Preventive administration of ethanol extract of Atractylodes lancea (Thunb.) DC. attenuates Staphylococcus aureus-induced lung-gut injury in mice: explanatory pharmacological evidence related to its traditional dampness-resolving use.

Atractylodes lancea (Thunb.) DC. (A. lancea), a major botanical source of Atractylodis Rhizoma, has traditionally been used to dry dampness, strengthen the spleen, dispel wind-dampness, and regulate disorders associated with phlegm and impaired fluid transformation. However, the modern pharmacological basis linking these traditional indications to measurable lung-gut pathological changes remains insufficiently clarified. This study aimed to evaluate whether preventive administration of the ethanol extract of A. lancea (EEA) could attenuate Staphylococcus aureus-induced acute lung injury (ALI) in mice and to explore whether pulmonary edema, MUC5AC upregulation, intestinal barrier impairment, gut microbiota disturbance, and histidine metabolic remodeling may provide explanatory pharmacological evidence related to its traditional dampness-resolving and spleen-strengthening use. The chemical profile of EEA and its absorbed prototype constituents in plasma were characterized by UPLC-Triple TOF-MS/MS. Female BALB/c mice were orally administered EEA for 15 consecutive days and then challenged intranasally with Staphylococcus aureus. Lung injury, pulmonary edema, MUC5AC expression, inflammatory responses, MPO activity, hematological changes, intestinal barrier damage, and gut microbiota composition were evaluated using histopathological staining, lung wet/dry weight ratio, qRT-PCR, ELISA, blood cell analysis, and 16S rRNA sequencing. Untargeted metabolomics of serum and lung tissues, molecular docking, qRT-PCR validation of histidine metabolism-related genes, and correlation analysis were further performed to explore pathways associated with EEA intervention. A total of 29 compounds were identified in EEA, and six prototype constituents were detected in plasma after oral administration of EEA. Staphylococcus aureus challenge induced lung inflammatory injury characterized by increased lung index, elevated lung wet/dry weight ratio, inflammatory cell infiltration, pulmonary pathological damage, increased MUC5AC expression, increased IL-6 and TNF-α levels, and decreased IL-10 levels. EEA attenuated these pulmonary abnormalities, reduced edema-related injury, decreased MUC5AC upregulation, and suppressed lung MPO activity. In parallel, EEA ameliorated intestinal pathological damage, restored mucin- and tight-junction-related gene expression, and partially modulated gut microbiota composition. Integrated serum and lung metabolomics consistently indicated that histidine metabolism was markedly perturbed in model mice and modulated by EEA intervention, as reflected by changes in L-histidine, histamine, N-methylhistamine, and methylimidazoleacetic acid. Molecular docking, qRT-PCR validation, and correlation analysis provided additional association-based evidence that histidine metabolic remodeling was correlated with the preventive effects of EEA. EEA attenuated Staphylococcus aureus-induced lung-gut inflammatory injury in mice, which was associated with its suppression of inflammatory responses, protection of intestinal barrier function, partial modulation of gut microbiota composition, and remodeling of histidine metabolism. These findings provide explanatory pharmacological evidence relevant to, rather than direct validation of, the traditional dampness-resolving and spleen-strengthening use of A. lancea.