**1. Introduction**

Over the past several decades, tremendous efforts have been made to develop a range of treatment options for cancer, including chemotherapy, radiotherapy, immunotherapy, and surgery, all of which have significantly reduced the mortality and morbidity associated with various forms of cancer [1]. Although the benefits of anticancer drugs and therapies are undeniable, safety aspects cannot be overlooked; for example, some treatments have been found to adversely affect the cardiovascular system [2,3]. Cardiotoxicity is a crucial factor to consider for individuals receiving cancer therapy because, even though most patients will recover from cancer, they will then have elevated long-term cardiac risks [4,5]. However, in-depth insights into the underlying molecular mechanisms and causal agents are lacking. Interestingly, a pioneering study including 1526 tumors and their adjacent normal tissues across seven cancer types (breast, lung, ovary, pancreas, melanoma, bone, and brain tumors) reported a distinct microbiome composition specific to cancer types [6]. The authors also correlated bacteria identified in the tumor microenvironment (TME), or their predicted functions, with tumor types and subtypes, smoking status, and response to immunotherapy [6]. Similarly, one of the long-term effects of cancer treatment is a shift in the composition of the gut microbiome, termed gut dysbiosis [7]. Importantly, low-grade chronic inflammation is one of the hallmarks of cardiac diseases and cancers, and is also caused by gut dysbiosis and an altered intestinal permeability barrier. Can the

**Citation:** Kunika; Frey, N.; Rangrez, A.Y. Exploring the Involvement of Gut Microbiota in Cancer Therapy-Induced Cardiotoxicity. *Int. J. Mol. Sci.* **2023**, *24*, 7261. https:// doi.org/10.3390/ijms24087261

Academic Editor: Maria Teresa Mascellino

Received: 8 March 2023 Revised: 4 April 2023 Accepted: 12 April 2023 Published: 14 April 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

gut microbiome be the missing link? Well-directed and thorough research is required to answer these questions.

The microbiome is defined as a collection of all microbial genomes found in a particular environment. Rapid advances in tools and techniques in recent years have provided new knowledge and insights into the interactions between microorganisms and their hosts [8]. Humans and microbes have evolved together, and microbial communities play a significant role in maintaining human health [9]. The number of gut microbiota, the microbial commensal organisms of the gastrointestinal system, exceeds the number of human cells and constitutes the largest surface area for microbial interactions with the host's immune system. In contrast, alterations in the microbial composition of the gut, or gut dysbiosis, play important physiological roles, primarily promoting the accumulation of proinflammatory substances [9]. Moreover, the gut microbiome plays an important role in regulating the risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer [9]. Of additional interest, it has been demonstrated that the gut microbiota co-evolves with the host and lies at the intersection of multiple antitumor and oncogenic metabolic, immune, and inflammatory pathways in cancer [10]. Several studies have highlighted that the connection among gut microbiota, genotoxins, and inflammatory responses to microbiota is associated with carcinogenesis [11]. Along these lines, it has been shown that the gut microbiota can vary the host response to chemotherapy through various mechanisms, including immune interactions, xenometabolism, and alterations in community structure [12]. These and similar findings put forth and support the gut microbiome–cancer axis, and a better understanding of these complex interactions may lead to new and better cancer therapy approaches [13,14].

In this review, we provide an overview of the potential relationship between gut microbiota and cancer treatment-induced cardiovascular toxicity (Figure 1). We also briefly discuss microbial signatures that are either unique or distinctly regulated in cancer therapy and heart diseases. Although thorough and targeted research is lacking in this direction, based on the available data on the microbiome in cancer therapy, we postulate a plausible relationship between treatment-induced microbial changes and long-term effects via the microbiota–gut–heart axis.

**Figure 1.** Among the most severe late side effects of cancer treatment in cancer survivors are cardiovascular problems, including heart failure, myocardial ischemia, hypertension, thrombosis, and

arrhythmias. Based on the current literature, we know that cancer therapy could result in gut dysbiosis. On the other hand, it is also recently reported that gut dysbiosis could worsen the cardiac function. However, we still do not know if and how gut dysbiosis play a role in cancer therapy induced cardiotoxicity (as shown with a question mark in the pictorial representation). Large-scale cancer survivor microbiome research may help identify patients at cardiovascular risk who may benefit from a more specialized microbiota-mediated treatment. Additionally, a deeper understanding of the link between the gut microbiome and cardiotoxicity brought on by cancer treatment may make it possible to lower the likelihood of this major and fatal adverse effect. (This Schematic representation was created using Biorender (https://biorender.com/)).

