Airway microbiome-host transcriptome networks link microbial dysbiosis to survival outcomes and therapeutic opportunities in severe COVID-19

The lower respiratory tract microbiome may critically influence outcomes in severe COVID-19, yet remains understudied. We analyzed bronchoalveolar lavage fluid from 86 severe patients requiring mechanical ventilation, stratified into two groups. We identified 213 bacteria with differential abundance, 11 bacteria associated with differentially expressed genes, and 39 of them were associated with patient survival. The more serious group exhibited reduced microbial network complexity, suggesting ecosystem disruption. To explore therapeutic potential, we employed our previously published model and predicted that compounds like palbociclib, XMD-1499, RS-17053, and RS-504393 may shift host gene expression favoring beneficial microbial signatures. These results highlight an important link between microbial dysbiosis and COVID-19 severity, offering promising directions for microbiome-informed therapeutic strategies. Our findings underscore the importance of the lung microbiome in modulating host responses and clinical outcomes, and suggest that modulating microbial-host interactions may serve as a novel adjunctive approach in the treatment of severe COVID-19.