Indole-3-acetic acid derived fromprotects against sepsis-induced acute lung injury.

Abstract

OBJECTIVES: Sepsis-induced acute lung injury (SI-ALI) significantly contributes to sepsis mortality, with CD8T cell depletion being a critical pathogenic factor. While, 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 ofin lethal SI-ALI. METHODS: Gut 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 ofsupplementation. Untargeted metabolomic analysis was conducted to identify key metabolites associated with. Functional studies were performed to assess lung injury, immune responses, CD8T cell abundance, and survival followingor metabolite administration. RESULTS: Gut microbiome analysis identified significantdepletion in SI-ALI patients compared to healthy controls. This pathogenic alteration was faithfully reproduced in cecal ligation and puncture (CLP) -modeled septic rats, in whichsupplementation attenuated lung injury, enhanced systemic immune responses,and improved survival. Untargeted metabolomic profiling identified indole-3-acetic acid (IAA) as a key-derived metabolite. Administration of IAA alone recapitulated the protective effects of, significantly ameliorating SI-ALI. Crucially, both interventions restored CD8T cell populations and augmented their functional responses. Clinical analysis revealed that elevatedabundance in sepsis patients inversely correlated with pulmonary injury severity and positively associated with augmented CD8T cell effector functions. DISCUSSION: Our findings establish thatand-derived IAA mitigates SI-ALI by counteracting CD8T cell depletion and dysfunction, highlighting a novel and promising mechanism-based therapeutic strategy for life-threatening sepsis.