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Review
. 2024 May 8;22(1):433.
doi: 10.1186/s12967-024-05232-5.

Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions

Chao Huang #  1 , Xiaoxia Li #  2 , Hanqing Li #  3 , Ruolan Chen  1 , Zhaoqing Li  1 , Daisong Li  1 , Xiaojian Xu  1 , Guoliang Zhang  1 , Luning Qin  1 , Bing Li  4   5 , Xian-Ming Chu  6   7
Affiliations
Review

Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions

Chao Huang et al. J Transl Med. .

Abstract

Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

Keywords: Cardiotoxicity; Doxorubicin; Gut microbiota; Interventions; Metabolites; Pathogenesis.

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Conflict of interest statement

There are no conflicts of interests.

Figures

Fig. 1
Fig. 1
Simplified scheme of the molecular mechanism on doxorubicin-induced cardiotoxicity. Oxidative stress and inflammation are considered to be the main molecular mechanisms of DIC. Furthermore, programmed cell death, including apoptosis and ferroptosis, has been revealed to be involved in DIC. DIC is also associated with mitochondrial dynamics abnormalities, which plays an important role in the regulation of cardiac energy balance during physiological or pathological stress, as well as changes in mitochondrial quality control [42]. Abbreviations ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase; AKT, protein kinase B; Ac-CoA, acetyl-coenzyme A; DOX, doxorubicin; ROS, reactive oxygen species; OXPHOS, oxidative phosphorylation; PUFA, polyunsaturated fatty acids; System Xc-, cystine-glutamate antiporter; TFEB, transcription factor EB; TLR, toll-like receptors; NLRP3, NOD-like receptor 3; NADPH, nicotinamide adenine dinucleotide phosphate; The figure was created with Figdraw (https://www.figdraw.com/)
Fig. 2
Fig. 2
The role of gut microbiota and its metabolites in DIC. Gut microbiota dysbiosis destroys the tight junctions, leading to gut bacterial translocation, entry of bacterial components (such as LPS) into the circulatory system, and induction of chronic inflammation by harmful metabolites such as TMAO and pro-inflammatory factors, causing harm to the cardiovascular system via the gut-microbiota-heart axis; Metabolites (like LPS, TMAO) produced by gut microbiota can enter the bloodstream and promote to the TLR4-mediated production of a wide range of proinflammatory response pathway (e.g. NF-κB and NLRP3), thus aggravating the DIC. However, SCFAs play an anti-inflammatory role in this axis. Abbreviations SCFAs, short-chain fatty acids; ROS, reactive oxygen species; TMAO, trimethyl-amine N-oxide; H2S, hydrogen sulfide; LPS, lipopolysaccharides; The figure was created with Figdraw (https://www.figdraw.com/)
Fig. 3
Fig. 3
The potential role of the gut-microbiota-heart axis in the pathogenesis and microbial-targeted interventions in DIC. DIC led to gut microbiota dysbiosis, decreased SCFs, increased pro-inflammatory cytokines and LPS, activated inflammatory signaling pathways (e.g. TLR4 and NF-κb), aggravated DIC. Whereas, microbiota-targeted interventions could alleviate DIC through reverse the microbiota dysbiosis. Probiotics, diet, FMT, and natural phytochemicals alleviate the DIC via improving beneficial microbiota and producing SCFAs. SCFAs modulate immune cells (e.g. T-cells) to release anti-inflammatory cytokine reducing inflammation. Abbreviations: DOX, doxorubicin; YWPC, yellow wine polyphenolic compound; FMT, Fecal microbiota transplantation; ALPP, Arctium Lappa L; GLA, Glabridin; The figure was created with Figdraw (https://www.figdraw.com/)
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