Harnessing probiotic foods: managing cancer through gut health

Abstract

One of the greatest threats to global health is cancer. Probiotic foods have been shown to have therapeutic promise in the management of cancer, even though traditional treatments such as radiation therapy, chemotherapy, and surgery are still essential. The generation of anticarcinogenic compounds, immune system stimulation, and gut microbiota regulation are a few ways that probiotics when taken in sufficient quantities, might help health. The purpose of this review is to examine the therapeutic potential of probiotic foods in the management of cancer. Research suggests that certain strains of probiotics have anticancer effects by preventing the growth of cancer cells, triggering apoptosis, and reducing angiogenesis in new tumors. Probiotics have shown promise in mitigating treatment-related adverse effects, such as diarrhea, mucositis, and immunosuppression caused by chemotherapy, improving the general quality of life for cancer patients. However, there are several factors, such as patient-specific features, cancer subtype, and probiotic strain type and dosage, which affect how effective probiotic therapies are in managing cancer. More research is necessary to find the long-term safety and efficacy characteristics of probiotics as well as to clarify the best ways to incorporate them into current cancer treatment methods.

Graphical abstract

Graphical representation showing the role of probiotic foods in cancer management.

Introduction

Cancer is caused by cells that have escaped the normal division route and continue to divide and grow abnormally. The uncontrolled growth of these cancer cells may be restricted, or they may also spread to other organs (malignant) (Hanahan, 2022). The cluster of these cancer cells is called a tumor. There are several types of cancer, including lung, breast, mouth, brain, and colorectal cancers. Breast cancer in women and prostate cancer in men are the two most common types of cancer. Lung and colon cancers are common in both sexes (Mattiuzzi and Lippi, 2019). The diagnosis provides information about the stage of cancers, how much it has spread, and which vital organs it has affected. Cancer treatments have advanced over the past few decades, but an entirely effective treatment has yet to be identified. This is difficult to achieve, as cancer is a combination of several diseases. This leads to several conditions, each with some common symptoms and some entirely different symptoms. The therapies for cancer treatment include surgery (removal of tumors by surgery), chemotherapy (the use of chemicals to kill cancer cells), and radiation (the use of X-rays to kill cancer cells). These treatments can significantly reduce cancer incidence, but there are several side effects of these treatments. To increase the success of the treatment and mitigate the side effects, doctors and researchers are focusing on an integrated treatment where other therapies such as acupuncture, naturopathy, and nutrition are also being blended. The target is not only to cure cancer but also to treat the pain, fatigue, and mental strain that accompany cancer in each patient (Hanahan and Weinberg, 2021; Hanahan, 2022). 

The microbiome refers to the population of microbes that live in the human body, especially in the gut. A strong microbiome consisting of healthy microbes affects the health of the individual and helps in fighting several diseases (Altveş et al., 2020). They affect immunity, protect against disease-causing bacteria and are also responsible for the production of vitamins such as B-complex and vitamin K (needed for blood coagulation. Probiotics consist of live microorganisms that may provide health benefits when consumed. They are typically present in yogurt, various fermented foods, and dietary supplements. These microbes enhance the gut microbiome and help the body fight against diseases. Recent studies have shown that the gut microbiome can influence the host’s response to chemotherapeutic agents by enhancing the efficacy of chemodrugs and mediating chemotherapy-induced side effects and toxicity through several mechanisms (Kalasabail et al., 2021). The microbiome can suppress tumors and strengthen the immune system through mechanisms such as anti-inflammation, barrier functions, synthesis of antioxidants, vitamins, fatty acids, and production of other beneficial metabolites. Dysbiosis of the microbiome leads to inflammation, gut permeability, barrier failure, DNA damage, exposure of bacteria to the circulation, and the development of bile acids, endotoxins, and excess conjugated estrogen. All these actions promote the development of tumors leading to cancer (AlHilli and Bae-Jump, 2020). Research performed on the gut microbiome and genetically predisposed mice against leukemia has shown that an intact microbiome protects mice against this disease. Murine models of precursor B-cell acute lymphoblastic leukemia (pB-ALL) were used to show that microbiome deprivation by antibiotic treatments triggered leukemia in the absence of an infectious stimulus. The use of full-length RNA sequencing of fecal samples showed that genetic susceptibility to pB-ALL was affected by a distinct gut microbiome. Machine learning and GC‒MS studies revealed that a lack of commensal microbiota promotes leukemia in genetically predisposed mice rather than the presence of any specific bacteria (Vicente-Dueñas et al., 2020). Various gut bacteria are involved in the regulation of the efficacy and toxicity of chemotherapy drugs. For example, oral supplementation of Lactobacillus lowers the toxicity of cisplatin, and Enterobacter and Pseudomonas metabolize the drug gemcitabine to 2’,2’- difluorodeoxyuridine (Wu et al., 2019; Geller et al., 2017).

Yogurt, kefir, sauerkraut, tempeh, kimchi, miso, kombucha, pickles, buttermilk, and natto are some of the most popular probiotic foods consumed worldwide. Probiotics survive in the intestine after being consumed and have proven health benefits. The microbes present in probiotics also assist in the breakdown and absorption of medications taken by patients. The consumption of probiotic foods has been linked to lowering the risk of cancer and mitigating its effects.

Probiotic foods-a potential alternative therapy for cancer

Probiotics are known to impart several health benefits to the human body. Probiotics can regulate the gut microbiome, degrading potential cancer-causing substances and strengthening the immune system. Probiotics outgrow the pathogenic microbes that grow in the gut, resulting in the exclusion of pathogens. The probiotics colonize the gut epithelium and do not allow the pathogenic bacteria to fix on those sites. Studies on different microbes that have been shown to have positive effects on different types of cancers have been performed (Nazir et al., 2018). Probiotics can be lactic acid-producing bacteria, nonlactic acid-producing bacteria or yeasts. Lactobacillus, Enterococcus, and Lactococcus are some of the most common bacterial probiotics. Probiotic yeasts include Bacillus spp., Saccharomyces cerevisiae, Pichia, etc. (Bedada et al., 2020). The anticancer and antimutagenic activity of probiotics is due to several mechanisms, such as binding with mutagens and degrading and inhibiting mutagens, preventing nontoxic procarcinogens from converting into harmful and toxic carcinogens, and strengthening the immune system of the individual by secreting certain anti-inflammatory substances (Raman et al., 2013). They also produce certain antimicrobial substances that have proven therapeutic effects on cancer patients. Bacteriocins are antimicrobial peptides produced by gram-positive bacteria. These compounds are nontoxic and cause no side effects on the human body. Nisin is one of the most common bacteriocins. It can perforate cancer cell membranes, promote apoptosis, and obstruct cancer cell generation (Molujin et al., 2022). Bacteriocins are able to act against cancer cells because they can differentiate between cancer and noncancer cells. The cell membrane surface of cancer cells is negatively charged, whereas that of noncancer cells is neutrally charged (Molujin et al., 2022). Probiotics also produce deconjugated bile acids, which are byproducts of bile salts. These acids have powerful antimicrobial properties in comparison to the normal bile salts produced in the human body (Oelschlaeger, 2010). The overall number of clinical studies on cancer and probiotics published in PubMed in the past 20 years has been shown in Fig. 1.

Fig. 1.

