P0123Therapy shapes disease: Biologic exposure drives extracellular matrix reprogramming in ulcerative colitis

Abstract Background Biologic therapy may imprint lasting molecular changes in IBD. Given the evolving view of ulcerative colitis (UC) as more than a mucosal disease1 and the higher treatment failure in biologic-experienced patients,2-3 we explored whether bio-naive and bio-experienced UC biopsies display distinct intrinsic molecular profiles. Methods Inflamed colonic biopsies (eMayo ≥ 2; n = 5 bio-naive, n = 5 bio-experienced) were cultured ex vivo for 24 h4 (n = 9/patient), and subsequently RNA-sequenced (NovaSeq 6000; DESeq2). Gene co-expression networks were constructed using Weighted Gene Co-expression Network Analysis (WGCNA) on all samples to identify modules associated with biopsy traits (FDR 0.05). Validation was performed in the TRIESTE-UC5 cohort (eMayo ≥ 2; n = 15 bio-naive, n = 35 bio-experienced). Results Comparison of bio-experienced versus bio-naive UC biopsies revealed 860 up- and 497 downregulated genes, independent of ex vivo treatment (Fig. 1A). Bio-experienced samples showed enrichment of pathways linked to collagen biosynthesis, fibrosis, and extracellular matrix (ECM) organization, with TGFB1, AGT, RRAS2, and TWIST1 identified as top predicted upstream regulators (z 4.5; Fig. 1B). WGCNA identified 20 co-expression modules, of which the brown (r = 0.47, p = 5.1 × 10−5; ECM) and tan (r = 0.56, p = 2.4 × 10−7; angiogenesis/ECM) modules showed the strongest association with biologic exposure (Fig. 1C–E). Both modules were independent of disease duration, and interestingly, the tan module was uniquely associated with biologic exposure. Validation in the TRIESTE-UC4 cohort confirmed enrichment of the bio-experienced gene signature (FDR 0.001), and preservation of key WGCNA modules signatures (FDR 0.001; Fig. 2A–B). Overlapping pathways and predicted upstream regulators in both cohorts, validated TGFB1 and collagen pathway activation in the TRIESTE cohort (Fig. 2C). Similarly, hub genes from the tan module (RAI14, INHBA, ADAM12, TWIST1, RRAS2) were validated (Fig. 2D–E), and hierarchical clustering based on the tan module segregated most bio-experienced samples into a distinct molecular cluster in the independent validation cohort (Fig. 2F). Conclusion Our data reveal intrinsic molecular reprogramming in biologic-experienced UC, marked by persistent activation of ECM and fibrotic pathways independent of inflammation, disease duration, or ex vivo treatment. These findings underscore the need to re-think the definition of UC as a non-fibrotic disease1. Recognizing therapy history as a molecular determinant is essential for interpreting treatment response and designing future translational and preclinical studies. References: 1. Eggermont et al., Lancet Gastro Hep, Online October 2025 2. Ando et al., Crohns Colitis 360; 2024 3. Feagan et al., Clin Gastroenterol Hepatol, 2017 4. Giorio, Arnauts et al., abstract MP564, UEGW, Vienna, 2024 5. Lenfant et al. abstract Tu1744, Gastroenterology 166-5,2024- ISSN 0016-5085 LG and KA are joint first authors Conflict of interest: Mr. Giorio, Lorenzo: Research support from Galapagos NV Arnauts, Kaline: Research support by Galapagos NV Lenfant, Matthias: None Zadora, Ward: No conflict of interest Abdurahiman, Saeed: None to declare Guedelha Sabino, João: Speaker’s fees: Lilly, Pfizer, Abbvie, Ferring, Falk, Takeda, Janssen, Fresenius, and Galapagos. Consultancy fees: Takeda, Pfizer, Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia. Research support: Galapagos, Viatris, and Eurogenerics. JS is supported by a Senior Clinical researcher grant from the Research foundation – Flanders. 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 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, 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.