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Emerging evidence implicates gut\u2013lung axis dysregulation in ARDS pathogenesis through microbiome\u2013host interactions, but the specific role of the microbiota\u2010derived metabolite, trimethylamine\u2010N\u2010oxide (TMAO), remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Plasma TMAO and hypersensitive C\u2010reactive protein (hs\u2010CRP) levels were measured in ARDS patients and healthy controls. A lipopolysaccharide (LPS)\u2010induced ALI mouse model was employed to evaluate the effects of TMAO administration versus the inhibition of its gut microbiome\u2013derived synthesis. In vitro, the necessity of VAV3 in the mechanism of TMAO was confirmed using gene knockdown techniques to assess endothelial barrier integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Plasma TMAO levels were significantly elevated in ARDS patients compared with healthy controls, and showed a positive correlation with hs\u2010CRP. 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\u2010regulating VAV3, which in turn drives Rac1\u2010dependent cortical actin reorganisation. Knockdown of VAV3 abolished the protective effects of TMAO on the endothelial barrier integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>This study identifies TMAO as an adaptive mediator within the gut\u2013lung axis that mitigates pulmonary vascular hyperpermeability. The protective mechanism operates via the VAV3\u2013Rac1\u2013cytoskeletal signalling pathway, highlighting the therapeutic potential of TMAO in ALI\/ARDS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70449","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T01:00:20Z","timestamp":1776992420000},"page":"4163-4177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gut microbiota\u2013derived trimethylamine\u2010N\u2010oxide protects pulmonary vascular barrier integrity via Vav guanine nucleotide exchange factor 3 (VAV3)\u2010mediated cytoskeletal remodelling in acute lung injury"],"prefix":"10.1111","volume":"183","author":[{"given":"Xilong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Zhujiang Hospital, Southern Medical University  Guangzhou China"},{"name":"State Key Laboratory of Respiratory 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