*2.2. Gut Microbiota and Chemotherapy*

Galloway-Pea et al. found a steady decline in the overall microbial diversity over time in the microbiota of AML patients after chemotherapy [33]. They observed an increase in Lactobacillus and a decrease in the anaerobic species *Blautia* [33]. Remarkably, chemotherapy increased the incidence of intestinal domination, a condition in which more than 30% of intestinal bacteria originate from a single taxon. The majority of the dominant incidents were caused by opportunistic pathogenic bacteria, such as *Staphylococcus*, *Enterobacter*, and *Escherichia* [33]. Deng et al. also compared the fecal microbiota composition of 33 healthy controls and 14 colorectal cancer (CRC) patients receiving tegafur and oxaliplatin [34]. Only CRC patients had *Veillonella dispar* in their systems, as opposed to

healthy controls. *Prevotella copri* and *Bacteroides plebeius* were also enriched in chemotherapy patients compared with controls [34]. Another study (*n* = 43) of CRC patients with stages II–IV reported increased ratios of *Bacteroidetes* to *Firmicutes*, *Bacteroidetes*, *Bilophila Comamonas*, *Collinsella*, *Butyricimonas*, *Eggerthella*, and *Anaerostipes*, and decreased ratios of *Morganella*, *Pyramidobacter*, *Proteus*, and *Escherichia-Shigella* following CTX [35]. Diversity and composition of the gut microbiome were compared using feces from patients (*n* = 28) before and after CTX [36]. At the genus level, *Ruminococcus*, *Oscillospira*, *Blautia*, *Lachnospira*, *Roseburia*, *Dorea*, *Coprococcus*, *Anaerostipes*, *Clostridium*, *Collin-sella*, *Adlercreutzia*, and *Bifidobacterium* are significantly less common [36]. To date, there is a paucity of literature elucidating the specific mechanisms by which the gut microbiota may contribute to the development of cardiovascular disease in patients who have undergone chemotherapy, and it is an important limitation of this review. Although some studies have indicated a potential link between changes in the gut microbiome and cardiovascular risk factors, such as inflammation and insulin resistance [37], the exact pathways underlying these changes remain poorly understood. Chemotherapy can cause negative effects on the heart, commonly known as chemotherapy-induced cardiotoxicity, which may lead to various clinical symptoms, such as reduced ejection fraction, cardiac arrhythmias, hypertension, and ischemia/myocardial infarction [38]. These cardiotoxic effects can have a significant negative impact on the quality of life and outcomes of cancer patients. Although several categories of chemotherapy agents have been associated with an increased risk of cardiotoxicity, the underlying mechanisms are not yet fully elucidated. Identifying patients at high risk of cardiotoxicity before treatment and monitoring them closely during and after therapy are critical measures in minimizing the effects of chemotherapy-induced cardiotoxicity on patient outcomes. On the other hand, recent studies suggest that the gut microbiota can indirectly influence the development of chemotherapy-induced cardiotoxicity, through the production of metabolites and other signaling molecules [39]. For instance, specific bacteria in the gut can produce compounds (such as butyrate) that interact with the immune system and modify the expression of genes involved in cardiac function and repair [40]. A growing body of evidence indicates that the gut microbiome plays a significant role in protecting against chemotherapy-induced bloodstream infections. Montassier et al. proposed a microbiota-based predictive risk index model that could potentially be utilized to stratify patients at risk of complications before treatment [41]. This model is based on the observation that microbiome diversity decreases before the commencement of therapy. Moreover, the gut microbiota can influence the metabolism of chemotherapy drugs, which could result in increased toxicity or altered efficacy. For example, Wallace et al. showed that gastrointestinal biota can metabolize the chemotherapy drug irinotecan into a toxic by-product, which, in turn, can cause severe diarrhea in some patients [42]. The researchers identified a bacterial enzyme, beta-glucuronidase, responsible for this process, and demonstrated that inhibiting the enzyme reduced the toxicity of irinotecan in mice [42]. These findings indicate that the microbiota can influence the metabolism of chemotherapy drugs, which may result in increased toxicity or altered efficacy.

Trimethylamine N-oxide (TMAO) is a metabolite that is produced by certain gut bacteria from dietary nutrients, such as choline and carnitine [43]. Chemotherapy-induced changes in the gut microbiota can increase the production of TMAO, which has been linked to an increased risk of atherosclerosis and cardiovascular disease. In addition, TMAO can also be implicated in chemotherapy-induced cardiotoxicity by exacerbating the negative effects of chemotherapy on the cardiovascular system. Research has shown that the composition of gut microbiota can affect the production of TMAO, and that certain gut bacteria are more efficient at producing TMAO than others [44]. Chemotherapy can cause changes in the gut microbiota, leading to an increase in the abundance of bacteria that produce TMAO. This increase in TMAO production can contribute to the development of cardiovascular disease, and may also exacerbate chemotherapy-induced cardiotoxicity [45]. Thus, gut metabolites such as TMAO might serve as a link between gut microbiota-induced cardiotoxicity and chemotherapy-induced cardiotoxicity. In addition, an imbalance in gut

microbiota composition and function can lead to chronic inflammation, oxidative stress, and other factors that can contribute to the development of cardiovascular disease, including cardiotoxicity induced by chemotherapy [43,46]. While the exact mechanisms underlying the relationship between gut microbiota and chemotherapy-induced cardiotoxicity are not yet fully understood, these findings suggest that targeting the microbiome may be a promising strategy for mitigating the cardiovascular side effects of cancer treatment. However, more research is required in order to gain a better understanding of the complex interactions among the gut microbiota, cancer therapies, and cardiovascular health.
