Effects and mechanism of combination of Platycodon grandiflorum polysaccharides and Platycodon saponins in the treatment of chronic obstructive pulmonary disease rats through the gut-lung axis

Ethnopharmacological relevance: Platycodon grandiflorum (Jacq.) A. DC. (PG), a traditional Chinese medicine that has pharmaceutical and edible value, widely used to alleviate symptoms such as cough, sputum, sore throat, and respiratory diseases in clinical practice. The small molecular compounds, Platycodon saponins (PGS), and the macromolecular Platycodon grandiflorum polysaccharides (PGP) commonly coexist in the decoctions and leaching solutions of PG. However, the therapeutic effect of combination of PGP and PGS in ameliorating lung damage in chronic obstructive pulmonary disease (COPD) remains largely unexplored.

Aim of the study: The objective of our study was to confirm the synergistic effect of PGP and PGS on the treatment of COPD rats, further examining the associated mechanisms pertaining to the gut-lung axis and microbial metabolism.

Methods: In a COPD rat model induced by cigarette smoke and sawdust, efficacy was assessed through various assays encompassing lung index and histomorphology of the colon, small intestine, and lungs. The number of white blood cells in BALF was quantified using Swiss-Giemsa staining to investigate inflammatory cells infiltration in the lungs. Techniques such as immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay, and western blotting were performed to evaluate the relevant expression of proteins in lung and intestine tissues. This aided in unveiling the protective mechanisms of co-administration of PGP and PGS in COPD rats. Additionally, bacterial genomic DNA was isolated and sequenced for intestinal microbiota analysis. Lastly, an in vitro anaerobic culture system was developed to co-incubate PGP and PGS with the objective of exploring the metabolic mechanisms mediated by gut microorganisms.

Results: Our findings indicated that co-administration of PGP and PGS significantly mitigated the infiltration of inflammatory cells and suppressed the lung damage phenotypes in COPD rats, as evidenced by reductions in Hyp, NO, MUC2, and Ly6G. Furthermore, the combination of PGP and PGS notably ameliorated intestinal barrier damage by elevating the expression of MUC2, ZO-1, and ki67, while diminishing inflammatory markers such as CCL20, IFN-γ, and TNF-α. Remarkably, PGP amplified the protective efficacy of PGS against lung inflammatory damage by modulating the mucosal immune interaction between lung and small intestine, reducing intestinal mucosa permeability, and inhibiting the activation of microbial LPS-induced TLR4/NF-κB signaling pathways. Microbiome assays further revealed that PGP combined with PGS displayed the reversal change of gut microbiota in the COPD model. HPLC analysis of PGS and its transformation products in an anaerobic culture system showed that PGP effectively enhanced the microbial metabolism of Platycodin D and Platycodin D3 in vitro.

Conclusions: The synergistic combination of PGP and PGS might alleviate the pulmonary inflammation by mending intestinal barrier damage, modulating the co-immune mechanism of gut-lung axis in COPD rats, and fostering gut microbiota-mediated biotransformation. This innovative approach will contribute to an enhanced understanding of the intricate interactions within the multi-component system characteristic of traditional Chinese medicines. Consequently, it enriches our comprehension of the role of P. grandiflorus in human health care.