Fibrosis in Crohn’s Disease: Emerging Pathophysiological Mechanisms and New Therapeutic Targets

Crohn’s disease (CD) is a chronic immune-mediated inflammatory disorder characterized by transmural inflammation and a progressive course that frequently leads to structural complications such as intestinal fibrosis. Fibrostenosing disease represents a major clinical challenge, affecting up to 50% of patients over time and often requiring surgical intervention. Despite advances in anti-inflammatory therapies, no effective treatments currently exist to prevent or reverse established fibrosis. Intestinal fibrosis arises from a dysregulated tissue remodeling process driven by excessive extracellular matrix deposition and persistent activation of mesenchymal cells, particularly fibroblasts and myofibroblasts. This process is orchestrated through complex interactions between immune and non-immune cells and mediated by key signaling pathways, including transforming growth factor beta (TGF-β1) and the TL1A/DR3 axis. Genetic susceptibility, notably variants in NOD2 and other fibrosis-related genes, contributes not only to disease risk but also to phenotype progression. Epigenetic mechanisms, particularly microRNAs such as the miR-29 and miR-200 families, further modulate fibrogenesis and represent promising non-invasive biomarkers. Additionally, intestinal dysbiosis and specific microbial signatures, including reduced short-chain fatty acid-producing bacteria and the presence of adherent-invasive Escherichia coli, play a critical role in promoting fibrotic pathways. Mesenteric adipose tissue, especially creeping fat, also contributes to fibrosis through immune and metabolic signaling. Emerging biomarkers related to collagen metabolism and advances in molecular profiling are improving early detection strategies. Novel therapeutic approaches targeting fibrogenic pathways, including anti-TL1A agents, show promising preliminary results. A deeper understanding of these mechanisms is essential to develop effective antifibrotic therapies and improve long-term outcomes in CD.