Microbiota-dependent mechanism of Jianpiyifei II in treating experimental virus-induced acute exacerbation of chronic obstructive pulmonary disease

BACKGROUND: Numerous studies have shown that infections caused by respiratory viruses, particularly influenza A virus, contribute to the triggering and worsening of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, targeted therapies remain lacking. Our previous research indicated that the Jianpiyifei II (JPYF II) formulation, composed of Codonopsis pilosula, Astragalus membranaceus, Bupleurum chinense, Cimicifuga foetida, Atractylodes macrocephala, Vitex trifolia, Cynomorium songaricum, and Prunus persica, may serve as a potential treatment for virus-induced AECOPD, although the precise mechanisms involved remain unknown. PURPOSE: This research sought to explore the effects of JPYF II on AECOPD and uncover the mechanisms driving its action. METHODS: A murine model of AECOPD was established by exposing animals to cigarette smoke and then infecting them with influenza A virus. The efficacy of JPYF II was comprehensively evaluated by assessing cell counts in bronchoalveolar lavage fluid (BALF), histopathologic changes of the lungs, lung function, Micro-CT imaging features of the lungs, and RT-qPCR analysis. Additionally, the intestinal microbiota and metabolites from cecal contents were systematically analyzed using 16S rDNA sequencing, non-targeted metabolomics, and MetOrigin metabolite traceability analysis to explore potential mechanisms of action. Furthermore, a microbiota depletion experiment was performed to demonstrate whether JPYF II's effects depend on gut microbiota. Finally, network pharmacology, western blotting, and transcriptomics analyses revealed the pathways affected by JPYF II. RESULTS: This study found that JPYF II treatment notably reduced the recruitment of white blood cells in both BALF and lung tissue, mitigated pulmonary inflammation, enhanced lung function, and alleviated emphysema. JPYF II also modulated the diversity and composition of intestinal flora, partially reversing dysbiosis in AECOPD mice. It promoted the presence of beneficial bacteria and simultaneously suppressed the growth of pathogenic microbes. These changes were associated with changes in metabolites such as α-ketoglutarate, sphingolipids, and bile acids. Further studies indicated that depleting gut microbiota with antibiotics partially limited the therapeutic effects of JPYF II on AECOPD. This mechanism is associated with the suppression of the Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway. CONCLUSION: JPYF II alleviated pulmonary inflammation, enhanced lung function, and reduced damage to lung structure and viral replication in a virus-induced AECOPD mouse model. The mechanisms involved the improvement of gut microbiota composition. Furthermore, JPYF II suppressed immune responses and the formation of emphysema by inhibiting the JAK-STAT signaling pathway, with these effects being dependent on the gut microbiota.