Graph showing the overall number of clinical studies on cancer and probiotics published in PubMed in the past 20 years

Probiotic bacteria can also detoxify and biotransform carcinogens and procarcinogens into less toxic substances, thus preventing the formation of tumors. This process of biotransformation occurs in the gut via enzymes. These enzymes are modulated by dietary agents, which depend on the type of diet a person consumes (Raman et al., 2013). Strains of certain bacteria, such as Lactobacillus acidophilus and Bifidobacterium, can decrease the activity of enzymes (β-glucuronidase, nitro reductase, and azo reductase) that regulate the process of carcinogenesis (Raman et al., 2013).

The metabolites produced by prebiotics maintain homeostasis in the gut and increase the growth of beneficial bacteria that restrict the formation of carcinogens from procarcinogens. They decrease the levels of harmful enzymes such as β-glucosidase, β-glucuronidase, and nitroreductase. Postbiotics include metabolic byproducts synthesized by live microorganisms, including bacteriocins, hydrogen peroxide, exopolysaccharides, and bacteriocins, or products released after bacterial lysis, including exopolysaccharides, cell surface proteins, muropeptides, and teichoic acids. Many these postbiotics have shown the ability to enhance antitumor activity, immunity, and antisepsis. In the past few years, postbiotic metabolites have gained popularity in medical treatments due to their understandable chemical structures, long shelf life, anti-inflammatory properties, and antiproliferative effects. The most common example is Lactobacillus species, which produce compounds that inhibit the growth of MCF7 breast cancer cell lines and inhibit the proliferation of pancreatic tumor cell lines through the action of polysaccharides (Noroozi et al., 2021). Synbiotics are combinations of both pre- and probiotics in a single form. These compounds can regulate various metabolic pathways, promote apoptosis, inhibit proliferation, and promote the formation of short-chain fatty acids. A recent study in mice showed that supplementation with a specific symbiotic dose suppressed colorectal cancer in test models. Intervention with synbiotics formed an intestinal barrier and inhibited cancer occurrence by upregulating the expression of anti-inflammatory cytokines and tight junction proteins and downregulating the expression of inflammation-causing cytokines. Synbiotics also improved the colonic microbiome of mice, promoting the development of short-chain fatty acids and secondary bile acids (Wu et al., 2023).

A better understanding of cancer biology and the action of probiotics in the control of cancer can help researchers find a solution for the management of this deadly disease more strategically.

Probiotics and fermented foods

Probiotics are live microorganisms that, when consumed, provide benefits to humans by supporting the intestinal microbial balance. Fermented foods have different microorganisms grown during the fermentation process. The action of these microbes results in the formation of various compounds including organic acids and alcohol which have the ability to inhibit spoilage in fermented foods and also improve the health of people who intake such foods regularly. The bacteria found in these fermented foods play a key role in human health, especially in the digestive tract, and are known as probiotics. They can enhance immunity against pathogenic bacteria. Lactic acid bacteria (LAB) produced in fermented foods are suitable probiotics that can replace antibiotics by overcoming pathogenic bacteria. Several fermented foods are good sources of these probiotics, including Brem and Rusip from Indonesia, Kimchi and Gochujang from Korea, Kefir from Russia, and Ergo from Ethiopia among others (Soemarie et al., 2021). Fermented foods are often labeled and matketed as “probiotic foods” and “contain probiotics”. These labels show that the foods have live, health-promoting microbes. However, the term “probiotic” should be used only if the health benefit has been proved by a well-defined live microorganism. The final food product should also have enough microbial strains known to impart specific health benefits. For example, sauerkraut has multiple strains of Lactiplantibacillus plantarum (previously Lactobacillus plantarum) which are unidentified and uncharacterized. But, if an L. plantarum 299v strain which has been genetically characterized and clinical demonstration has been shown, will remain present in the efficient dose until the product is consumed, the sauerkraut will meet the minimum requirement to be labeled as a probiotic fermented food. It can then be labeled and sold as “Probiotic sauerkraut with L. plantarum 299v can improve intestinal well-being”. In some cases, if the stain is not specific, a label “contains probiotics” can be used. This will be allowed only if at least one strain from the fermented food meets the criteria mentioned above. For some common species like Bifidobacterium and Lactobacillus, the “probiotic foods” term can be used, provided they provide a minimum of 10⁹ colony-forming units (CFU) in each serving (Marco et al., 2021). Yogurt containing Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus should have 10⁷ CFU/g until its expiry date. The European Food Safety Authority has allowed the health claim on yogurt that it contains live bacteria which improve lactose digestion in people suffering from lactose maldigestion, with the condition that the yogurt contains a minimum of 10⁸ CFU/g of the live starter culture by the end of the shelf life. For any fermented food to be used and labeled as a ‘biotic’ (pre or pro), the product should be characterized, tests should be done on the health benefits. The genome sequencing must have been done to identify and name the microorganism responsible for the probiotic action (Vinderola et al., 2023).

Understanding cancer and its management

Research on cancer management has been ongoing for several decades. There is no accurate cure for this disease. The treatments available are only a way to reduce the effect of cancer and not eliminate it. Additionally, these treatments leave patients with other side effects that add to the already deteriorating health conditions of cancer patients. Understanding cancer at the cellular level might help in finding the relationship between probiotics and their potential to manage cancer at an early stage.

Understanding cancer biology

Worldwide, more than 18 million people are diagnosed with cancer. Among the four major types, breast cancer, lung cancer, colorectal cancer, and prostate cancer are the most common (Hesketh, 2023). A cancer cell is a normal body cell that has undergone a series of changes and escaped the normal route followed by other noncancerous cells. Cancer cells develop into tumors, and tumors transform into cancerous masses over time. Several genetic and lifestyle factors promote the formation of cancer cells. Genetic mechanisms include chromosomal translocation (Bcr gene and Abl oncogene in blood cancer), point mutation (Ras gene- colon cancer), deletion (Erb-B gene; breast cancer), amplification (N-myc in neuroblastoma), and insertion activation (in acute blood cancer). Similarly, chronic blood cancer in elderly people occurs through the exchange of genetic materials between chromosome numbers 9 and 22. This causes the formation of a ph1 biomarker, which is detected in approximately 95% of patients (Hassanpour and Dehghani, 2017). Mutation of the p53 gene leads to the development of cancer cells. Abnormal p53 gene expression has been detected in more than 60% of cancer cases. Normally, this gene plays a role in normal cell division, cell differentiation, and death (Hassanpour and Dehghani, 2017).

Cell apoptosis is a major factor in maintaining a fine balance between cell survival and death. Cancer cells escape apoptosis, which causes uncontrolled growth and enlargement of cancerous masses in the body (Goldar et al., 2015). An imbalance between the antiapoptotic and proapoptotic B-cell lymphoma-2 (Bcl-2) protein families lead to the survival of cancer cells (Kang and Reynolds, 2009). In several cancer patients, genetic and epigenetic remodeling of the proapoptotic members of the Bcl protein family has been detected. Inactivation of these proapoptotic proteins and an increase in the levels of antiapoptotic proteins are other reasons for the evasion of cancer cell apoptosis. There is enough scientific evidence indicating that the dysregulation of microRNAs (miRNAs) is related to human cancer. miRNA-21, miRNA-17/92, miRNA-272/273, and miRNA-221/222 negatively control apoptotic activity and enhance the rate of cancer cell growth and resistance to cancer treatment drugs (Goldar et al., 2015). Another mechanism that leads to the development and proliferation of cancer is inflammation. Inflammation promotes cancer and occurs even before the formation of a tumor. The association between cancer and inflammation has been scientifically proven, as leukocytes have been detected in tumors. For example, inflammatory diseases such as inflammatory bowel syndrome, chronic hepatitis, and bladder inflammation all increase the risk of developing colorectal cancer, liver cancer, stomach cancer, and bladder cancer. Several environmental factors also promote inflammation, which leads to the development of cancer. Alcohol consumption, smoking, obesity, and a sedentary lifestyle are factors that promote inflammation in the body (Greten and Grivennikov, 2019).

