<i>Lactobacillus fermentum</i> remodeled the lung microbiota by crosstalk with the gut and lungs and regulated the PI3K–AKT pathway to alleviate acute lung injury

Acute lung injury (ALI) is a syndrome of acute inflammatory lung injury triggered by diverse etiological factors, which can lead to atelectasis, prolonged hypoxemia, severe respiratory distress, and high mortality. There is increasing evidence that the gut microbiota is involved in regulating pulmonary immunity, and the gut-lung axis plays a critical role in pulmonary diseases. The primary objective of this study was to investigate the effect of <i>Lactobacillus fermentum</i> on lipopolysaccharide (LPS)-induced ALI. After the establishment of an LPS-induced ALI model and gavage with <i>L. fermentum</i>, pulmonary edema and inflammatory cell infiltration in mice were significantly reduced. In addition, <i>L. fermentum</i> regulated the gut microecology, restored the gut barrier, remodeled the lung microecology and increased the abundance of Lactobacillaceae through gut-lung cross-talk. Multi-omics results suggested that <i>L. fermentum</i> intervention regulated sphingolipid metabolism and downregulated the PI3K-AKT pathway. Moreover, intervention of lung organoids with the cell-free supernatant (CFS) of <i>L. fermentum</i> significantly reduced LPS-induced autoinflammatory responses and confirmed the down-regulation of the PI3K-AKT signaling pathway. In conclusion, <i>L. fermentum</i> alleviates LPS-induced lung injury by regulating the PI3K-AKT signaling pathway <i>via</i> the gut-lung axis, offering a potential therapeutic approach for ALI.