A colon mimetic screening approach reveals Lactobacillus fermentum as a microbiome-based therapy for COPD

Abstract Chronic obstructive pulmonary disease (COPD) remains a major health burden with few effective therapies, particularly for emphysema. The gut–lung axis and microbial metabolites, such as short-chain fatty acids (SCFAs), have emerged as modulators of lung inflammation. We investigated the therapeutic effects of Lactobacillus fermentum HEM20792 (LF), identified through a colon mimetic personalized pharmaceutical meta-analytical screening (PMAS) platform using fecal samples from severe COPD patients. LF and Lactobacillus sakei HEM20224 (LS) were orally administered to smoke-exposed mice, followed by lung function testing, histopathology, RNA sequencing, single-cell transcriptomics, and fecal microbiome/SCFAs analyses. LF attenuated emphysematous changes, improved compliance, and reduced macrophage and IL-17+ lymphocyte infiltration. Single-cell analysis showed restoration of alveolar macrophages and reduction of pathogenic C1q + macrophages, while transcriptomics revealed normalization of NF-κB and arachidonic acid pathways and attenuation of IL-17– and SPP1-associated signaling. LF also increased fecal SCFAs levels. These findings provide preclinical evidence for LF as a promising microbiome-based therapeutic candidate for COPD.