What question did this study set out to answer?

To investigate the molecular mechanisms underlying different clinical subtypes of perianal fistulising Crohn’s disease and their implications for surgical repair.

January 23, 2026

P0121Molecular Signatures of Epithelial Remodelling Associate with Surgical Repair Feasibility and Ileostomy Risk in Perianal Fistulising Crohn’s disease

Key Points

To investigate the molecular mechanisms underlying different clinical subtypes of perianal fistulising Crohn’s disease and their implications for surgical repair.
Collected paired biopsies from fistula tract and rectal orifice of patients
Performed bulk RNA sequencing to create transcriptomic datasets
Applied Multi-Omics Factor Analysis and hierarchical clustering
Conducted weighed gene co-expression network analysis to define patient subgroups.
Identified three distinct molecular patient subgroups (C1-C3) based on transcriptomic profiles
C1 and C2 showed patterns of epithelial-mesenchymal transition, while C3 exhibited keratinization
C3 patients were significantly more likely to be suitable for surgical repair (TopClass 2a)
C2 subgroup displayed a more aggressive disease phenotype with higher inflammatory scores
C2 subgroup among TopClass 2a patients had a greater risk of requiring ileostomy.

Abstract

Abstract Background Perianal fistulising Crohn’s disease (pCD) affects 20-50% of Crohn’s disease (CD) patients with ∼90% requiring a surgical procedure at least once. The recently proposed TopClass framework provides a pragmatic clinical classification of pCD1. Class 2a denotes patients suitable for repair through medical-surgical management, whereas classes 2b or higher denotes stages where symptom control rather than repair becomes the primary treatment goal. However, the molecular mechanisms underlying these clinical subtypes remain poorly defined. Methods Paired biopsies from two sites - the fistula tract and rectal orifice of 54 unique patients (n = 44 CD, n = 10 Cryptoglandular fistula (CPTGL)), supplemented by longitudinal samples to have a total of 81 profiles (70 CD and 11 CPTGL) - underwent bulk RNA sequencing to generate site paired transcriptomic datasets. Multi-Omics Factor Analysis (MOFA) was applied, followed by hierarchical clustering and weighed gene co-expression network analysis (WGCNA) to characterise patient subgroups. Results Integration and unsupervised clustering of paired fistula and rectal transcriptomes identified three molecular patient subgroups (C1–C3), independent of concomitant proctitis or diagnosis (p 0.05, Fig 1A-C). Molecular characterization of the gene programs revealed distinct epithelial remodelling patterns specific to each patient subgroup. C1 and C2 were both driven by epithelial-mesenchymal transition (EMT) in the fistula but differed in rectal programs where C1 displayed homeostatic glycosylation patterns and C2 exhibited keratinization. However, C3 showed a uniquely different molecular profile in the fistula with strong keratinization signature (Fig 1D) instead of EMT. Notably, C3 patients were significantly enriched for TopClass 2a, indicating suitability for surgical repair (Fig 2A) (p 0.05). Among patients with recent MR imaging available (n = 10: 2a; n = 13: 2b), we observed that the C2 subgroup exhibited higher MAGNIFI-CD2 inflammatory mass sub-score (p 0.05), suggesting a more aggressive disease phenotype (Fig 2B). Consistent with this, of all the TopClass 2a patients, those belonging to C2 molecular subgroup had a significantly increased risk of requiring ileostomy (p 0.05, Fig 2C). Conclusion This study demonstrates a clinically meaningful molecular stratification of pCD by assigning distinct epithelial remodelling signatures—independent of proctitis—to three patient classes. These classes exhibit clear clinical distinctions, separating repair-amenable presentations from more aggressive disease associated with higher inflammatory burden and progression to ileostomy within TopClass 2a. References: 1.Jeroen Geldof, Iqbal N, LeBlanc JF, et al. Classifying perianal fistulising Crohn’s disease: an expert consensus to guide decision-making in daily practice and clinical trials. The Lancet Gastroenterology 7(6):576-584. doi: https://doi.org/10.1016/s2468-1253(22)00007-3 2.Pieter Hindryckx, Vipul Jairath, Zou G, et al. Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2019;157(5):1233-1244.e5. doi: https://doi.org/10.1053/j.gastro.2019.07.027 Conflict of interest: Dr. Abdurahiman, Saeed: No conflict of interest Guedelha Sabino, João: None to declare Verstockt, Sare: Grant: Postdoctoral fellowship of the Research foundation – Flanders (FWO), Belgium Johnson, Kristin: Consultant: Spago Nanomedical Speaker: Siemens Healthineers, Pfizer Shareholder: Sectra Giorio, Lorenzo: Research support from Galapagos NV Arnauts, Kaline: Research support by Galapagos NV Caenepeel, Clara: Speaker fee: Abbvie, Alfasigma Consultancy fee: Alfasigma, Janssen Lenfant, Matthias: None Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Raes, Jeroen: JR has received grants from Beneo, Cargill, Colruyt group, Danone, DSM, J & J, MRM/Prodigest, Nestle, Pfizer, Takeda and VectivBio and has received consulting and/or speaking fees from Aphea, Biofortis, DSM-Firmenich, Ferring, GSK, Janssen Pharmaceuticals, Metagenics, MSD, MRM/Prodigest, Nutricia, Takeda, Tsumura D’Hoore, André Jan Louis: Personal Fees: Takeda, Janssens Vermeire, Séverine: Grant: AbbVie, Pfizer, Takeda, J&J, Galapagos Personal Fees: AbbVie - AbolerIS Pharma - AgomAb - Alimentiv - Arena Pharmaceuticals - AstraZeneca - Avaxia- BMS - Boehringer Ingelheim - Celgene - CVasThera - Dr Falk Pharma - Ferring - Galapagos - Genentech-Roche - Gilead - GSK - Hospira - Imidomics - Janssen - J&J - Lilly - Materia Prima - MiroBio - Morphic - MrMHealth - Mundipharma - MSD - Pfizer - Prodigest - Progenity - Promakhos Therapeutics - Prometheus - Robarts Clinical Trials - Second Genome - Shire - Surrozen - Takeda - Theravance - Tillots Pharma AG - Zealand Pharma - Other: AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer Inc, Galapagos, Mundipharma, Bislenghi, Gabriele: no conflict of interest Verstockt, Bram: - Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. - Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. - Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. - Stock options Vagustim and Thethis Pharma.

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