Tetrastigma hemsleyanum polysaccharides ameliorate inflammatory bowel disease via sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 -mediated gut vascular barrier repair.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder characterized by compromised intestinal barrier integrity. PURPOSE: This study aimed to elucidate the therapeutic mechanisms of Tetrastigma hemsleyanum polysaccharides (THP) in restoring the gut vascular barrier (GVB) via the sphingosine-1-phosphate (S1P)/S1P receptor 2 (S1PR2) signaling axis. METHODS: A dextran sulfate sodium (DSS)-induced murine colitis model and tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-stimulated human umbilical vein endothelial cells (HUVECs) were used. Multiple techniques including laser speckle contrast imaging, transmission electron microscopy, immunofluorescence, Western blotting, Transwell permeability assays, tube formation assays, and gene silencing were employed to evaluate the effects of THP. RESULTS: THP treatment significantly ameliorated clinical symptoms, histopathological damage, and pro-inflammatory cytokine secretion in colitis mice. Specifically, THP preserved GVB integrity by upregulating tight junction proteins (ZO-1, Claudin-1, Occludin) and adherens junction proteins (VE-cadherin, β-catenin) proteins, thereby reducing vascular permeability and suppressing pathological angiogenesis. Mechanistically, THP effectively modulated the S1P/S1PR2 signaling axis, there restoring endothelial homeostasis. CONCLUSION: Collectively, this study demonstrates that THP alleviates IBD by repairing the GVB through the S1P/S1PR2 axis, providing a mechanistic basis for GVB-targeted therapeutic strategies.