Current treatments for chronic obstructive pulmonary disease (COPD) fail to reverse disease progression. In recent years, the role of the "gut-lung axis" and short-chain fatty acids (SCFAs)-metabolites of the gut microbiota-in regulating inflammation in COPD has attracted considerable attention. Shashen Maidong Decoction (SSMDT) is a classic prescription for treating pulmonary diseases; however, whether it ameliorates COPD by modulating the gut microecology and the SCFA/GPRs signaling pathway remains to be elucidated. Furthermore, studies involving elderly patients are lacking.

Based on the gut-lung axis theory, this study aimed to investigate the therapeutic effects of SSMDT on pulmonary function, lung histopathological injury, systemic inflammation, and gut microbiota dysbiosis in aged mice with COPD, and to explore whether these effects are associated with regulation of the gut microbiota, SCFAs, and G protein-coupled receptor 41/43 (GPR41/GPR43)-related signaling in lung tissue.

From March to May 2025, specific pathogen-free (SPF) healthy aged male C57BL/6JNifdc mice, aged 18-20 months, were selected. Ten mice were randomly assigned to the normal group and maintained under routine conditions; the remaining mice were used to establish a chronic obstructive pulmonary disease (COPD) model by cigarette smoke (CS) exposure combined with intranasal instillation of lipopolysaccharide (LPS). After successful modeling, the modeled mice were randomly divided into the model group, Shashen Maidong Decoction low-dose group (SSMDT low-dose group), Shashen Maidong Decoction middle-dose group (SSMDT middle-dose group), Shashen Maidong Decoction high-dose group (SSMDT high-dose group), and positive drug group (dexamethasone). After 8 weeks of continuous intragastric administration, pulmonary function was assessed using a small-animal pulmonary function instrument; histopathological changes in lung tissue were observed and injury scores were evaluated by hematoxylin-eosin (HE) staining; serum levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) , and interleukin 1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA); gut microbiota structure was analyzed by 16S ribosomal RNA (16S rRNA) gene high-throughput sequencing; the contents of SCFAs, including acetate, propionate, and butyrate, in intestinal contents were determined by gas chromatography-mass spectrometry (GC-MS); and the mRNA and protein expression of GPR41 and GPR43 in lung tissue were detected by quantitative real-time polymerase chain reaction (qPCR) and Western blot (WB), respectively.

Compared with the normal group, mice in the model group showed significantly impaired pulmonary function, emphysema, bronchial wall thickening, inflammatory cell infiltration, increased lung histopathological injury scores, and elevated serum levels of IL-6, TNF-α, and IL-1β (all P<0.05). In addition, gut microbial alpha diversity was reduced, the Firmicutes/Bacteroidetes (F/B) ratio decreased, pathogenic bacteria were enriched whereas beneficial bacteria were reduced, SCFAs concentrations in intestinal contents decreased, and the mRNA and protein expression levels of GPR41 and GPR43 in lung tissue were downregulated (all P<0.05). Compared with the model group, SSMDT treatment significantly ameliorated the above abnormalities (all P<0.05). Specifically, pulmonary function improved, lung histopathological injury was attenuated, and serum inflammatory cytokine levels decreased. Moreover, gut microbial diversity increased, the Firmicutes/Bacteroidetes ratio was elevated, beneficial bacteria such as Akkermansia and Bifidobacterium were enriched, SCFAs concentrations in intestinal contents increased, and the mRNA and protein expression levels of GPR41 and GPR43 in lung tissue were upregulated.

Shashen Maidong Decoction effectively improves pulmonary function and alleviates pulmonary inflammation in aged mice with COPD. The underlying mechanisms may involve remodeling the gut microbiota structure and maintaining intestinal microecological homeostasis, thereby suppressing systemic inflammatory responses and regulating the "gut-lung axis" pathway.