BACKGROUND: Biglycan (BGN) is a small proteoglycan rich in leucine, which plays a crucial role in the excessive production of extracellular matrix (ECM) and its association with fibrosis across various organs. Nevertheless, the precise contribution of BGN to intestinal fibrosis remains undisclosed. This study aimed to investigate the role and mechanism of BGN in intestinal fibrosis. METHODS: Human Crohn's disease (CD) tissue samples were obtained from patients with Crohn's disease who underwent surgical resection of the intestine and were categorized as stenotic/nonstenotic regions. A dextran sodium sulfate (DSS)-induced mouse model of intestinal fibrosis was established. Bgn-/0 (BGN KO) mice and primary human intestinal fibroblasts were applied for the study of experimental fibrosis. Coimmunoprecipitation, immunofluorescence staining, western blot, and qRT-PCR were conducted to identify the regulatory effects of BGN on bone morphogenetic protein-7 (BMP-7) expression and intesinal fibrosis. RESULTS: In both human CD samples and the DSS-induced mouse model of intestinal fibrosis, we observed a significant upregulation of BGN in areas activated by fibrosis. The genetic deletion of BGN resulted in the alleviation of intestinal fibrosis in mice administered DSS. The knockdown of BGN through siRNA significantly attenuated TGF-beta1-induced ECM deposition and fibroblastic activation in primary human intestinal fibroblasts. Mechanistically, BGN directly interacted with and negatively regulated the anti-fibrotic protein BMP-7. Rescue experiments demonstrated that BGN facilitated intestinal fibrosis by modulating Smad1/5/8 phosphorylation and activating ECM deposition. CONCLUSION: Our data indicate that BGN deficiency inhibits intestinal fibrosis through activation of the BMP-7-Smad1/5/8 signaling pathway. BGN and BMP-7 may become new biomarkers of intestinal fibrosis and novel targets for disease prevention and treatment.