Intestinal epithelial Syndecan-1 maintains mucosal homeostasis in inflammatory bowel disease by enhancingbiofilm formation.

Abstract

Despite the rising global incidence of inflammatory bowel disease (IBD), curative therapies remain unavailable. While our previous work implicated the intestinal proteoglycan Syndecan-1 (SDC1) in IBD-associated barrier dysfunction and inflammation, the underlying mechanism was unclear. This study aimed to elucidate how SDC1 maintains intestinal barrier integrity through interactions with the gut microbiome. In DSS-induced colitis, global knockout of() exhibited exacerbated inflammatory infiltration and greater impairment of barrier structure and function than wild-type (WT). Formation of intestinal organoids was independent of genotype, indicating thatdoes not impair barrier function via disrupting epithelial development. The heightened colitis susceptibility inmice was abolished in the antibiotic-treated pseudo-germ-free models, and transmissible to WT mice via fecal microbiota transplantation. Similar results were reproduced in a germ-free mouse model. Metagenomic sequencing identifiedas the most significantly depleted species uponknockout., SDC1-attached glycosaminoglycans (heparan sulfate (HS) and chondroitin sulfate (CS)) but not the SDC1 core protein promotedgrowth. Prokaryotic transcriptome profiling indicated that HS/CS induces cobalamin biosynthesis in. The critical role of cobalamin as a mediator was confirmed, as its synthetic inhibition significantly diminished the growth-promoting effect of HS/CS. Mechanism studies showed that HS/CS enhanced biofilm formation in, thereby facilitating cobalamin biosynthesis. Oral administration of HS ameliorated DSS-induced colitis and promoted mucosal colonization of, independent of the host genotype. Finally, human IBD biopsies revealed a positive correlation between epithelial SDC1 and mucosalas well as an inverse correlation with bacterial translocation and the number of LPS‑positive cells. Our study elucidates a novel mechanism in which the glycosaminoglycan chains of SDC1 promotecolonization and growth through enhanced biofilm formation and cobalamin synthesis, thereby highlighting the therapeutic potential of HS for IBD and offering a new basis for host-directed microbiota regulation.