Abstract: Background Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with a particularly high prevalence among older adults. Current pharmacological treatments primarily alleviate symptoms but fail to reverse disease progression, underscoring the clinical importance of exploring its underlying therapeutic mechanisms. Objective Based on the gut-lung axis theory, this study aimed to investigate the therapeutic effects of Shashen Maidong Decoction (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, short-chain fatty acids (SCFAs), and G protein-coupled receptor 41/43 (GPR41/GPR43)-related signaling in lung tissue. Methods 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 short-chain fatty acids (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. Results Compared with the normal group, mice in the model group showed significantly impaired pulmonary function, emphysema, bronchial wall thickening, inflammatory cell infiltration, increased lung 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, SCFA 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, SCFA concentrations in intestinal contents increased, and the mRNA and protein expression levels of GPR41 and GPR43 in lung tissue were upregulated. Conclusion 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.

Key words: Pulmonary disease, chronic obstructive, Aged, Shashen maidong decoction, Gut-lung axis, Gut microbiota, Inflammation

摘要： 背景 慢性阻塞性肺疾病（COPD）是常见的呼吸系统疾病，尤其在老年人群中患病率较高。现有治疗主要缓解症状，无法逆转病程，因此深入探讨其治疗机制具有重要意义。目的 基于肺肠轴理论，探讨沙参麦冬汤通过调节肠道菌群、短链脂肪酸（SCFA）及肺组织SCFA受体G蛋白偶联受体41（GPR41）、G蛋白偶联受体43（GPR43）信号通路，改善COPD老年小鼠肺功能、肺组织病理损伤、系统性炎症及肠道菌群紊乱的作用及可能机制。方法 2025年3—5月，选取18～20月龄SPF级健康老年雄性C57BL/6JNifdc小鼠。随机选取10只作为正常组，常规饲养；其余小鼠采用香烟烟雾（CS）暴露联合鼻腔滴注脂多糖（LPS）的方法建立COPD模型。造模成功后，将成模小鼠随机分为模型组、沙参麦冬汤低剂量组（SSMDT低剂量组）、沙参麦冬汤中剂量组（SSMDT中剂量组）、沙参麦冬汤高剂量组（SSMDT高剂量组）、阳性药组（地塞米松）。连续灌胃给药8周后采用小动物肺功能仪检测肺功能，苏木精-伊红（HE）染色观察肺组织病理变化并进行损伤评分，酶联免疫吸附测定（ELISA）检测血清中白介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、白介素-1β（IL-1β）水平，16S核糖体RNA（16S rRNA）基因高通量测序分析肠道菌群结构，气相色谱-质谱联用技术（GC-MS）法检测肠道内容物SCFA（乙酸、丙酸、丁酸）含量，实时荧光定量聚合酶链式反应（qPCR）法及蛋白质印迹法（WB）分别检测肺组织GPR41、GPR43的mRNA及蛋白表达。结果 与正常组比较，模型组小鼠肺功能显著下降，肺组织出现肺气肿、支气管壁增厚及炎性细胞浸润等病理改变，肺损伤评分及血清IL-6、TNF-α、IL-1β水平均升高（P<0.05）；肠道菌群Alpha多样性降低（P<0.05），厚壁菌门/拟杆菌门（F/B）比值降低，致病菌富集而有益菌减少，肠道短链脂肪酸（SCFA）含量降低，肺组织GPR41、GPR43mRNA及蛋白表达下调（P<0.05）。与模型组比较，沙参麦冬汤各剂量组上述指标均改善（P<0.05）：肺功能提升，肺组织病理损伤减轻，血清炎症因子水平降低；肠道菌群多样性提高，F/B比值升高，阿克曼菌属（Akkermansia）、双歧杆菌属（Bifidobacterium）等有益菌富集；肠道SCFA含量升高，肺组织GPR41、GPR43 mRNA及蛋白表达上调。结论 沙参麦冬汤能有效改善COPD老年小鼠的肺功能和肺部炎症，其机制可能为通过重塑肠道菌群结构、维持肠道微生态平衡，从而抑制系统性炎症反应，调节“肺肠轴”通路。

关键词: 肺疾病, 慢性阻塞性；老年人；沙参麦冬汤；肺肠轴；肠道菌群；炎症