Recombinant BMP9 Reinforces Gut Vascular Barrier in Experimental Colitis.

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 investigation.