**6. Gut Microbiota-Derived Metabolites in Cancer Treatment**

Numerous metabolic illnesses, such as obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease, are influenced by the gut microbiome and its metabolites. The maintenance of host physiology depends on communication between microbes and their hosts, which is mediated by metabolites generated by the microbiota [108]. These metabolites have been found to affect both the toxicity and effectiveness of cancer treatment, through modulation of immune processes and protective epithelial functions, respectively (Figure 3). Metabolites such as SCFAs, secondary bile acids, polyamines, lipids, and vitamins are produced by gut microbiota [109]. The colon produces SCFAs, primarily acetate, butyrate, and propionate, from dietary fiber and polysaccharides. The most common bacterial species that produce SCFAs include *Faecalibacterium prausnitzii*, *Clostridium leptum*, *Eubacterium rectale*, and *Roseburia* species, as well as lactate-utilizing species such as *Anaerostipes* and *Eubacterium hallii,* which synthesize SCFAs from lactate and acetate [110]. The regulation of T cell homeostasis has been associated with SCFAs that can control the differentiation of T cells into effector or regulatory (Treg) cells in response to immunological conditions, such as the presence or absence of important cytokines [72] Gut microbial metabolites, including bacteriocins, short-chain fatty acids, and phenylpropanoidderived metabolites, display direct and indirect anticancer activities via different molecular mechanisms [111]. Recent studies have confirmed the differential expression of SCFA in immunotherapy responders compared to non-responders. SCFAs are well known for their anti-inflammatory and antioxidant effects on the host, which help stop the proliferation of cancer cells. Bile acid profiles may change as a result of bacterial bile acid transformation, which may then affect systemic inflammatory and fibrotic processes [72]. In terms of

cancer development and anticancer activity, the mechanisms of the action of gut microbial metabolites are not fully understood.

**Figure 3.** Metabolites produced by the gut microbiota have a key role in controlling the activity of intestinal cells, as well as local and systemic immunological and inflammatory responses. The most effective method for dealing with gut microbiota-derived metabolites and their widespread impacts in order to enhance cancer therapy outcomes will need to be determined. Different colors in circle represent different gut microbes, whereas, different shapes in oval form represent individual metabolite, e.g., star shape for metabolite A, triangle for metabolite B, etc. (This Schematic representation was created using Biorender (https://biorender.com/)).

#### **7. Conclusions**

Patients with cancer endure a variety of immediate and long-term side effects throughout the body, including gastrointestinal- and cardiotoxicity. Preclinical and clinical research, in addition to reports on the link between microbiota and cancer, has revealed that this subject may be a key mediator of how the body reacts to cancer treatment. Clinical trials on a substantial cohort of cancer survivors are urgently needed and may open up novel possibilities for microbiota-mediated therapies to stop or lessen the long-term side effects of cancer therapy. Future therapies may employ techniques that can help achieve more precise manipulation of microbiota composition, such as the relative proportion of a particular bacterial genus in the microbiota. In order to discover dysbiotic conditions linked to negative or poor cancer treatment outcomes and to identify microbial targets that can be modified, personalized biomarkers are urgently needed. Improving the physical well-being of cancer survivors requires a thorough understanding of the microbiota–gut–heart axis and the effects of the changed intestinal microbiome on immunological and metabolic pathways. We can only maximize the regulation of the intestinal microbiota and enhance the potential of cancer treatment by fully comprehending which intestinal bacteria and their metabolic product(s) could be altered. Overall, our review aimed to shed light on the potential complex interplay among the microbiome, cancer treatment, and cardiovascular health, and to identify potential avenues for future research into this important area of study. However, direct evidence supporting proposed postulations and hypotheses is still missing. This lack of significant direct evidence suggests that further research is needed in order to explore the potential effects of gut microbiota and its metabolites in cardiotoxicity, which may lead to new therapeutic opportunities and the identification of predictive biomarkers.

**Author Contributions:** Conceptualization, K. and A.Y.R.; Resources, N.F. and A.Y.R.; Writing original draft preparation, K.; Writing—review and editing, N.F. and A.Y.R.; Supervision, N.F. and A.Y.R.; Funding acquisition, N.F. and A.Y.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) (grant numbers RA 2717/4-1 and FR 1289/17-1).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
