New insights into Inflammatory Bowel Disease-associated fibrosis

Fibrosis is a pathological repair response to chronic or persistent tissue injury, characterized by excessive extracellular matrix deposition and disruption of normal architecture. In the intestine, it represents a major complication of inflammatory bowel diseases (IBD), occurring in both Crohn’s disease (CD) and ulcerative colitis (UC), although with greater frequency and severity in CD. Once established, intestinal fibrosis can lead to stricture formation, obstruction, and the need for surgical intervention. Despite its clinical relevance, the molecular mechanisms driving intestinal fibrogenesis remain incompletely defined, and no specific antifibrotic therapies are currently available. The overarching goal of this thesis was to provide a broader and more dynamic understanding of fibrogenesis as an active process, tightly regulated at both transcriptional and translational levels. We developed an inflammation-driven fibrosis model using intestinal organoids derived from biopsies of CD and UC patients, and healthy controlsto recapitulate the interaction between inflammation and tissue remodeling. Stimulation with TNF-α and TGF-β1 reproduced key fibrotic features and revealed a distinct CD-associated transcriptional signature enriched in nuclear regulators, highlighting intrinsic differences across IBD subtypes. In parallel, we evaluated the anti-inflammatory and antifibrotic potential of the natural compounds Scutellaria baicalensis Georgi and Boswellia serrata in intestinal epithelial cells and fibroblasts. Both extracts attenuated pro-inflammatory and fibrotic markers and modulated ZNF281, a central transcription factor linking epithelial–mesenchymal transition to fibroblast activation. Finally, we explored translational control as a regulatory layer of intestinal fibrogenesis, showing that ZNF281 may influence protein synthesis through modulation of eIF4EBP1 and eIF4EBP2, suggesting a connection between transcriptional and translational networks during fibrosis. Taking advantage of multiple and complementary approaches, this work proposes an integrated view of intestinal fibrogenesis, identifying novel experimental tools, mechanistic insights, and potential therapeutic strategies aimed at preventing or mitigating fibrotic complications in IBD.