Investigating the Mechanism of Pulmonary Toxicity in SD Rats Mediated by the Microbiota-Gut-Lung Axis Due to Podophyllotoxin Based on the Concept of the Toxicological Evidence Chain (TEC)

Podophyllotoxin (PPT), widely utilized as an antitumor lead compound, is limited in clinical application due to its inherent pulmonary toxicity, whose mechanisms remain elusive. This study leverages the novel "Toxicological Evidence Chain" theory pioneered by our team to explore the potential involvement of the "Gut-Lung Axis" in PPT-induced pulmonary toxicity. PPT exposure disrupts both intestinal and pulmonary microbiomes, with a significant enrichment of Morganella in the pulmonary microbiota, which negatively correlates with beneficial metabolites such as Propanoic acid, Hexanoic acid, Butanoic acid, and Acetic acid, and probiotics like Marvinbryantia and Enterorhabdus, while showing a significant positive correlation with pathogens Escherichia-Shigella and Bilophila. The substantial enrichment of Morganella leads to imbalances in the abundance and diversity of major bacterial phyla and genera in the lung microbiome, triggering downstream immune responses and abnormalities in short-chain fatty acid metabolism, potentially leading to pulmonary toxicity. This study offers new insights into the mechanisms of PPT-induced pulmonary toxicity, highlights the role of the "Lung-Gut Axis," and provides avenues for therapeutic intervention.