It has also been reported that cancer cells can ingest noncancerous cells. This theory has been supported by the detection of cells in cell structures in several cancers. Cancer cells ingest neighboring cells, leading to the spread of cancer to other organs and parts of the body (Fais and Overholtzer, 2018). This trait of cancer cells was detected when tumor cells exhibited a crescent-shaped nucleus and another smaller cell within a large vacuole. This process is referred to as cancer cell cannibalism. Like any other unicellular entity, cancer cells need nutrients for survival. Nutrient requirements are increased in cancer cells because the tumor vasculature is deficient, as observed in many cancers. This leads to the engulfment of nearby cells by cancer cells to fulfill their nutrient requirements in bulk. This property is acquired by cancer cells in later stages of cancer progression, as was observed in metastatic cells and not in cells that arose from primary tumors. (Fais and Overholtzer, 2018) Cannibalism activity has also been seen in the breast cancer cell line MDA-MB-231, which cannibalizes mesenchymal stem cells (Bartosh et al., 2016). Cannibalism is similar to phagocytosis, the major difference being that cancer cells engulf both live and dead cells. Cell-in-cell mechanism or cannibalism has been seen in several types of cancers, such as blood cancer, breast cancer, skin cancer, lung cancer, ovarian cancer, prostate cancer, and urinary tract cancer (Fais and Overholtzer, 2018).

Current approaches to cancer treatment

Chemotherapy, radiation therapy, and surgery are common methods for treating cancer. Targeted therapies, immunotherapy, hormonal therapy, cryotherapy, laser therapy, photodynamic therapy, and hyperthermia are other alternatives. Tumors are removed by surgery, cancer cells are eradicated by chemotherapy, and X-rays are used in radiation. Treatments can be mixed according to the needs of the patient and the stage of malignancy. Three stages of chemotherapy are used to treat cancer: primary, neoadjuvant, and adjuvant. When there are no other options for treating advanced-stage cancer, primary chemotherapy is used. Neoadjuvant chemotherapy decreases tumor size before surgery and is used for localized tumors such as breast and rectal cancer. Adjuvant chemotherapy is often administered for stomach, breast, and colon cancers to improve survival and lower recurrence (Chu and Sartorelli, 2018).

Repeated doses of chemotherapy drugs are used to inhibit cell proliferation. Cytotoxic drugs target the S phase of the cell cycle, while others restrict spindle formation during the M phase. Alkylating agents, such as bendamustine and cisplatin, inhibit DNA replication and transcription by generating unstable alkyl groups that react with nucleophilic centers in proteins and nucleic acids (Amjad et al., 2023). Antimetabolites, including cytidine analogs and folate antagonists, inhibit DNA synthesis and repair. Antibiotics like daunomycin and bleomycin also inhibit DNA and RNA synthesis. Additional drugs like hydroxyurea and tretinoin are used for their unique mechanisms. Combination therapy, using multiple drugs, maximizes effectiveness but often causes side effects like fatigue, nausea, and hair loss (Amjad et al., 2023).

The discovery of X-rays by Wilhelm Röntgen in 1895 revolutionized cancer treatment with radiation therapy, which is used in about 50% of cancer cases (Baskar et al., 2012). Radiation therapy, often combined with surgery and chemotherapy, plays a major role in killing cancer cells by damaging their genetic material, preventing further growth. Radiotherapy targets cancer cells while minimizing exposure to normal cells and can be applied before or after surgery to manage tumors. Radiation is delivered as external beam radiation, using high-energy photons, protons, or particle rays, or as internal radiation, placing radioactive substances directly into tumors (Baskar et al., 2012). Early cancers like skin, lung, prostate, and cervical cancers are curable with radiation alone, while others require combined treatments. Advanced techniques such as 3D radiation and intensity-modulated radiation therapy (IMRT) enhance precision, safeguarding vital organs and targeting tumors. Radiation treatments are typically administered over weeks or months (Allen et al., 2017).. Surgical treatment involves removing tumors and surrounding healthy tissue. Laparoscopic surgery, with minimal incisions and camera guidance, provides a detailed tumor view. Surgery type depends on tumor size and patient preference, aiming to relieve pain and discomfort caused by tumors pressing on nearby body parts (Abbas and Rehman, 2018).

Anticancer mechanism-cellular mechanism and immunity enhancing effects/tumor suppressing action

Probiotics influence the gut microbiota and contribute to the well-being of the human body. They support a balance by reducing the number of diseases causing microbes and do not allow them to deplete the nutritional sources and habitat in the gut. Probiotics play a pivotal role in enhancing the immune system by interacting with the T cells and dendritic cells in the lymphoid tissue associated with the gut. They do so by modulating and activating the immunological responses (Yousefi et al., 2019). This activation results in the release of cytokines which suppress the inflammation-inducing factors and enhance the anti-inflammatory response. They regulate the innate immune cells like natural killer (NK) cells, macrophages, and dendritic cells (Gui et al., 2000). This regulation helps in enhancing the antimicrobial action of the cells. The probiotics influence the T and B cells activity. They promote the development of regulatory T cells responsible for immunological actions and boost the B cells to produce more IgA immunoglobulin antibodies. These actions contribute to the immune-enhancing property of probiotics. Probiotics also fortify the barrier property of the gut epithelial tissue by reducing the permeability of pathogenic microbes, contributing to overall health. The probiotics also prevent the development and inhibit the activity of pathogenic viruses and bacteria in the digestive tract (Liu et al., 2020) Certain probiotics can regulate the acidity of the stomach, making an unfriendly environment for the growth of pathogenic microbes. Probiotics suppress the production of inflammation-causing cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF) (Zhou et al., 2024). The short-chain fatty acids (SCFA) produced by the probiotics inhibit pathogen growth. The SCFA encourages the epithelial cells to produce antibacterial peptides thus stabilizing the intestinal barrier property. They regulate the tight junction proteins and seal the top epithelium and endothelium thus strengthening the epithelial permeability and preventing damage to the epithelial structure. They also restore the abnormal transepithelial resistance caused by pathogenic lipopolysaccharides leading to a reduction in inflammation and excessive apoptosis. Certain probiotic strains also regulate the T helper cells 17 (Th17) and encourage the secretion of IL-17 alpha which in turn triggers the type 3 lymphocytes to produce IL-22. IL-22 is an important immune defense cytokine that maintains intestinal homeostasis and also promotes tissue regeneration and healing (Cristofori et al., 2021). Probiotics occupy the spaces available on the intestinal wall leaving no space for the pathogens. Conjugated linoleic acid (CLA) induces the expression of apoptosis genes- Bcl-2, capsases3, and 9 thus inhibiting the spread of colon cancer cells. Probiotics significantly reduce the Fusibacter genus which is a major factor responsible for tumorigenesis (Lu et al., 2021). By activating pro-caspases and modifying the expression of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins, probiotics such as Lactobacillus and Bifidobacterium strains can overcome apoptosis resistance in cancer cells and ultimately induce apoptosis in tumor cells. Probiotics protect cells from oxidative damage and oxidative stress, which are connected to the development of cancer. They do this by expressing antioxidant enzymes, binding reactive oxygen species (ROS), releasing antioxidants, and chelating transition metals (Nowak et al., 2019). Short-chain fatty acids (SCFAs), such as butyric acid, act as a carbon source for healthy colonocytes and increase the activity of glutathione transferase (SGT), which is responsible for the increase in apoptosis in tumor cells. This process helps eliminate tumor cells without inflaming or harming surrounding healthy cells. Other SCFAs like acetate, propionate, and butyrate interact with G protein-coupled receptors 43 of T helper1 cells or inhibit histone deacetylases (HDACs) of cytotoxic T lymphocytes to exert immunotherapy effects. SCFAs mediate the differentiation and function of regulatory T cells, influence cytokine production in the tumor immune microenvironment (TIME), and modify epigenetic regulation of CD8 + T cells by inhibiting HDACs. Butyrate enhances anti-tumor activity by inhibiting class I HDAC activity, slowing proliferation, promoting apoptosis, improving intestinal integrity, and affecting cancer stromatogenesis (Dong et al., 2023). In terms of oral cancer, probiotics modulate the oral microbiome composition, promoting the growth of beneficial bacteria like Lactobacilli spp. and inhibiting the growth of pathogenic species such as Streptococcus mutans and Candida albicans. They produce biofilms that possess antibacterial properties, inhibiting the growth and colonization of oral pathogens within the oral cavity, and protecting against oxidative damage. They also decrease the expression of pro-inflammatory marker cyclooxygenase 2 (COX-2), and inhibit cell proliferation, thus suppressing oral carcinogenesis at the cellular level (Mohd Fuad et al., 2023). Probiotics can inhibit the activation of oncogenes by interfering with the nuclear translocation of specific proteins like b-catenin and NF-B, which are crucial for cancer cell survival and proliferation. They have been found to decrease the expression levels of proinflammatory cytokines such as IL-6, IL-1b, and TNF-a, which are associated with cancer progression and inflammation (Badgeley et al., 2021). Through these cellular mechanisms, the probiotics strengthen the immune system and suppress cancer (Fig. 2).

