Breast cancer stands for a substantial global health concern [1] and is the most commonly diagnosed cancer worldwide, with an estimated 2.26 million cases documented in 2020; it is one of the main justifications for cancer mortality among women, with more than 680 thousand deaths in 2020 (6.9% of global cancer-associated deaths) [1]. Despite advancements in investigations, diagnostics, and treatment, such shocking numbers persist. To reduce morbidity and/or mortality rates, understanding the exact etiology of breast cancer and designing/developing novel treatment/management approaches are necessary [2].

The role of diet and dietary patterns/habits in the etiology of breast cancer is undeniable [3]. For example, some diets/dietary patterns, such as a high intake of fructose and low intake of seafood and vegetables, and an inflammatory diet containing saturated fatty acids (SFA) and red and processed meat, are associated with increased risk of triple-negative breast cancer in in vivo and in vitro models ^[4][5][4,5]. On the other hand, the effect of some diets and food compounds such as polyphenols, antioxidant diets, and vitamins involved in one-carbon metabolism has been shown to reduce the risk of triple-positive breast cancer ^[3][6][7][3,6,7]. However, epidemiological evidence and randomized clinical trials for the relationship between dietary-related factors and breast cancer are robust; etiologic mechanisms are primarily uncertain and inconsistent [8]. A new approach to elucidating the relationship between nutrition and breast cancer is through novel omics science, especially metabolomics [9]. In brief, nutritional metabolomics is the study of diet-related metabolites to highlight diet and health outcome associations and may provide a method to seize exogenous dietary exposures more precisely and appraise endogenous markers mediating diet–cancer associations, or both ^[10][11][12][10,11,12]. Nutritional metabolomics allows us to consider multiple exposures related to diet and the metabolic procedures that they affect. Several studies used the nutritional metabolomics procedures in the lung, prostate, ovarian, and colorectal cancers [13] and colon adenoma [14] to determine serum metabolites that are associated with particular dietary exposures, such as intake of vegetables, fruit, nuts, meat, fish, fat, coffee, alcohol, and multivitamins. Findings from those studies regarding the role of diet-related biomarkers linked to metabolomics are able to potentially assist objective dietary explanation, abate errors/biases related to self-reported dietary patterns, agnostically assess metabolic pathways, and discern mechanistic mediators [15].

2. Critical Role of the Gut Microbiome in the Network

The gut microbiome refers to microorganisms existing in the gut and includes over a thousand bacterial species and, partly, fungi, viruses, archaea, and protists ^[16][57]. The microbiome describes a set of genomes that the microbiota (the bacterial population) own ^[17][58]. The microbiota contains up to 90% of human cells ^[18][59] and has been related to health and chronic disease ^[19][20][60,61]. The microbiota also has a significant role in the immune system, so improper proportions of healthy and harmful bacteria can lead to chronic conditions such as cancer ^[17][21][22][58,62,63]. When the ratios of microbiota species are suitable, they prepare energy by fermentation, synthesize vitamins, produce amino acids, and prevent chronic conditions and diseases ^[23][64]. Lifestyle factors such as diet and physical activity influence the complex relationship between gut microbiota and estrogen metabolism and affect both breast cancer recurrence and metastasis possibility ^[24][65]. Interventions that increase microbial diversity through dietary recommendations can affect health, particularly in patients with breast cancer ^[24][65]. The consumption of a poor diet containing a high level of processed meat, simple sugars, and salt and a sedentary lifestyle have a significant negative impact on the gut microbiota ^[24][65]. The estrobolome—the bacteria that are the subgroup of the microbiota responsible for estrogen metabolism and degradation—plays a significant role in breast cancer’s development and/or progression ^[25][66]. The primary source of energy for the estrobolome is fiber, and breast cancer risk is often associated with elevated levels of estrogen, which may be mitigated by a high-fiber diet that prevents breast cancer cells from accessing the fiber. However, recommending a diet high in fiber and polyphenols for individuals with breast cancer can reduce inflammation and improve breast cancer survival rates ^{[26][27][28][29][30][31]}[67,68,69,70,71,72]. In addition, a study investigated the gut microbiome profile concerning tumor grade and stage, HER2 and ER/PR status, and selected risk factors in women diagnosed with breast cancer ^[32][73]. Women with early menarche and HER2+ compared with later menarche and HER2− breast cancers showed a significantly less diverse microbiome and a distinguished bacterial composition profile, including an abundance of Firmicutes. Women with breast cancer with an earlier menarche age (≤11) and with high total body fat (≥46%) had a lower diversity of gut microbiome ^[32][73]. In another study, recently diagnosed breast cancer postmenopausal women had a lower gut microbiota diversity and a divergent composition than those without breast cancer. Additionally, the breast-cancer-suffering women had a high level of urinary estrogens; however, it was independent of microbiota dissimilarities. The results highlight the fact that gut microbiota may have an effect on the risk of breast cancer, and perhaps it is through pathways independent of estrogen ^[33][74]. Several studies have shown that certain types of gut bacteria can affect the metabolism of dietary components, such as phytoestrogens, which are plant-derived compounds that can have either protective or harmful effects on breast cancer, depending on their concentration and form ^[34][35][75,76]. For instance, some gut bacteria can convert phytoestrogens to more active forms, stimulating breast cancer cell growth ^[36][77]. Conversely, other gut bacteria can metabolize phytoestrogens to less active forms, which can reduce breast cancer risk ^[36][77]. Furthermore, dysbiosis, a state of imbalance in the gut microbiome, has been associated with chronic inflammation, which can promote the growth and spread of cancer cells ^[37][78]. In addition, the gut microbiome can affect the absorption and bioavailability of nutrients from the diet, such as vitamins and minerals, which are important for maintaining healthy tissues and preventing cancer ^[38][79]. On the other hand, a special association between some bacteria and the decrease or increase in breast cancer has been shown. For instance, certain strains of Lactobacillus spp. bacteria in the gut have been associated with beneficial effects, including immune modulation and anti-inflammatory properties. Some studies suggest that specific Lactobacillus species may have a protective role against breast cancer development ^[39][80]. On the contrary, some studies have found an increased abundance of Bacteroides fragilis, a common gut bacterium associated with inflammation and immune dysregulation, in breast cancer patients, particularly in hormone receptor-negative breast cancer cases ^[40][81]. Overall, the gut microbiome is an important player in the diet and breast cancer network, and understanding its complex interactions with dietary components and immune function may provide novel avenues for the prevention and treatment of breast cancer.