Metabolomics with gut microbiota analysis of podophyllotoxin-mediated cardiotoxicity in mice based on the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan isolated from the traditional Chinese medicine Dysosma Versipellis, with significant anti-tumor activity. However, its cardiotoxicity restricts its clinical application. This study aims to investigate the cardiotoxicity of PPT in mice and its underlying mechanisms based on the concept of toxicological evidence chain (TEC). In this study, alterations in body weight, behavior, and the levels of myocardial enzymes and histopathology in mice were observed. Additionally, microbiome and metabolome were integrated to identify potential microorganisms, metabolic markers and major pathways with correlation analysis. The results indicated that PPT induced pathological changes in mice, including weight loss, diarrhea, alopecia and dehydration accompanied by increased levels of serum myocardial enzymes. The results of microbiome showed that PPT altered the gut microbiota composition, changing the abundance of microbial community. The results of metabolome studies indicated total of 55 differential metabolites were involved in glycine, serine, and threonine metabolism, alanine, glutamate, and aspartate metabolism, purine, pyrimidine metabolism, and steroid hormone metabolism. Integrating the results of microbiome and metabolome, it was concluded that PPT remodeled the gut microbiota composition, which in turn modified the gut microbiota metabolism, affecting amino acid metabolisms, nucleotide metabolism, and steroid hormone metabolism in the heart, potentially leading to energy metabolism disorders, apoptosis, and oxidative stress, ultimately inducing cardiotoxicity.