The gut microbiota-butyrate axis restores cardiomyocyte autophagy to alleviate Doxorubicin-induced cardiotoxicity

Abstract
Background Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is widely used for treating various malignancies. However, its clinical application is limited by dose-dependent cardiotoxicity (DOX-induced cardiotoxicity, DIC). Recent studies have shown that the gut microbiota and its metabolites may be involved in the occurrence and development of cardiovascular diseases through the 'gut-microbiota-heart axis'. Especially，doxorubicin may affect the structure and function of the gut microbiota due to its potential antimicrobial properties and its gut-damaging side effects, but the molecular mechanisms through which gut microbiota affects DIC remain poorly understood.
Results The results of 16S rRNA gene amplicon sequencing of fecal samples showed that the gut microbiota structure of the C57BL/6 DIC model mice changed. The depletion of gut microbiota by antibiotics partially improved DIC. Fecal microbiota transplantation (FMT) from DOX-treated donors impaired cardiac structure and function in recipient mice. Conversely, control-donor FMT significantly alleviated DOX-induced cardiac dysfunction, whether co-administered or given post-modeling. Mechanistically, we analyzed the metabolomics of fecal samples from mice after DOX administration and identified butyric acid (BA) as a key metabolite. Further experiments have shown that after BA treatment, the fatty acid oxidation levels impaired by DOX was restored meanwhile the glycolysis was inhibited. Besides, it was preliminarily confirmed that this metabolic alteration affects 4-hydroxynonenal (4HNE) and autophagy levels, which in turn affects DIC.
Conclusions The gut microbiota-butyrate axis restores fatty acid oxidation and normalizes glycolytic activity, further enhancing 4-HNE-mediated autophagy as a therapeutic strategy against DIC.
Keywords Doxorubicin, Gut microbiota, Cardiotoxicity, Butyric acid