Abstract

Background:Refractory ulcerative colitis (rUC) represents a critical therapeutic challenge, with emerging evidence implicating gut vascular barrier (GVB) dysfunction in disease persistence. We investigated whether dysregulation of the endothelial BMP9-ALK1 signaling axis—a pathway not previously studied in UC—is associated with GVB impairment and treatment resistance, and explored its therapeutic potential.Methods:Serum BMP9 and mucosal ALK1 levels were compared across rUC, non-rUC, and healthy cohorts. The therapeutic efficacy of BMP9 was evaluated in DSS-induced murine colitis by examining vascular permeability, histopathology, and inflammatory markers, while mechanistic roles were investigated using human intestinal microvascular endothelial cells.Results:Serum BMP9 levels were significantly reduced in rUC versus non-rUC patients, inversely correlating with post-treatment disease severity (Modified Mayo Score: r = −0.471, 95% CI: −0.618 to −0.293,p< 0.001; UCEIS: r = −0.495, 95% CI: −0.637 to −0.321,p< 0.001). Stratified analyses confirmed that BMP9 deficiency was associated with treatment-refractory status independent of baseline disease severity. Intestinal ALK1 was downregulated in rUC mucosa. In murine DSS-colitis, BMP9 attenuated disease severity, colon shortening, histopathological damage, inflammatory cytokines, and early pro-fibrotic markers (Col1a1, Col3a1, α-SMA). BMP9 activated SMAD1, restored VE-cadherin, and reduced hyperpermeability (FITC-dextran leakage decreased from 10.2-fold to 2.1-fold,p< 0.001). In vitro, BMP9 inhibited TNF-α-induced neutrophil migration and enhanced endothelial tube stability via ALK1.Conclusions:Dysregulated BMP9-ALK1 signaling may contribute to GVB dysfunction in UC. BMP9 supplementation attenuates vascular leakage and inflammation in experimental colitis, identifying a potential therapeutic target warranting further investig