Early Gut-Vascular Barrier Breakdown Precedes Colitis Onset in Murine Models.

BACKGROUND & AIMS: The gut-vascular barrier plays a pivotal role in inflammatory bowel disease pathogenesis. We introduce a novel 3-dimensional multiphoton endomicroscopy approach for real-time and sensitive detection of vascular permeability in the colon to identify colitis-associated vascular changes in the early stages.

METHODS

Using fluorescence-based multiphoton endomicroscopy, we visualized dynamic changes in vascular permeability in vivo during longitudinal observations in different experimental colitis models (dextran sodium sulfate- and T cell transfer-induced colitis). Vascular permeability changes were systematically compared with conventional inflammatory markers, including weight loss, endoscopic scoring, colon length, histopathology, and immune cell infiltration. To assess molecular regulation of barrier functions, the expression of key molecules of vascular (plasmalemma vesicle-associated protein, vascular endothelial cadherin) and epithelial (epithelial cadherin) barriers was investigated during development of colitis at the single-cell level.

RESULTS

Multiphoton endomicroscopy provided unprecedented 3-dimensional visualization of vascular permeability dynamics and showed that vascular dysfunction occurs prior to epithelial barrier breakdown and the detection of traditional inflammatory markers across all colitis models. Distinct spatial vascular permeability patterns strongly correlated with mucosal damage severity, further supporting that early gut-vascular barrier disruption precedes mucosal barrier breakdown. Additionally, this sequence was confirmed at the molecular level, with the vascular upregulation of the transendothelial permeability channel plasmalemma vesicle-associated protein occurring before downregulation of the epithelial barrier molecule E-cadherin.

CONCLUSIONS

Multiphoton endomicroscopy with 3-dimensional imaging demonstrated gut-vascular barrier dysfunction in the very early stages of experimental colitis. Further development of multiphoton endomicroscopy-based vascular permeability analysis for use in routine clinical monitoring of patients may provide new perspectives to improve diagnosis and clinical decision-making in inflammatory bowel disease.