Table 1_Indole-3-acetic acid derived from Blautia protects against sepsis-induced acute lung injury.docx

ObjectivesSepsis-induced acute lung injury (SI-ALI) significantly contributes to sepsis mortality, with CD8+ T cell depletion being a critical pathogenic factor. While Blautia, a gut commensal bacterium with established probiotic benefits in diverse diseases, its role in SI-ALI pathogenesis remains undefined. Here, we investigated the therapeutic potential of Blautia in lethal SI-ALI.
MethodsGut microbiome profiling was performed in SI-ALI patients and healthy controls to identify disease-associated microbial alterations. A cecal ligation and puncture (CLP) rat model of sepsis was used to validate microbiota changes and evaluate the therapeutic effects of Blautia supplementation. Untargeted metabolomic analysis was conducted to identify key metabolites associated with Blautia. Functional studies were performed to assess lung injury, immune responses, CD8+ T cell abundance, and survival following Blautia or metabolite administration.
ResultsGut microbiome analysis identified significant Blautia depletion in SI-ALI patients compared to healthy controls. This pathogenic alteration was faithfully reproduced in cecal ligation and puncture (CLP) -modeled septic rats, in which Blautia supplementation attenuated lung injury, enhanced systemic immune responses,and improved survival. Untargeted metabolomic profiling identified indole-3-acetic acid (IAA) as a key Blautia-derived metabolite. Administration of IAA alone recapitulated the protective effects of Blautia, significantly ameliorating SI-ALI. Crucially, both interventions restored CD8+ T cell populations and augmented their functional responses. Clinical analysis revealed that elevated Blautia abundance in sepsis patients inversely correlated with pulmonary injury severity and positively associated with augmented CD8+ T cell effector functions.
DiscussionOur findings establish that Blautia and Blautia-derived IAA mitigates SI-ALI by counteracting CD8+ T cell depletion and dysfunction, highlighting a novel and promising mechanism-based therapeutic strategy for life-threatening sepsis.