Abstract Background Intestinal fibrosis is a major cause of stricturing complications in Crohn’s disease (CD), yet no approved therapy directly targets fibrotic progression. The cellular and microbial drivers that irreversibly push mucosal healing toward fibrosis remain incompletely understood. Methods We integrated fibrosis-focused bioinformatics, clinical stenotic tissue profiling, DSS-induced fibrotic mouse models, HIMF functional assays, metagenomic sequencing, and engineered E. coli overexpressing microbial DPP4. Therapeutic interventions targeting host DPP4 (sitagliptin) and microbial DPP4 (Dau-d4) were evaluated alone and in combination. Results DPP4 emerged as a central, convergent, and previously underappreciated fibrotic amplifier. DPP4 expression was profoundly increased in stenotic CD lesions and experimental fibrosis. Both membrane-bound DPP4 and soluble DPP4 acted as potent fibroblast activators, triggering PI3K–AKT signaling and driving an aggressive profibrotic program characterized by enhanced HIMF proliferation, migration, and extracellular matrix deposition. Strikingly, metagenomic sequencing revealed a fibrosis-associated expansion of microbial Dpp4 genes, and in vivo colonization with engineered E. coli overexpressing microbial DPP4 precipitated rapid collagen accumulation and accelerated fibrotic remodeling, demonstrating that the microbiota can supply an additional, independent fibrogenic DPP4 source. Therapeutically, pharmacologic inhibition of host or microbial DPP4 each mitigated fibrosis, but dual-source blockade produced a synergistic antifibrotic effect, markedly suppressing collagen deposition and reversing fibroblast activation to a degree unattainable by single-source inhibition. Conclusion This study reveals DPP4 as a dual-origin, dual-form master regulator of intestinal fibrosis, acting simultaneously through host epithelium/immune cells and the gut microbiota. By demonstrating that microbial DPP4 is not merely correlative but causally suffices to accelerate fibrosis, and that combined targeting of host and microbial DPP4 yields superior therapeutic benefit, our work establishes dual-source DPP4 inhibition as a powerful, mechanism-guided strategy to prevent stricture formation—directly addressing one of the most critical unmet needs in Crohn’s disease. Conflict of interest: Li, Jiajia: No conflict of interest Wang, Mingyuan: No conflict of interest Zhang, Hongjie: No conflict of interest
Li et al. (Thu,) studied this question.
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