Re-Du-Ning Alleviates Airway-Intestinal Inflammation of COPD Rats by Regulating Glycerophospholipid Metabolism and Modulating Gut Microbiome

Background: Re-Du-Ning (RDN) is a traditional Chinese medicine (TCM) formulation composed of Lonicera japonica, Gardenia jasminoides, and Artemisia annua. Previous in vitro studies have demonstrated that RDN suppresses pro-inflammatory cytokine release in RAW264.7 macrophages and exhibits potential anti-COPD activity; however, its precise molecular mechanism remains elusive. Methods: A rat COPD model was established by combining cigarette smoke exposure and intratracheal instillation of lipopolysaccharide (LPS). Rats were intragastrically administered with gradient doses of RDN to evaluate its in vivo pharmacological efficacy. Untargeted metabolomics and 16S rRNA microbiome sequencing were performed to screen differential metabolites and gut bacterial genera following RDN intervention, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of core metabolic pathways. Further functional validations were conducted via antibiotic-mediated gut microbiota depletion, fecal microbiota transplantation (FMT), targeted glycerophospholipid supplementation, and human clinical cohort datasets from the Gene Expression Omnibus (GEO) to verify the central roles of gut microbiota and glycerophospholipid metabolism. Results: RDN intervention partially improved lung-function impairment and attenuated histopathological changes in the lung and colon in rats with COPD, while simultaneously reducing the levels of IL-1β, TNF-α, and IL-6 in serum, BALF, and feces. Mult-omics analysis further revealed that RDN partially restored glycerophospholipid metabolic profiles and reshaped gut microbiota composition, and a “host phenotype–metabolite–gut microbiota” network was constructed using correlation analysis. Finally, antibiotic depletion and faecal microbiota transplantation (FMT) experiments suggested that an intact gut microbiota is required for the full protective effect of RDN and that part of this effect is transferable by FMT; LPC (14:0) and LPC (16:0) can regulate cytokine release in BEAS-2B cells, and data from the GEO human cohort further validated the role of glycerophospholipid metabolism in COPD. Conclusions: RDN effectively alleviates symptoms in rats with COPD by regulating the gut microbiota and glycerophospholipid metabolism, providing a comprehensive and in-depth understanding of the multisystem regulatory network underlying COPD.