Doxorubicin induced left ventricular dilation, reduced contractility, and altered gut microbiota composition, while depletion of gut microbiota with antibiotics alleviated doxorubicin-induced myocardial injury.
Does gut microbiota depletion alleviate doxorubicin-induced cardiotoxicity in a mouse model?
Gut microbiota composition imbalance and functional changes contribute to doxorubicin-induced cardiotoxicity, and microbiota depletion can alleviate myocardial injury in a mouse model.
Objectives Doxorubicin (Dox), a chemotherapeutic anthracycline agent for the treatment of a variety of malignancies, has a limitation in clinical application for dose-dependent cardiotoxicity. The purpose of this study was to explore the relationship between the composition/function of the gut microbiota and Dox-induced cardiotoxicity (DIC). Methods C57BL/6J mice were injected intraperitoneally with 15 mg/kg of Dox, with or without antibiotics (Abs) administration. The M-mode echocardiograms were performed to assess cardiac function. The histopathological analysis was conducted by HE staining and TUNEL kit assay. The serum levels of creatine kinase (CK), CK-MB (CK-MB), lactic dehydrogenase (LDH), and cardiac troponin T (cTnT) were analyzed by an automatic biochemical analyzer. 16S rRNA gene and metagenomic sequencing of fecal samples were used to explore the gut microbiota composition and function. Key Findings Dox caused left ventricular (LV) dilation and reduced LV contractility. The levels of cardiomyocyte apoptosis and myocardial enzymes were elevated in Dox-treated mice compared with the control (Con) group. 16S rRNA gene sequencing results revealed significant differences in microbial composition between the two groups. In the Dox group, the relative abundances of Allobaculum , Muribaculum , and Lachnoclostridium were significantly decreased, whereas Faecalibaculum , Dubosiella , and Lachnospiraceae were significantly increased compared with the Con group at the genus level. Functional enrichment with Cluster of orthologous groups of proteins (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the Dox mice displayed different clusters of cellular processes and metabolism from the Con mice. The different species and their functions between the two groups were associated with the clinical factors of cardiac enzymes. Moreover, depletion of the gut microbiota could alleviate Dox-induced myocardial injury and cardiomyocyte apoptosis. Conclusions The study here shows that composition imbalance and functional changes of the gut microbiota can be one of the etiological mechanisms underlying DIC. The gut microbiota may serve as new targets for the treatment of cardiotoxicity and cardiovascular diseases.
Huang et al. (2022) studied Doxorubicin-induced cardiotoxicity (n=30). Doxorubicin vs. Control (no treatment) was evaluated on Cardiac function (left ventricular ejection fraction and fractional shortening) and gut microbiota composition. Doxorubicin induced left ventricular dilation, reduced contractility, and altered gut microbiota composition, while depletion of gut microbiota with antibiotics alleviated doxorubicin-induced myocardial injury.