Jiegeng decoction ameliorates COPD-like pulmonary injury in association with changes in PPARγ expression, arachidonic acid metabolism, and gut microbial composition

Background The Jiegeng Decoction (JGD) is a classic traditional Chinese medicinal formulation that consists of Platycodon grandiflorus (Jacq.) A. DC. and Glycyrrhiza uralensis Fisch. This formulation was first recorded in the “Treatise on Cold Damage and Miscellaneous Diseases” during the Eastern Han Dynasty. Clinically, JGD has been employed as a fundamental prescription in the clinical management of various pulmonary disorders. Unlike previous studies, which focused primarily on the addition and subtraction prescriptions derived from JGD, the present study first sought to investigate the associated mechanisms and identify the principal bioactive metabolites of this foundational prescription for the treatment of chronic obstructive pulmonary disease (COPD)-like pulmonary injury, with particular attention to its underexplored effects on the intestine. Methods A cigarette smoke/lipopolysaccharide (LPS)-induced rat model of COPD-like pulmonary injury was used to assess the effects of JGD on pulmonary and intestinal injury. This assessment utilized histological staining, immunofluorescence, and enzyme-linked immunosorbent assays. To explore and validate the underlying mechanisms and bioactive metabolites, lung transcriptomics, untargeted metabolomics, 16S rRNA sequencing, UPLC‒Q‒Orbitrap‒MS/MS, and LPS-stimulated RAW264.7 macrophages were utilized. Results An animal study revealed that JGD mitigated pulmonary histopathological damage, mucus hypersecretion, and the release of inflammatory cytokines in rats exposed to cigarette smoke/LPS-. Comprehensive transcriptomic and metabolomic analyses suggested that JGD may ameliorate inflammatory responses by modulating arachidonic acid metabolism, potentially through the upregulation of PPARγ expressions. Additionally, JGD alleviated intestinal injury and inflammation, restored the expressions of the barrier-associated proteins MUC2 and ZO-1, and was associated with alterations in the composition of the gut microbiota. Notably, specific microbial taxa were significantly correlated with pathological indicators and arachidonic acid metabolites. A total of 156 JGD-derived metabolites were detected and annotated in JGD, 77 of which were absorbed into the bloodstream. Among these compounds, liquiritigenin (LG) has emerged as a potential bioactive metabolite that can interact with PPARγ. In vitro studies demonstrated that both JGD and LG mitigated LPS-induced inflammation in RAW264.7 cells by restoring PPARγ expressions. Importantly, pharmacological inhibition of PPARγ using GW9662 significantly reduced these protective effects, supporting the involvement of PPARγ signaling in LG-mediated inflammatory regulation. Conclusion JGD may mitigate COPD-like pulmonary injury through a multitarget approach associated with the upregulation of PPARγ expressions, the modulation of arachidonic acid metabolism, the restoration of intestinal barrier-associated protein expression, and changes in the gut microbial composition. The LG within JGD may serve as a bioactive metabolite that contributes to these therapeutic effects.