Fig. 2.

Cellular mechanisms of probiotics’ immunomodulatory effects against cancer

Probiotics: exploring the basics and types of probiotics

Probiotics are live microorganisms that provide several health benefits when consumed in adequate amounts. They are available in both dairy (yogurt, kefir, kumis) and nondairy forms (kombucha, kimchi, miso, tempeh). The most common probiotics include strains of Lactobacillus and Bifidobacterium. Lactobacillus species include L. bulgaricus, L. acidophilus, L. casei, L. rhamnosus and L.pantarum. These bacterial strains are acid-tolerant in the acidic environment of the stomach and adhere well to the cells of the intestine (Stavropoulou, and Bezirtzoglou, 2020). Bifidobacterium probiotics include B. bifidum, B. lactis, B. longum, Streptococcus thermophilus, Pediococcus, and Bacilli, and yeasts such as Saccharomyces are also considered probiotics (Stavropoulou, and Bezirtzoglou, 2020). Probiotics are capable of adhering to the gastrointestinal tract and thus are not passed through waste. They can multiply and regulate the immune system of the host. Each strain of probiotic microbe has a unique mechanism of action. They produce antimicrobial substances (organic acids, bacteriocins, hydrogen peroxides) and do not allow pathogenic compounds to adhere to the GI tract, starve pathogens from nutrient sources, and enhance the barrier function of the intestine (Ashaolu, 2020). The antimicrobial compounds produced by probiotics target pathogenic cells by inhibiting cell wall synthesis and pore formation. The lactic acid and acetic acid produced by probiotic microbes inhibit the growth of pathogenic Salmonella species (Ashaolu, 2020). Probiotics have several effects on the human body, including the synthesis of vitamins, the metabolism of bile salts, the neutralization of cancer cells, the production of acids and short-chain fatty acids, and the exclusion of pathogens by competition, among others. These properties have been found in several probiotic studies. The sources of probiotic foods are nutrient-rich foods such as grains, milk, and legumes, which are excellent sources of carbohydrates, proteins, vitamins, and minerals. In some fermented foods, such as yogurt, the fermentation process is initiated by the addition of a specific strain of microorganisms called the starter culture. In other foods such as sauerkraut, there is not a specific strain, but wild or indigenous microorganisms are present. The health-imparting properties of particular strains of microbes have been proven by clinical trials. For example, yogurt consumption was associated with a reduction in the development of metabolic syndrome in older adults, a reduced risk of weight gain, and improved digestion in lactose-intolerant individuals. Studies have also revealed that the association between consuming yogurt and soy milk decreases the likelihood of developing cardiovascular diseases (Sanders et al., 2018). A daily study of adults in Korea who consumed high amounts of other probiotic kimchi showed a reduced occurrence of the skin disease atopic dermatitis (Kim et al., 2017). The intake of fermented soy products such as miso and natto reduces the risk of hypertension (Nozue et al., 2017). The various probiotics and associated foods that help to manage cancers have been given in Table 1.

Table 1.

Probiotics in the management of various cancers

Probiotic food	Probiotics	Effects	References
Yogurt	Lactobacillus bulgaricus, Streptococcus thermophilus	Lower risk of Nonalcoholic Fatty Liver Disease	Zhang et al. (2020)
Kefir	Lactobacillus species, Saccharomyces cerevisiae	Obesity management by reduction in serum zonulin levels, glucose and High- density lipoprotein	Pražnikar et al. (2020)
Sauerkraut	Leuconostocmesenteroides, Lactobacillus plantarum and Lactobacillus brevis	Antioxidant, anti-inflammatory and anticarcinogenic properties	Peñas et al. (2017)
Kombucha	Bacillus coagulans, Lactobacillus species andGluconobacter	Antioxidant, anti-carcinogenic properties, aids in cardiovascular disease management and hypoglycemic activity	Selvaraj and Gurumurthy (2022)
Miso	Aspergillus oryzae	Reduced occurrence of cardiovascular diseases and hypertension	Ito (2020)
Buttermilk	Lactococcus lactis, Lactobacillus casei, Lactobacillus acidophilus	Antidiabetic, Anticancer, and Cholesterol-lowering	Bhukya and Bhukya (2022)
Kimchi Natto	Leuconostoc, Lactobacillus, and Weissella Bacillus subtilis	Anticancer properties Anticarcinogenic, antibacterial, immunity boosting, anti-inflammatory	Lee et al. (2023) Afzaal et al. (2022)
Hawaijar	Bacillus species	Anticancer, anti-diabetic, hypocholesterolaemia	Premarani and Chhetry (2011)
Fermented Bamboo shoots	Lactobacillus species	Anticancer, antioxidant, anti-aging, antimicrobial	Behara and Balaji (2021)

Probiotic foods and their role in cancer management

Probiotic foods, having beneficial live microorganisms, play a crucial role in cancer management by modulating the immune system, enhancing gut microbiota diversity, producing anticancer metabolites, and reducing inflammation. These actions collectively help inhibit cancer cell growth and improve the overall immune response, contributing to better cancer prevention and treatment outcomes. The anticancer properties of probiotic foods are shown in Fig. 3.

Fig. 3.

