Dual-source DPP4 drives intestinal fibrosis in Crohn’s disease: synergistic therapeutic targeting of host and microbiota pathways

Crohn's disease (CD), a chronic inflammatory bowel disorder, often progresses to intestinal fibrosis and stricture, yet no effective anti-fibrotic treatments exist. This study reveals dipeptidyl peptidase 4 (DPP4) as a pivotal driver of fibrosis through bioinformatics analysis, clinical samples, and experimental models. Elevated DPP4 expression was observed in stenotic intestinal tissues of CD patients and dextran sodium sulfate (DSS)-induced fibrotic mice. Mechanistically, both membrane-bound DPP4 and soluble DPP4 (sDPP4) activated human intestinal myofibroblasts (HIMFs) via the PI3K-AKT pathway, stimulating migration, proliferation, and extracellular matrix deposition. Importantly, metagenomic sequencing revealed enrichment of microbial <i>Dpp4</i> genes in fecal samples from CD patients with stenosis, and <i>in vivo</i> colonization with engineered <i>E. coli</i> overexpressing microbial DPP4 exacerbated fibrotic remodeling, confirming microbiota-derived DPP4 (mDPP4) as a pathogenic driver. Furthermore, pharmacological inhibition of host DPP4 (sitagliptin) or selective blockade of mDPP4 (Dau-d4) attenuated fibrosis in murine models, with combined therapy showing enhanced efficacy. These findings underscore the roles of DPP4, originating from both host and microbiota, and existing in membrane-bound and soluble forms, in promoting CD-associated intestinal fibrosis. This study identifies DPP4 as a novel therapeutic target, proposing dual-source inhibition as a promising strategy to prevent stricture formation in CD patients, thereby addressing a critical unmet clinical need.