Dysregulated gut microbiota alters zinc homeostasis conferring doxorubicin-induced cardiotoxicity: protection by Zn(II)-curcumin

The mechanisms underlying doxorubicin-induced cardiotoxicity have been investigated extensively but remain largely unresolved, and no effective cardioprotective adjuvants exist to prevent doxorubicin-induced cardiotoxicity in cancer survivors. Dietary zinc, an essential nutrient, is required to maintain steady-state tissue levels of zinc and intestinal homeostasis, and may yield therapeutic benefits in diseases associated with zinc dysregulation or gut dysbiosis. Here, we adopted a beagle dog model and a rat model to study the potential mechanisms of doxorubicin-induced cardiotoxicity and the cardioprotective effects of Zn(II)–curcumin solid dispersions. Doxorubicin induced acute and subacute cardiotoxicity characterized by body weight loss, heart dysfunction, histomorphological impairments, and increased cardiomyocyte apoptosis, upregulation of markers of inflammation and cardiac injury in animals. Interestingly, doxorubicin-induced systemic and cellular zinc dyshomeostasis was mirrored by dysregulation of zinc levels and zinc-related transporters. Doxorubicin treatment significantly changed gut microbiota composition, with a reduction in inflammation-suppressing bacteria. Moreover, doxorubicin downregulated small intestinal tight junction proteins and SLC39A4, which may contribute to gut microbiota dysbiosis and zinc deficiency. Notably, transferred fecal microbiota from doxorubicin-treated rats to normal rats was sufficient to facilitate zinc dsyhomeostasis and cardiomyopathy. However, daily administration of Zn(II)–curcumin solid dispersions significantly prevented these deleterious effects of doxorubicin. Overall, our findings reveal that doxorubicin cardiotoxicity is mediated through gut microbiota dysbiosis, which is associated with changes in zinc homeostasis. Zn(II)–curcumin may be a promising therapeutic agent for prevention of doxorubicin-induced cardiotoxicity in patients with cancer.