Gut microbiota vesicle reprogramming by Ganoderma lucidum polysaccharide alleviates mycoplasmal pneumonia via the gut-lung axis.

Respiratory infections remain a major global health challenge, further compounded by antibiotic resistance. Among these, mycoplasmal pneumonia represents a particularly prevalent and refractory form. Here, using targeted enzymatic fragmentation combined with multidimensional NMR analysis, we resolved the structure of a homogeneous Ganoderma lucidum polysaccharide, GLFP2, and identified β-(1→6)-linked galactosyl motifs as key structural features. Despite minimal systemic absorption, oral GLFP2 alleviated mycoplasmal pneumonia in mice. Instead, GLFP2 reshaped the gut microbiota and functionally reprogrammed gut microbiota-derived extracellular vesicles (GMEVs), whose transplantation alone was sufficient to confer pulmonary protection. Orally administered GMEVs remained bioactive, showed systemic exposure, associated with the lung, and were preferentially taken up by alveolar macrophages. These vesicles activated AMP-activated protein kinase (AMPK) signaling, suppressed the S100A8/A9 inflammatory axis, and limited neutrophil-driven immunopathology. Collectively, these findings identify microbiota-derived vesicles as effectors of gut-lung communication and use a defined polysaccharide to uncover a remote protective mechanism against pneumonia.