Gut Metabolites and Breast Cancer: The Continuum of Dysbiosis, Breast Cancer Risk, and Potential Breast Cancer Therapy

Abstract

The complex association between the gut microbiome and cancer development has been an emerging field of study in recent years. The gut microbiome plays a crucial role in the overall maintenance of human health and interacts closely with the host immune system to prevent and fight infection. This review was designed to draw a comprehensive assessment and summary of recent research assessing the anticancer activity of the metabolites (produced by the gut microbiota) specifically against breast cancer. In this review, a total of 2701 articles were screened from different scientific databases (PubMed, Scopus, Embase and Web of Science) with 72 relevant articles included based on the predetermined inclusion and exclusion criteria. Metabolites produced by the gut microbial communities have been researched for their health benefits and potential anticancer activity. For instance, the short-chain fatty acid, butyrate, has been evaluated against multiple cancer types, including breast cancer, and has demonstrated anticancer potential via various molecular pathways. Similarly, nisin, a bacteriocin, has presented with a range of anticancer properties primarily against gastrointestinal cancers, with nominal evidence supporting its use against breast cancer. Comparatively, a natural purine nucleoside, inosine, though it has not been thoroughly investigated as a natural anticancer agent, has shown promise in recent studies. Additionally, recent studies demonstrated that gut microbial metabolites influence the efficacy of standard chemotherapeutics and potentially be implemented as a combination therapy. Despite the promising evidence supporting the anticancer action of gut metabolites on different cancer types, the molecular mechanisms of action of this activity are not well established, especially against breast cancer and warrant further investigation. As such, future research must prioritise determining the dose-response relationship, molecular mechanisms, and conducting animal and clinical studies to validate in vitro findings. This review also highlights the potential future directions of this field.

Keywords: breast cancer; butyrate; cancer; gut microbial metabolites; inosine; nisin; sodium butyrate; standard chemotherapy.

Figure 1

Dysbiosis (imbalance of the health gut microbial population) can lead to the development of different cancer types, including breast, colon, lung, stomach, and intestinal cancers.

Figure 2

The effect of dietary and other epigenetic factors on the production of gut microbial metabolites. These factors possess precursor compounds and bacterial species, i.e., non-digestible carbohydrates, adenosine and Bifidobacterium pseudolongum and Lactococcus lactis, that undergo metabolic processes to synthesise common gut microbial metabolites, SCFAs, natural purine nucleosides, and bacteriocins, respectively [4].

Figure 3

PRISMA Flow Diagram depicting the screening process for the review.

Figure 4

The differences in gut microbiota and mammary microbiota present in healthy individuals, in comparison to a diseased (cancerous) state. This includes increases or decreases in the abundance of protective or pro-tumoural bacterial species and subspecies between the two states.

Figure 5

The multiple proposed metabolic processes involved in breast cancer cell proliferation, including the Warburg metabolism theory, sterol and fatty acid synthesis, glutamine metabolism, and protein translation.

Figure 6

A diagrammatic representation of the effects of specific gut metabolites, sodium butyrate (NaB) and nisin, on common targeted cancer therapies, trastuzumab and gut homeostasis restoration, and standard chemotherapies (doxorubicin, 5-fluorouracil, and docetaxel) as evident in in vitro and in vivo studies in the literature. The red arrow is indicative of an increase in a certain effect, and the blue arrow is representative of a decrease in a certain effect.

Figure 7

A schematic depiction of the observed in vitro molecular mechanisms of action of the sodium butyrate (NaB) against breast cancer cells including the induction of cell cycle arrest in the G₂/M checkpoint phase, an increased expression of caspase-10, the induction of apoptosis, and the initiation of intracellular calcium influx [19,25,26,64].