The anticancer properties of probiotic foods

Yogurt

Yogurt is a probiotic, milk-based product formed by the fermentation of milk by lactic acid bacteria. It is a nutrient-dense product that provides numerous health benefits to consumers. The dominant bacterial species in yogurt include Lactobacillus bulgaricus, Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus casei, Bifidobacterium lactis, and Bifidobacterium bifidum (Nyanzi et al., 2021). The production of lactic acid by the fermentation of lactose results in a reduction in pH. This prevents the growth of foodborne pathogens, as a reduction in pH creates a harsh environment unsuitable for their growth (Kamal et al., 2018). Fermentation also leads to a reduction in lactose content and makes yogurt an excellent choice for people who are lactose intolerant (Moineau-Jean et al., 2019). Yogurt has bioactive peptides that impart antioxidant activities (Ali et al., 2022). The consumption of yogurt has been linked to a reduced risk of colorectal cancer. The gut microbiome is a major factor affecting the risk of cancer development. A healthy gut microbiome prevents the formation of tumors in the intestinal tract. A detailed analysis of studies on yogurt intake and its effect on colorectal cancer was performed by Sun et al. (2022). Sixteen studies including 1,129,035 people were analyzed. The high consumption of yogurt by the test participants decreased the possibility of developing colorectal cancer. Yogurt helps in the formation of short-chain fatty acids, which modulate the immune system, prevention of pathogenic compound entry into the intestinal epithelium, and antimicrobial compound production. It also lowers the activity of fecal enzymes (nitroreductase, b-glucuronidase, and azoreductase), which are responsible for the formation of carcinogens from procarcinogens in the colon. Another study on dietary fiber and yogurt consumption and its association with lung cancer was performed by Yang et al. (2020). The study showed a reduction in the risk of lung cancer in test patients with proper lifestyle habits, including the intake of dietary fibers along with yogurt. More than 1.44 million individuals were considered for this study. A total of 15 to 19% of individuals who consumed large amounts of yogurt had a positive effect on the incidence of lung cancer. In addition to yogurt, the intake of dietary fiber reduced the risk of lung cancer by 39%. Yogurt has anti-inflammatory properties that help individuals with inflammation from squamous cell carcinoma, alcohol intake, and lung carcinogenesis. Research has suggested that the colonization of the intestinal tract by probiotic species such as Lactobacillus and Bifidobacterium improves the gut microbiome and positively affects the physical health of individuals (Yang et al., 2020). Figure 4 shows some of the bioactive compounds synthesized by microorganisms found in different fermented foods.

Fig. 4.

Some bioactive compounds synthesized by microorganisms found in fermented food

Kefir

Kefir is a popular fermented drink with an acidic and bubbly taste profile produced by the fermentation and carbonation of kefir grains. It can be milk or water based. It has become popular among consumers worldwide because of the many health benefits it provides. Kefir is slightly different from the other fermented foods because of the specific property of its starter, kefir grains. These bacteria are whitish to yellow and are composed of exopolysaccharides kefiran and proteins along with a symbiotic association of lactic acid bacteria, acetic acid bacteria, and yeasts (Garofalo et al., 2020). The dominant bacterial species in kefir include Lactobacillus para-casei, Lactobacillus kefiranofaciens, Lactobacillus plantarum, Lactobacillus bulgaricus and Lactobacillus acidophilus. The dominant yeast species included Saccharomyces unisporus, Saccharomyces cerevisiae, Kluyveromyces marxianus, and Candida kefyr. Kefir consumption has been associated with valuable health benefits, such as anti-diabetic, anti-inflammatory, antimicrobial, anticarcinogenic, and antitumor effects. These properties are attributed to the several microbes present in kefir, the metabolites they produce, and the exopolysaccharide kefiran present in kefir (Wyk, 2019). Fermentation products include acetic acid, lactic acid, essential amino acids, vitamins, folic acid, bioactive peptides, and other nutraceutical metabolites (Garofalo et al., 2020). Kefir has anticancer effects because of its ability to retard tumor growth, modulate the gastrointestinal microbiota, decrease DNA damage, and inhibit the spread and activation of procarcinogens (Sharifi et al., 2017). The anticancer effects of kefir have been studied and reported in various types of cancer, such as blood cancer, breast cancer, colorectal and gastric cancer, and tumors. Kefir had apoptotic, antioxidant, and antiproliferative effects on the human melanoma cell line HMV-1/SK-MEL, the human mammary cancer cell line MCF-7, the human T-cell leukemia cell line HuT-102, the gastric cancer cell line SGC7901, the colorectal cell line Caco-2/HT-29, and the colon cancer cell line. These studies were performed in vivo and in vitro among various test organisms, including humans and mice (Azizi et al., 2021).

Sauerkraut

Sauerkraut is a widely consumed traditional Chinese fermented food with a distinctive sour flavor. It is also popular in the northeastern regions of India. It is an excellent source of probiotics, minerals, and organic acids. Sauerkraut provides several health benefits to consumers, including anti-inflammatory, antioxidant, anticancer and antiobesity effects (Lavefve et al., 2019). It is produced by placing cabbage leaves in a brine solution having 0.5 to 3.5% salt. The microbes that cause fermentation include lactic acid bacteria, Enterobacteriaceae, Pseudomonadaceae, and yeast species. The salt concentration is the governing factor of fermentation and the taste and quality of the final product. A suitable concentration of salt inhibits the growth of pathogenic microorganisms and favors the proper growth of lactic acid bacteria (Pérez‐Díaz et al., 2020). Sauerkraut is known to have anticancer properties. This is because of the chemical compound glucosinolates. These compounds are sulfur-containing phytochemicals with a β-D glucose unit and an aliphatic amino acid-derived side chain. It can protect the body against the development of cancer. Isothiocyanates and indoles are produced upon the breakdown of glucosinates. These compounds lower cancer risk by activating genes that suppress tumors, slow tumor growth, and increase the self-destruction of cancer cells. Glucosinates stimulate enzymes that are responsible for the deactivation of carcinogens and decrease the ability of cancer cells to spread (Zawadzki, 2023). Bacillus lipopeptide-iturin A-2, a metabolite produced by Bacillus velezensisstrainT701, was isolated from sauerkraut. It showed antitumor and cytotoxic effects on the breast tumor cell line BT474 and cytotoxic effects on the cervical cancer cell lines HeLa and MCF-7 (Jiang et al., 2021).

Kombucha

Kombucha is a probiotic beverage produced by the fermentation of black tea dissolved in sugar by SCOBY, a symbiotic culture of bacteria and yeast. SCOBY is a bell-shaped, spongy, textured culture commonly known as tea fungus. Freshly fermented Kombucha fruits have a sweet taste like that of apple cider fruits, whereas prolonged fermentation leads to the formation of acidic flavors similar to those of vinegar. The bacterial strains and yeasts found in Kombucha include Acetobacter aceti, Gluconacetobacter xylinus, Acetobacter xylinoides, Acetobacter pasteurianus, Sachharomycodes ludwigii, Saccharomyces cerevisiae, Torulaspora, Pichia and Candida. The combined action of yeasts and bacteria on tea results in the formation of several bioactive compounds that have health-enhancing potential (Dutta and Paul, 2019). Several studies on the anticancer action of Kombucha have been performed and have shown positive results. Kaewkod et al., 2022, investigated the effect of traditional kombucha combined with other medicinal plants and its anticancer effect on colorectal cancer cells. Kombucha was prepared with black tea and additional extracts of Aegle marmelos and Terminalia catappa. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) studies were conducted on Caco-2 colorectal cancer cells. DNA damage and apoptosis in cancer cells after treatment with the enhanced Kombucha extracts were detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. All the treated samples showed DNA damage during the later stages of apoptosis and cell cytotoxicity to Caco-2 cancer cells. Kombucha showed enhanced anticancer activity along with doxorubicin against the colorectal cell line HCT-116. Kombucha extracts are capable of 1.2 times earlier induction of apoptosis and a twofold increase in G₀ and G₁ phase arrest (Rasouli et al., 2021). The anticancer potential of kombucha is linked to the presence of dimethyl 2-(2-hydroxy-2-methoxypropilidine) malonate, a compound that can suppress cancer cells (Taupiqurrohman et al., 2022). The anticancer compound in common probiotics has been given in Table 2.

