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

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.