Dynamic Gut–Lung Microbiome Interactions Beyond Dysbiosis Across the Course of COPD

Yuan Ren,1 Yiwen Hu,1 Hao Qin,1 Yao Zhang,2 Hui Zhao21Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Hui Zhao, Email hui_zhao@sxmu.edu.cnAbstract: Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory disorder characterized by persistent airflow limitation, progressive functional decline, and recurrent exacerbations. Increasing evidence indicates that microbiome alterations in COPD extend beyond the airways and involve coordinated changes across respiratory and intestinal compartments. Importantly, these alterations are dynamic rather than static, varying across stable disease, disease progression, acute exacerbations, and distinct inflammatory phenotypes. Changes in the gut microbiome are accompanied by alterations in microbial metabolites, particularly short-chain fatty acids and tryptophan-derived metabolites, as well as impaired intestinal barrier integrity and systemic inflammatory responses. Emerging evidence from respiratory samples further suggests that airway microbial functional features and local metabolic alterations may contribute to pulmonary host responses, although respiratory microbial metabolites remain less extensively characterized. Experimental studies further suggest that microbiome-derived signals can modulate neutrophils, macrophages, T-cell balance, and innate lymphoid cells, thereby influencing pulmonary inflammation and tissue injury. Fecal microbiota transplantation studies provide additional evidence that disease-associated microbial communities can modify susceptibility to smoke-induced lung injury, supporting a potential causal contribution of the gut microbiome. Meanwhile, probiotics, dietary fiber, short-chain fatty acid supplementation, macrolides, and traditional Chinese medicine or natural products have shown preliminary microbiome-associated benefits, although clinical evidence remains limited and heterogeneous. This review summarizes dynamic airway and gut microbiome alterations across the course of COPD, integrates current evidence on microbial metabolism, intestinal barrier dysfunction, and immune responses, and evaluates emerging microbiome-related therapeutic strategies. Future studies should prioritize longitudinal multi-compartment sampling, standardized microbiome methodology, mechanistic validation, and adequately powered clinical trials to determine whether microbiome modulation can provide reproducible clinical benefit in defined COPD populations.Keywords: chronic obstructive pulmonary disease, gut–lung axis, microbiota dysbiosis, microbial metabolites, microbiota-targeted interventions