Table 2.

Anticancer compounds in common probiotics

Probiotic food	Anticancer compound	Mechanism of action	References
Yogurt	Bioactive peptides (beta-casein and kappa casein fragments (β-CN 135–144,193–209 and κ-CN 18–29,141–146,161–169 fragments)), butyrate, short-chain fatty acids	Inducing apoptosis of cancer cells (negatively charged cancer cells bind to positively charged peptides), rupturing the cancer cell membranes, and causing their death	Nyanzi et al. (2021), Mann et al. (2017)
Kefir	Interferon-β, BAX	Anti-inflammatory, anti-proliferative, and immunomodulatory effects by increasing macrophage production and phagocytosis, decrease the levels of TGF-α, TGF-β, causing initiation of apoptosis, low levels of TGF-α, TGF-β, show antiproliferative effects in cancer cells, apoptosis regulation	Verruck et al. (2019)
Sauerkraut	Isothiocyanates, ascorbigen, ascorbic acid	Decrease cell mutation and prevent oxidative DNA damage, inhibition of pro-inflammatory cytokines	Ciska et al. (2021), Shahbazi et al. (2021)
Kombucha	Glucuronic acid, acetic acid, vitamin C, B1, B2, B12, ethyl alcohol, dimethyl malonate, vitexin, DSL (D-saccharic acid-1, 4- lactone)	Antiproliferation activity, antioxidant activity Genetic mutation inhibition, induction of apoptosis, terminating metastasis, hepatoprotective action against toxic liver carcinogens	Villarreal-Soto et al. (2019) Chelho et al. (2020)
Miso	isoflavones (genistein and daidzein) and phenolic acids (syringic and vanillic acid), saponins, lunasin	Estrogen binding activity prevents hormone-related cancer, prevents angiogenesis in tumor masses, prevents the growth of tumor cells, promotes cell apoptosis, and positive regulation of mRNA expression of various tumor-suppressing genes thus inhibiting cell malignancy	Chan et al. (2021) Prado et al. (2022)
Natto	Isoflavones, flavonoids, phytoestroptease inhibitor, phytic acid Natto kinase	Antitumor activity, inhibit expression of transcription factors CD44, CD31, FOXM1, and vimentin which regulate the proliferation of tumors thus reducing the growth rate of tumor	Wang et al. (2023), Yuan et al., (2022)
Kimchi	Nisin, GABA (γ-Aminobutyric Acid), ornithine, mannitol, dextran, 3- Phenyllactic acid, and 2-hydroxyisocaproic acid	Apoptosis, anti-proliferation activity, cell cycle arrest, inhibition of mutagenesis and angiogenesis, oxidative stress modulation	Lee et al. (2021)
Buttermilk	Phospholipids (phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine), sphingolipids (lactosylceramide, glucosylceramide, and sphingomyelin)	Antiproliferative activity, anti-inflammatory	Ali (2019), Freitas Mascarello et al. (2019)
Hawaijar	Amino acids, minerals	Anticancer properties	Saibhavani et al. (2020)
Fermented bamboo shoots	Sitosterol-3-O-β-d-glucoside	Enhancement of proapoptotic genes (Bax, P53, caspases) and the downregulation of antiapoptotic gene- BCL2	Abdelhameed et al. (2020)

Miso

Miso is a popular traditional fermented food in Japan with a typical savory flavor profile. The production of miso involves a two-stage fermentation in which the first stage involves the development of koji with Aspergillus oryzae followed by the addition of koji to a soybean and salt mash. This mixture is then kept for fermentation for the development of the desired taste (Allwood et al., 2021). The color of the miso depends on the duration of fermentation and the amount of salt and koji used. Miso has several bioactive compounds that are responsible for its health-promoting properties. These include vitamins, minerals, phenolic acids (syringic acid and vanillic acid), and isoflavones (genistein and daidzein) (Chan et al., 2021). Isoflavones isolated from miso have shown antiproliferative effects on certain cancer cell lines. Hydroxygenistein showed the highest antiproliferative activity against the promyelocytic leukemia cancer cell line HL-60. It has also been reported that miso has the potential to prevent cancer by enhancing the cytotoxic activity of cancer cells in the spleen and reducing tumor formation (Jung et al., 2006). Miso fermented with Aspergillus oryzae and Bacillus subtilis has exhibited antiproliferative effects on several human cancer cell lines, including H_EPG2 (liver carcinoma), MCF7 (breast carcinoma), and HCT116 (colon carcinoma). The anticancer activity was due to the presence of more isoflavones in miso than in unfermented soybeans (El‐Shenawy et al., 2012). Miso suppressed liver tumors in mice and breast tumors in rats (Watanabe, 2013).

Natto

Natto is a traditional Japanese dish prepared by the fermentation of steamed soybean seeds by Bacillus subtilis. It has become popular due to its nutritional profile, which has several health benefits. It has a unique flavor with a sticky and slimy consistency. The health benefits are due to the presence of bioactive compounds and essential nutrients such as soybean isoflavone, natto kinase, γ-polyglutamic acid, biogenic amines, and vitamin K_2. It also has 100 times more menaquinone-7 than most cheeses (Afzaal et al., 2022). Natto kinase extracted from natto treated early subcutaneous breast cancer in mice by encouraging vascular regeneration and inhibition of tumor angiogenesis. FOXM1, a biomarker present in various malignant cancers, promotes the proliferation of cancer stem cells and promotes the renewal of pancreatic cancer cells and the spread of cancer in the liver, stomach, lung, and pancreas. Natto kinase hampers the expression of this transcription factor, thus resulting in cancer management. Another family of enzymes, MMP2, which enhances tumor invasiveness and tumor growth, is reduced by natto kinase. Thus, it has been clearly shown that the bioactive component of natto has the potential to fight cancer-causing agents (Zhang et al., 2019). Freeze-dried natto water extracts have been shown to remediate melanoma through cytotoxic effects. Autophagy acridine orange staining and flow cytometry assays revealed a shift from autophagy to apoptosis in the melanoma cell lines. Natto extracts also increase oxidative stress in cancer cells and initiate apoptosis by suppressing AMP-activated protein kinase (Chou et al., 2021). Nattokinase extracts were administered to hepatocellular carcinoma-infected mouse models. The results showed a 31% increase in the survival rate of the mice, and ultrasound images revealed a significant reduction in the tumor size. This was also due to the ability of natto kinase to suppress the expression of the cancer biomarkers CD44, CD31, FOXM1, and vimentin. These factors are responsible for the proliferation, drug resistance and survival of various cancers (Yan et al., 2019). A fructose polysaccharide, Levan, which is produced by Bacillus subtilis in natto, induces apoptosis in a neuroblastoma cancer cell line (SH-SY5Y) via caspase 3/7 activation (Vieira et al., 2021).

