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.

Summary

This translational study shows that plasma TMAO is elevated in ARDS and correlates with inflammation, while exogenous TMAO attenuates vascular leak and neutrophil influx in LPS-induced ALI. Mechanistically, TMAO strengthens endothelial barrier integrity via VAV3 upregulation and Rac1-dependent cortical actin remodelling; VAV3 knockdown abrogates protection.

Key Findings

• Plasma TMAO levels were higher in ARDS patients than in healthy controls and positively correlated with hs-CRP.
• Exogenous TMAO reduced lung vascular leakage and neutrophil infiltration in an LPS-induced ALI mouse model.
• Inhibition of gut microbiome-derived TMAO synthesis aggravated lung injury.
• TMAO upregulated VAV3, promoting Rac1-dependent cortical actin remodelling to enhance endothelial barrier integrity.
• VAV3 knockdown abolished TMAO’s endothelial barrier-protective effects.

Clinical Implications

TMAO or pathways that augment VAV3–Rac1 signaling could be leveraged to preserve pulmonary vascular integrity in ARDS/ALI, supporting biomarker-guided and barrier-targeted interventions pending safety evaluation.

Limitations

• Human cohort size and clinical outcomes beyond biomarker correlations were not reported in the abstract
• ALI model based on LPS may not capture full ARDS heterogeneity; systemic effects of TMAO warrant safety evaluation before clinical translation

Future Directions

Prospective ARDS cohorts to link TMAO trajectories with outcomes, dose–response and safety studies, and cell-specific modulation of VAV3–Rac1 signaling to refine therapeutic windows.