Yang_2026_Front.Microbiol_17_1860203

Dysregulated inflammation and barrier dysfunction are central features of acute lung injury (ALI). Mounting evidence underscores the gut-lung axis as a critical pathway in pulmonary inflammation, yet how specific commensal bacteria confer distal organ protection remains unclear. Here, we demonstrate that the gut commensal Odoribacter splanchnicus elicits marked protection against lipopolysaccharide-induced acute lung injury (ALI) in mice, primarily through its extracellular vesicles (O-EVs). Depletion of O. splanchnicus exacerbated pulmonary damage and inflammatory cytokine release, whereas restoration of its abundance or administration of purified O-EVs significantly attenuated lung injury. Integrated transcriptomic and proteomic analyses identified caveolin (Cav1) and carboxylesterase 1d (Ces1d) as critical host targets of O-EVs. We found that O-EVs were associated with enhanced Cav1-Ces1d interaction, which correlated with suppressed activation of NF-kappaB and STAT3 signaling and decreased levels of downstream pro-inflammatory mediators (TNF-alpha, IL-1beta, IL-6, iNOS, SOCS3). Concurrently, O-EVs reduced leukotriene B4 (LTB4) production, indicating restraint of Ces1d-associated lipid inflammatory pathways. Lipidomic profiling revealed that O-EVs are enriched in bacterial sphingolipids and anionic phospholipids with immunomodulatory potential. Collectively, these data indicate that the gut bacterium O. splanchnicus acts as a key regulator of gut-lung axis communication, mediating anti-inflammatory protection in acute lung injury through vesicle-dependent modulation of inflammatory signaling, lipid mediators, and immune responses.