Kimchi

Kimchi is an Asian fermented dish prepared from natural napa cabbage (Brassica rapa) or Chinese cabbage by crossbreeding northern Chinese turnip and Bok choy cabbage from China. Kimchi has also been registered at the Codex Alimentarius and received international recognition. It is produced by fermenting cabbages or radishes and additional ingredients such as those in closed containers at low temperatures to allow microbial activity and the development of the desired flavor. Fermenting microbes include Bacillus subtilis, Bacillus mycoides, Lactobacillus brevis, Lactococcus carnosum, Lactobacillus kimchi, Serratia marcescens, Saccharomyces species, Candida species and Leuconostoc species, among others (Surya and Lee, 2022). Cancer cachexia is a health condition in patients with advanced cancer that results in skeletal muscle degeneration, weight loss, and adipose tissue loss. Interleukins are the primary mediators of cachexia. Kimchi can modulate and suppress the interleukin-6 (IL-6) response, resulting in the treatment of cancer cachexia. Kimchi intake significantly inhibited muscle degenerating and lipolysis genes, including muscle ring finger protein-1 (MuRF-1), hormone sensitive ligase (HSL), adipose triglyceride lipase (ATGL), and atrogin-1 (An et al., 2019). Kimchi intake can also prevent colitis-related cancer through several mechanisms, such as weakening inflammasomes (IL-18 and caspase-1); inducing anti-proliferative effects through the regulation of BAX, caspase-3 and beta-catenin; enhancing antioxidant effects; and regulating cytoprotective actions. It also induces the tumor suppressor 15-PGDH and inactivates ERK1/2, contributing to cancer prevention (Han et al., 2020). Weissellacibaria, found in kimchi, has anticancer properties due to its ability to produce tumor necrosis factors. It has been shown to suppress cancer cell growth in colorectal cancer cells (Ahn et al., 2013). These studies indicate the potential of kimchi as an anticancer food.

Buttermilk

Buttermilk is a byproduct of butter manufacture and is a rich source of various phospholipids, enzymes, glycoproteins, and unsaturated fatty acids. Sphingolipids and glycerophospholipids regulate several metabolic processes (Ferreira et al., 2022). However, bulky sphingomyelin and lactosylceramide inhibited the growth of SW480 colon cancer cells. Buttermilk caused the deactivation of ERK1/2, an enzyme family responsible for the proliferation of human colorectal cancer cells (Kuchta-Noctor et al., 2016). Bacteriocin isolated from Lactococcus lactis, a bacterium predominant in buttermilk, has shown anticancer activity against cancer cell lines in breast cancer (MCF-7) and a lymphoid cell line (CCL-119). The results clearly showed the greater toxicity of bacteriocin against cancer cells than against normal cell lines (Abbdul-Kaliq et al., 2020). Lipid fractions isolated from buttermilk were studied for their antiproliferative activity against several cancer cell lines, including skin cancer (U252, HaCaT), breast cancer (MCF7), ovarian cancer (NCI), kidney cancer (786–0), lung cancer (NCI-H460), colon cancer (HT29), and bone marrow cancer (K-562) cell lines. The sphingolipid- and phospholipid-rich fractions were found to have strong antiproliferative effects on the different cancer cell lines studied (Castro-Gomez et al., 2016). The above studies indicate that buttermilk is a rich source of nutritional compounds with anticancer potential.

Hawaijar

Hawaijar is a common traditional fermented soybean food produced by the Manipur. It has a sticky texture. The seeds were soaked in water overnight, washed, and then boiled until soft. After washing with hot water, the boiled seeds are placed in bamboo baskets lined with a layer of fig or banana leaves. The closed basket is then wrapped with jute cloth and buried in a paddy or kept in the sun or near a stove. The fermented hawaijar is ready for consumption within 3 to 4 days. The production of ammonia-like flavors and the development of mucilage indicate good-quality hawaijars (Devi et al., 2013). The functional microorganism Bacillus imparts antioxidant and antidiabetic properties to Hawaiju (Singh et al., 2023). It is also a rich source of proteins (Sarkar et al., 2015). It has anti-osteoporosis, anticancer, and hypocholesterolemic effects (Saibhavani et al., 2020). Further research studies need to be performed to fully explore the anticancer potential of hawaijars.

Fermented bamboo shoots

Bamboo shoots are fermented and consumed by tribes in northeast India because of their medicinal value and health benefits. As a storehouse of several microorganisms, they can be used as functional probiotic foods. Several food products based on fermented bamboo shoots include soibum, mesu, soijim, soidon, heccha, ekung, hirring, tabah bam shoot pickle, and soidonmahi. They are rich in mineral content and dietary fiber and low in fat. Fermented bamboo shoots contain certain bioactive compounds, such as flavones and glycosides, which have anticancer, antioxidant, and antiaging effects.Lactobacillus species (L. plantarum, Brevis, and L. lactis) are the dominant microorganisms (Behara and Balaji, 2021). These phytosterols are rich sources of phytosterols that have been shown to have anticancer and antitumor effects on lung, ovarian, and breast cancers. The mechanism of action involves enabling the antitumor response, boosting the immune recognition of cancer, and managing hormone-related endocrine tumor growth. Phytosterols inhibit the growth of tumors by inducing apoptosis and slowing the cell cycle progression of cancer cells. Moso bamboo has been utilized for the production of an antitumor agent (Hiromichi, 2007). Phenolic acids in tender bamboo shoots are powerful antioxidants that prevent cancer (Nirmala et al., 2014). A phytochemical study of bamboo shoot skins revealed the presence of sitosterol-3-O-β-d-glucoside, which has cytotoxic effects on MCF-7 cancer cells. It also blocked the progression of these cell lines. This was caused by the increase in the expression of proapoptotic genes (Bax, P53, and caspases) and the decrease in the expression of the antiapoptotic gene BCL2 (Abdelhameed et al., 2020).

Microbial metabolites and their mechanism of action against cancer cell lines

The bioactive compounds produced by probiotic microorganisms play an important role in the metabolic activities of consumers. These include bacteriocins, enterocins, exopolysaccharides, short-chain fatty acids (lactic acid, butyric acid, propionic acid, and acetic acid), amino acids (arginine, tryptophan, and tyrosine), vitamins (folate, thiamin, riboflavin, pyridoxine, vitamin B12), and enzymes (amylase,β-galactosidase, superoxide dismutase, and catalase) (Indira et al., 2019). A study on the characterization of exopolysaccharides synthesized by Lactobacillus plantarum RJF4 revealed its cytotoxic and proliferative effect on the MiPaCa-2 pancreatic cancer cell line. MTT assays revealed that exopolysaccharides had no inhibitory effects on the normal L6 and L929 fibroblast cell lines, indicating that foods fermented by Lactobacillus plantarum RJF₄ are safe for consumption. The Alamar Blue assay depicted the antiproliferative effect of the EPS extracts on pancreatic cancer cells (in a dose-dependent manner, with the highest concentration being 1 mg/ml) (Dilna et al., 2015).

