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 Dpp4 genes in fecal samples from CD patients with stenosis, and in vivo colonization with engineered E. coli 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.