Aromatic Molecular Compatibility Attenuates Influenza Virus-Induced Acute Lung Injury via the Lung–Gut Axis and Lipid Droplet Modulation

<b>Background:</b> Acute lung injury (ALI) is a major cause of death in patients with various viral pneumonias. Our team previously identified four volatile compounds from aromatic Chinese medicines. Based on molecular compatibility theory, we defined their combination as aromatic molecular compatibility (AC), though its therapeutic effects and underlying mechanisms remain unclear. <b>Methods:</b> This study used influenza A virus (IAV) A/PR/8/34 to construct cell and mouse models of ALI to explore AC's protective effects against viral infection. The therapeutic effect of AC was verified by evaluating the antiviral efficacy in the mouse models, including improvements in their lung and colon inflammation, oxidative stress, and the suppression of the NLRP3 inflammasome. In addition, 16S rDNA and lipid metabolomics were used to analyze the potential therapeutic mechanisms of AC. <b>Results:</b> Our in vitro and in vivo studies demonstrated that AC increased the survival of the IAV-infected cells and mice, inhibited influenza virus replication and the expression of proinflammatory factors in the lung tissues, and ameliorated barrier damage in the colonic tissues. In addition, AC inhibited the expression of ROS and the NLRP3 inflammasome and improved the inflammatory cell infiltration into the lung tissues. Finally, AC effectively regulated intestinal flora disorders and lipid metabolism in the model mice, significantly reduced cholesterol and triglyceride expression, and thus reduced the abnormal accumulation of lipid droplets (LDs) after IAV infection. <b>Conclusions:</b> In this study, we demonstrated that AC could treat IAV-induced ALIs through multiple pathways, including antiviral and anti-inflammatory pathways and modulation of the intestinal flora and the accumulation of LDs.