Abstract
H9N2 influenza virus infections represent a significant respiratory health concern, yet the functional role of gut microbiota during infection progression remains poorly understood. Here, we show that H9N2 infection causes dose-dependent alterations in gut microbial communities in a mammalian infection model, particularly the depletion of Prevotella species. Prophylactic administration of Prevotella copri improved survival and clinical outcomes in infected mice by restructuring the gut microbiome, promoting beneficial bacteria, and suppressing pathogens. Metabolomic profiling revealed increased isovaleric acid levels in the intestine and serum. Isovaleric acid pretreatment reduced pulmonary inflammation, alleviated tissue damage, and preserved epithelial integrity. Isovaleric acid pretreatment alleviates lung inflammation, reduces tissue damage, and maintains epithelial integrity. Additionally, isovaleric acid mitigates infection caused by the H1N1 influenza virus. These findings highlight the immunomodulatory role of gut commensals and their metabolites in antiviral defense, offering a new approach to influenza virus treatment.