Gut microbiota combined with metabolomics: Tanshinone IIA alleviates doxorubicin/trastuzumab-induced cardiotoxicity

Objective Although sequential treatment with doxorubicin (Dox) and trastuzumab (Trz) is initially effective in breast cancer patients, its efficacy is often transient due to severe cardiotoxicity. Tanshinone II A (DST II A ), the active ingredient in the traditional Chinese medicine Salvia miltiorrhiza , is known for its cardiovascular benefits. However, its protective role when used alongside anticancer drugs remains unclear. This study aimed to investigate the cardioprotective effects of DST II A in a Dox/Trz-mediated cardiotoxicity model and elucidate its potential mechanism. Methods A Dox/Trz-mediated cardiotoxicity rat model was established by sequential injection of Dox and Trz. The therapeutic effect of DST II A on the cardiotoxicity model was first assessed by monitoring cardiac function parameters, biochemical indicators and pathological changes in heart tissues. Next, 16S rRNA sequencing and non-targeted metabolomics were used to identify the distinct gut microbiota and metabolites of the cardiotoxic rat following DST II A intervention. Finally, the influence of DST II A on the interactive functional information between microbial species, cardiac function indicators and altered metabolites associated with Dox/Trz-induced cardiotoxicity was assessed by Spearman correlation analysis. Results Tanshinone II A significantly improves cardiac dysfunction and pathological alterations induced by Dox/Trz. It can also improve colonic pathological damage caused by Dox/Trz, and can modulate Dox/Trz-induced dysbiosis by increasing the proportion of beneficial bacteria (e.g. Bacteroides ) and reducing the abundance of harmful bacteria (e.g. Ruminococcus and Oscillibacter ). DST II A also reversed Dox/Trz-induced alterations in metabolite levels by regulating tryptophan metabolites, such as 5-hydroxytryptophan, 5-methoxyindoleacetate, formylanthranilic acid, L -tryptophan, and tryptamine. Correlation studies suggested that DST II A alleviated Dox/Trz-induced myocardial dysfunction by modulating the gut microbial community and associated metabolites. DST II A demonstrated protection against Dox/Trz-induced cardiotoxicity in a gut microbiota-dependent manner. Conclusions This study highlights the potential of DST II A from the traditional Chinese medicine Salvia miltiorrhiza Bge. to attenuate Dox/Trz-induced cardiotoxicity through the regulation of metabolic function and gut microbiota composition, providing new insights into the treatment of cardiotoxicity associated with anti-tumor drugs and other metabolic disorders by natural compounds.