Turin A, a bioactive compound produced by Bacillus subtilis, showed anticancer activity on the HepG2 hepatoma cell line. 2-D and 3-D cell culture models were used to study the anticancer effects of these compounds. Compared with 2-D culture at a concentration of 11.91 µM, 3-D culture at a concentration of 55.26 µM had a much greater 50% inhibitory effect. Autophagy, apoptosis, reactive oxygen species accumulation, high expression of apoptotic proteins, and caspase activation were detected in both cell lines (Zhao et al., 2019). The antiproliferative effect of short-chain fatty acids on the colorectal cancer cell line DLD-1 through gene expression inhibition was studied. Acetic acid, butyric acid, and isobutyric acid inhibited DLD-1 cell proliferation. The expression levels of cell proliferation and DNA replication genes were reduced by ≥ 50% after treatment with butyric acid. Among the tested fatty acids, butyric acid had the strongest antitumor activity. Short-chain fatty acids also suppress the metabolic functions of tumors, such as DNA replication, repair, and recombination. All these actions lead to the death of tumor cells (Ohara and Mori, 2019). Another study investigated the anticancer effects of nisin, a bacteriocin produced by Lactobacillus species, on several cancer cell lines, such as SW48, LS180, Caco2, and HT29. Nisin (40–50 IU/ml) suppressed the proliferation of LS180 cells. A higher concentration of nisin (250–350 IU/ml) suppressed the proliferation of the Caco2, HT29 and SW48 cell lines. Nisin also downregulates the expression of the metastasis-promoting genes MMP2F, MMP9F, CEAM6, and CEA (Norouzi et al., 2018). Pistachio milk fermented by Streptococcus, Lactobacillus, and Bifidobacterium species has a large amount of acetate, as it is rich in proteins and fats. This acetate-rich fermented milk has apoptotic and cytotoxic activities against Caco-2 colon carcinoma cells. This is caused by nuclear damage and disruption of microtubules by the caspase-3 protein. Fermented pistachio milk at concentrations of 1%, 2.5%, and 5% had cytotoxic effects on 78%, 56%, and 29% of Caco-2 cells, respectively. Additionally, 5% fermented pistachio milk caused a sixfold increase in early and late apoptosis (Lim et al., 2023). The exopolysaccharide MSR101 EPS (400 µg/ml), which is produced from Lactobacillus kefiri, showed 44.1% anticancer activity against HT-29 colon cancer cells. It also caused upregulation of the expression of cancer suppressor factors, including BAX, Cyto-c, BAD, and caspases 3, 8, and 9, and downregulation of the proapoptotic BCl-2 gene, leading to the death of cancer cells (Rajoka et al., 2019).

Challenges

Although several studies have supported the use of probiotics as an adjunct to cancer therapy, many challenges remain to be managed. These differences arise due to variability in the response of individual patients to the probiotic dose, as a strain that is beneficial to one patient might cause a negative reaction in another patient. Deciding and standardizing an optimal dose, timing, and specific strain is a complex task. Moreover, advanced studies must be performed to understand the impact of probiotics on the cancer microenvironment, interactions with chemotherapeutic drugs, and safety. Balancing the positives and the negatives becomes a significant obstacle in utilizing the full potential of probiotic foods as adjunct therapy to cancer treatment.

Future perspectives

Probiotic foods, which are rich sources of nutritional and bioactive compounds, have appeared as potential anticancer agents. The intestinal microbiome plays a significant role in the regulation and suppression of cancer-causing factors. An improper diet, the consumption of processed foods, the intake of alcohol, smoking, and a sedentary lifestyle contribute to an imbalance in intestinal homeostasis. Compared with pathogenic microbes, probiotics modulate this microbiota and maintain the balance of good microbes. The dominant microbes found in all the probiotic foods included Lactococcus, Lactobacillus, Enterococcus, Streptococcus, and Bifidobacterium species. Several studies conducted on different types of cancers have supported the tumor-suppressive, antiproliferative, anti-inflammatory, and apoptosis-inducing effects of probiotic foods. These properties are due to the presence of specific compounds produced by different microbes during fermentation of the raw materials. The intake of probiotic foods in addition to a healthy lifestyle can result in the prevention and management of cancer and its negative effects on human health. Advanced clinical trials should be conducted to fully determine the potential of probiotic foods as alternatives to usual cancer therapy. Patients prefer natural treatments rather than treatments based on the use of chemical drugs along with the long-term side effects associated with each medicine. This has led to increased demand for and expansion of the probiotic market. Research studies performed on human and animal models have yielded positive results. For the commercialization and use of probiotics as an alternative treatment to cancer therapy, accurate information on the types of strains used, the dose to be administered and the period for consumption should be obtained. Most people are not aware of the scientific mechanism behind the health-implementing properties of probiotic foods. However, medicinal claims are not mentioned in most marketed probiotic foods. Product labeling and regulatory issues related to the marketing and commercialization of probiotic foods have become a matter of discussion. A unique label showing the health claims of each probiotic can help in its better understanding and utilization. Advanced molecular-level technologies will further help in understanding the complex action of specific compounds that play a pivotal role in anticancer activities. People have become aware of the link between health and diet. This has led to an increase in clinical studies on the use of probiotics not only as alternative treatments but also as potential agents for minimizing the side effects of traditional treatments and reducing and preventing chronic diseases such as cancer. The current market for probiotics is expected to grow as consumers are looking for food items that are not only palatable but also a source of health-improving components. The target audience includes scientists and researchers, doctors, directors of food companies, and the general public looking for healthier options. The high costs of cancer treatments and their long-term side effects have increased the economic and emotional burden on patients. The majority of deaths occur in lower- and middle-class income populations that fail to receive proper and timely medical treatment. Fermented foods can be easily prepared at low cost and have a high concentration of probiotics for the treatment of cancer. All the above findings indicate the potential of probiotic foods to emerge as powerful remedies for several cancers.

This review highlighted the basic mechanism of cancer and how probiotics regulate cancer via specific mechanisms of action. Cancer is still one of the leading causes of death worldwide. It is caused by the abnormal activity of cells, which first causes tumors to develop through uncontrolled growth and then leads to the spread of those cancerous cells to other vital organs. Lung cancer, colon cancer, and breast cancer are the most prevalent types of cancer. Cell proliferation, escape from apoptosis, dysregulation of microRNAs, inflammation, and ingestion of noncancerous cells are the mechanisms responsible for the spread and development of cancer. There is still no proper and complete treatment for cancer. Chemical treatments combined with surgical operations and radiation therapy are used to treat cancer patients. Diet plays an important role in fighting chronic diseases. Recent studies have focused on the use of probiotic foods as alternative therapies for cancer management. Microorganisms and the bioactive nutritional compounds they synthesize have been shown to have anticancer effects on several cancer cell lines. The most popular and health-packed probiotic foods include yogurt, kefir, sauerkraut, tempeh, kimchi, miso, kombucha, pickles, buttermilk, and natto. Each of these is prepared by fermentation by a specific strain of microorganism. The microbial species that are dominant in most probiotic foods include Lactobacillus, Bifidobacterium, Streptococcus, Bacillus and Saccharomyces species. They produce specific substances such as organic acids, enzymes, vitamins, and bioactive compounds that are responsible for anticancer mechanisms. Lactic acid and short-chain fatty acid production in yogurt, exopolysaccharide kefiran and interferon-β in kefir, glucosinolates, ascorbigen in sauerkraut, glucuronic acid in kombucha, isoflavones in miso and natto, nisin in kimchi and phospholipids in buttermilk are among the unique compounds developed by microbes. They have shown positive results in studies against various cancers, such as lung cancers, the human T-cell leukemia cell line HuT-102, the human mammary cancer cell line MCF-7, the breast tumor cell line BT474, the colorectal cell line HCT-116, and the colon cancer cell line SW480, among others. The mechanisms involved the induction of apoptosis, anti-inflammatory activity, rupturing of cancer cell membranes, anti-proliferative activity, increased phagocytosis, decreased cell mutation, prevention of oxidative DNA damage and inactivation of cancer-promoting genes. Based on these studies, it can be concluded that probiotic-rich fermented foods can play a major role in the management, reduction, and prevention of several types of cancers.

Funding

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Data availability

The datasets used and analyzed during the present study are available from the corresponding author upon reasonable request.

Declarations

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The author declare that they have no competing interests.

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