Yupingfeng powder attenuates influenza A virus induced lung injury via gut microbiota-dependent modulation of branched-chain amino acid metabolism and macrophage polarization

Beyond respiratory effects, Influenza A virus (IAV) infection disrupts intestinal homeostasis. We observed gut microbiota dysbiosis in individuals with influenza. While Yupingfeng powder (YPF) modulates gut microbiota, the mechanisms of microbial mediation require systematic study. Here, we show that preventive administration of YPF alleviated IAV-induced lung injury in mice, improved lung macrophage polarization imbalance, modulated gut microbiota composition, and downregulated gut branched-chain amino acids (BCAA) levels. Depletion of gut microbiota using an antibiotic cocktail attenuated the protective effects of YPF, which were subsequently restored following the transplantation of YPF-associated gut microbiota. Mechanistically, YPF regulated lung macrophage polarization and alleviated IAV-induced lung injury by modulating gut microbiota and BCAA metabolism. Furthermore, we identified Parabacteroides goldsteinii and Lactobacillus johnsonii as the key gut bacteria through which YPF exerted its effects. We confirmed that preventive intervention with these gut bacteria can alleviate IAV-induced lung injury and downregulate BCAA levels in the gut and lungs. Our findings provide new mechanistic insights into the therapeutic potential of YPF through gut microbiota-dependent modulation of BCAA metabolism and macrophage polarization in preventing IAV infection.