Gut microbiota-derived trimethylamine-N-oxide protects pulmonary vascular barrier integrity via Vav guanine nucleotide exchange factor 3 (VAV3)-mediated cytoskeletal remodelling in acute lung injury.

BACKGROUND AND PURPOSE: Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterised by increased pulmonary capillary permeability, but lack effective pharmacotherapies. Emerging evidence implicates gut-lung axis dysregulation in ARDS pathogenesis through microbiome-host interactions, but the specific role of the microbiota-derived metabolite, trimethylamine-N-oxide (TMAO), remains unclear.

EXPERIMENTAL APPROACH: Plasma TMAO and hypersensitive C-reactive protein (hs-CRP) levels were measured in ARDS patients and healthy controls. A lipopolysaccharide (LPS)-induced ALI mouse model was employed to evaluate the effects of TMAO administration versus the inhibition of its gut microbiome-derived synthesis. In vitro, the necessity of VAV3 in the mechanism of TMAO was confirmed using gene knockdown techniques to assess endothelial barrier integrity.

KEY

RESULTS

Plasma TMAO levels were significantly elevated in ARDS patients compared with healthy controls, and showed a positive correlation with hs-CRP. In the murine ALI model, TMAO administration reduced lung vascular leakage and neutrophil infiltration, whereas inhibiting its synthesis worsened the injury. Mechanistically, TMAO enhances the integrity of the endothelial barrier by up-regulating VAV3, which in turn drives Rac1-dependent cortical actin reorganisation. Knockdown of VAV3 abolished the protective effects of TMAO on the endothelial barrier integrity.

CONCLUSION AND IMPLICATIONS: This study identifies TMAO as an adaptive mediator within the gut-lung axis that mitigates pulmonary vascular hyperpermeability. The protective mechanism operates via the VAV3-Rac1-cytoskeletal signalling pathway, highlighting the therapeutic potential of TMAO in ALI/ARDS.