A first-in-class orally available DC-SIGN agonist octaparin alleviates TNBS-induced colitis by preserving gut barrier integrity

Disruption of the intestinal epithelial barrier is a hallmark of inflammatory bowel disease (IBD), and pharmacological interventions that promote mucosal healing without systemic adverse effects represent an unmet clinical need. Here, we investigated the therapeutic potential and underlying mechanism of octaparin, a rationally designed synthetic heparin-like octasaccharide with defined chain length and fixed molecular weight, in a murine model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Oral administration of octaparin significantly ameliorated disease severity, as evidenced by attenuated body weight loss, improved histopathological scores, reduced colonic myeloperoxidase activity, and decreased pro-inflammatory cytokine production, without provoking bleeding complications. Octaparin treatment robustly reinforced intestinal barrier function, demonstrated by increased expression of tight-junction proteins and reduced mucosal permeability to fluorescein isothiocyanate (FITC)-dextran. Mechanistically, we identified that octaparin acts as a specific ligand for Dendritic Cell-Specific ICAM-3-Grabbing Non-Integrin (DC-SIGN) expressed on intestinal epithelial cells. Engagement of DC-SIGN by octaparin triggered a protective signaling cascade that suppressed pathological Reactive Oxygen Species (ROS) accumulation, reduced epithelial cell Apoptosis. Furthermore, octaparin administration favorably modulated the gut microbiota composition, enriching beneficial commensals while reducing the abundance of potential pathobionts. Collectively, these findings establish octaparin as a first-in-class, orally available DC-SIGN agonist that effectively uncouples mucosal healing from anticoagulant activity. This study highlights the therapeutic potential of targeting DC-SIGN with engineered oligosaccharides of uniform size as a novel pharmacological strategy to restore gut homeostasis in IBD, with implications for the development of structurally defined carbohydrate-based therapeutics..