not suitable for all patients.
NEW FINDINGS
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This study is the first to delineate molecularly defined patient subtypes in perianal fistulizing Crohn’s disease. It further characterizes a psoriasis-like keratinization program in a subset of fistulas. Finally, it identifies molecular features and histological indicators that may explain-and potentially help predict-favorable surgical outcomes in selected patients
LIMITATIONS
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Functional and mechanistic studies will be required to further dissect the drivers and dynamics of the epithelial remodeling identified.
CLINICAL RESEARCH RELEVANCE
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Raises the possibility of refining of existing clinical stratification using molecular markers for improved therapeutic management and outcome.
BASIC RESEARCH RELEVANCE
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Proposes keratinization as an opposing molecular process to EMT within the perianal fistula tract.
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Identifies robust gene signatures associated with EMT and keratinization in the fistula for further experimental and clinical studies.
