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.

阿霉素（doxorubicin）诱导的心脏毒性的潜在机制已被广泛研究，但迄今仍未完全阐明，且目前尚无有效的心脏保护佐剂可用于预防癌症幸存者出现阿霉素诱导的心脏毒性。膳食锌作为一种必需营养素，对维持机体组织稳态锌水平与肠道稳态至关重要，且可能在锌稳态失调或肠道菌群失调相关疾病中发挥治疗益处。本研究采用比格犬模型与大鼠模型，探究阿霉素诱导心脏毒性的潜在机制，以及二价锌-姜黄素（Zn(II)–curcumin）固体分散体的心脏保护作用。阿霉素可诱导动物出现急性与亚急性心脏毒性，具体表现为体重减轻、心脏功能障碍、组织形态学损伤、心肌细胞凋亡增加，以及炎症与心肌损伤标志物的表达上调。有趣的是，阿霉素诱导的全身与细胞锌稳态失衡，与锌水平及锌相关转运蛋白的失调表现一致。阿霉素处理可显著改变肠道菌群组成，使抑炎细菌丰度降低。此外，阿霉素可下调小肠紧密连接蛋白与溶质载体家族39成员4（SLC39A4）的表达，这可能加剧肠道菌群失调与锌缺乏。值得注意的是，将阿霉素处理大鼠的粪便菌群移植至正常大鼠体内，足以诱发锌稳态失衡与心肌病变。然而，每日给予二价锌-姜黄素固体分散体，可显著逆转阿霉素的上述有害作用。综上，本研究结果表明，阿霉素心脏毒性是通过肠道菌群失调介导的，该过程与锌稳态改变密切相关。二价锌-姜黄素有望成为预防癌症患者阿霉素诱导心脏毒性的潜在治疗药物。