### **2. Cancer Treatment Efficacy and Toxicity Are Influenced by Gut Microbiota**

Over the past century, tremendous progress has been made in cancer treatment, resulting in improved quality of life and survival for cancer patients. However, these advances in cancer treatment are often accompanied by treatment-related complications, including secondary systemic side effects. Recently, there has been increasing evidence that cancer treatments can disrupt the host immune response, leading to gut dysbiosis, disturbed immune system, and reduced effectiveness of the treatment [15,16]. Several studies have shown that the absence of gut microbiota reduces therapeutic efficacy, suggesting that commensal microbes modulate treatment-induced anticancer immune responses through various mechanisms. Ground-breaking results from animal models demonstrated the importance of commensals in regulating the effectiveness of radiation therapy, chemotherapy, and immunotherapy drugs [17–19]. For example, the intestinal microbiota and the myeloid cells that infiltrate tumors while a patient is receiving platinum-based therapy have been linked together [17]. The current understanding of the relationships among gut bacteria, host reactions, and anticancer medication was analyzed by Huang et al. in 2022 [20], with an emphasis on the immunomodulatory function of microbiota, which supports the effectiveness of immune checkpoint inhibitors. Importantly, this work focuses on the intricate and dynamic relationships between the microbiota and anticancer drugs, as well as the possibility for microbiome-based therapies to potentially enhance the effectiveness of cancer treatment. Huang and colleagues discovered that the gut microbiota affects the pharmacokinetics and pharmacodynamics of anticancer drugs. Furthermore, their work emphasizes the possibility of using microbiota-based therapies, such as probiotics or fecal microbiota transplantation, to increase the efficacy and decrease the toxicity of anticancer medications, as well as the response to immunotherapy. Additionally, anticancer medication response and individualized cancer treatment may be predicted using microbiota-based biomarkers. Nevertheless, additional systematic studies are required in order to completely comprehend the complex connections between the microbiota and anticancer therapies and determine the best methods for modifying the microbiota in order to improve cancer treatment outcomes.

Studying the relationship between microbes and cancer will contribute to a better understanding of the role of microbes in the mechanisms underlying tumorigenesis and other types of cancer, and hopefully improve therapeutic efficacy [21]. Sivan et al. [22] showed that the microbiome could be modulated to alter cancer immunotherapy. An important finding of this study was that *Bifidobacterium* alone could enhance tumor control to a level comparable to that of programmed cell death protein 1 ligand 1 (PD-L1) specific antibody therapy (checkpoint blockage) [22]. Antibodies targeting cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) have been effective in cancer immunotherapy, and specific *Bacteroides* species are required for the anticancer effects of CTLA-4 inhibition [23].

T-cell responses specific to *B. thetaiotaomicron* and *B. fragilis* have been linked to the effectiveness of CTLA-4 inhibition in mice and humans [23]. Nevertheless, thorough research is required in order to fully understand the mechanisms underlying the effects of the gut microbiota on treatment toxicity.

The non-specificity of several chemotherapeutic agents causes damage to healthy, noncancerous cells [24]. Chemotherapy-related toxicities include cardiovascular and metabolic

diseases, secondary cancer, avascular necrosis, cognitive impairment, cancer-related fatigue, poor mental health-related quality of life, nephrotoxicity, hypogonadism, neurotoxicity, pulmonary toxicity, anxiety, and depression. Cardiotoxicity caused by chemotherapy results in severe heart dysfunction, with heart failure (HF) as the most serious outcome. Following radiotherapy or chemotherapy, there is a considerable risk of developing cardiovascular disease (CVD), particularly in individuals with breast cancer and hematological malignancies [25]. Fibrosis, vascular damage, and shrinkage of damaged tissues or organs are examples of chronic toxicities caused by radiotherapy [26]. Although there is a dearth of information about whether and how the microbiota controls the response to radiotherapy, investigations of drug–microbiome interactions have revealed that several chemotherapeutic agents, such as gemcitabine, vidarabine, and etoposide phosphate, have impaired therapeutic efficacy, reduced mouse survival, and increased cytotoxicity [27]. Similarly, according to a previous study [28] pelvic radiation therapy altered the gut microbiota, with a 10% decrease in *Firmicutes* and a 3% increase in *Fusobacterium*. Through several mechanisms, including modulation of immunological responses, the gut microbiota has been shown to influence the efficacy and toxicity of several chemotherapies and immunotherapies [14]. Thus, targeting the microbiota is a potential strategy for increasing the effectiveness of chemotherapy and decreasing its toxicity.

Taken together, these results suggest that the efficacy of cancer therapy and the degree of gastrointestinal toxicity caused by cancer therapy are influenced by gut microbiota. Studies have indicated that gut microbes play an important role in cancer therapy by reversing anticancer effects and modulating the efficacy of drugs that mediate toxicity. These gut microbes may provide new avenues to improve the efficacy, reduce the toxicity of current chemotherapeutic agents, and improve susceptibility to immunotherapy.
