Amirhossein Davoodvandi1,2Farzaneh Fallahi3Omid Reza Tamtaji4Vida Tajiknia5Zarrin Banikazemi3Hadis Fathizadeh6Mohammad Abbasi-Kolli7
Michael Aschner8Maryam Ghandali9*Amirhossein Sahebkar10,11*Mohsen Taghizadeh3
Hamed Mirzaei3*- 1Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- 2Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- 3Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
- 4Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- 5Department of Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- 6Department of Laboratory Sciences, Sirjan Faculty of Medicine Sciences, Sirjan, Iran
- 7Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- 8Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
- 9School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- 10Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- 11Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
Because of their increasing prevalence, gastrointestinal (GI) cancers are regarded as an important global health challenge. Microorganisms residing in the human GI tract, termed gut microbiota, encompass a large number of living organisms. The role of the gut in the regulation of the gut-mediated immune responses, metabolism, absorption of micro- and macro-nutrients and essential vitamins, and short-chain fatty acid production, and resistance to pathogens has been extensively investigated. In the past few decades, it has been shown that microbiota imbalance is associated with the susceptibility to various chronic disorders, such as obesity, irritable bowel syndrome, inflammatory bowel disease, asthma, rheumatoid arthritis, psychiatric disorders, and various types of cancer. Emerging evidence has shown that oral administration of various strains of probiotics can protect against cancer development. Furthermore, clinical investigations suggest that probiotic administration in cancer patients decreases the incidence of postoperative inflammation. The present review addresses the efficacy and underlying mechanisms of action of probiotics against GI cancers. The safety of the most commercial probiotic strains has been confirmed, and therefore these strains can be used as adjuvant or neo-adjuvant treatments for cancer prevention and improving the efficacy of therapeutic strategies. Nevertheless, well-designed clinical studies are still needed for a better understanding of the properties and mechanisms of action of probiotic strains in mitigating GI cancer development.
Introduction
The incidence of gastrointestinal (GI) neoplasms is rapidly increasing globally (Ashrafizadeh et al., 2020; Pourhanifeh et al., 2020; Shafabakhsh et al., 2021). GI cancers are a complex set of heterogenous diseases and disorders (Wang et al., 2021) and are classified into more frequent sporadic and rare inherited forms. Environmental and genetic risk factors can cooperatively alter normal tissue into a precursor or a premalignant injury, culminating in malignancy. While the precise genetic mechanisms are somewhat understood in a tissue-type– and cell-type–specific context, many common aspects exist between GI cancers of heterogenous origin (Wang et al., 2021). Consistent with the advances made in developing new diagnostic and therapeutic approaches for GI cancers, several probiotic strains are being used as nutritional supplements.
Probiotics are a group of viable microorganisms including bacteria and yeasts that if consumed in sufficient amounts, may afford health benefits to the host (Ganguly et al., 2011; Tamtaji et al., 2019a; Tamtaji et al., 2019b; Alipour Nosrani et al., 2021; Davoodvandi et al., 2021). The major advantage of probiotic administration is its ability to maintain gut microbial homeostasis, reduce pathogenic microorganisms in the GI tract, and restores homeostasis of intestinal microorganisms (Floch et al., 2011; Butt and Epplein, 2019). Moreover, by modulating microbiota and immune responses, decreasing bacterial translocation, promoting the function of the gut barrier, inducing anti-inflammatory properties, triggering anti-pathogenic activity, and decreasing tumor development and metastasis, probiotics might contribute to the prevention and treatment of GI cancers (Servin, 2004; Cotter et al., 2005; Javanmard et al., 2018). Considering the potential roles of Helicobacter pylori (H. pylori) in the initiation of colorectal (Teimoorian et al., 2018; Butt and Epplein, 2019) and gastric cancers (Alfarouk et al., 2019), the possible properties of probiotics against GI neoplasm in humans have been investigated in relation to their suppressive effects on H. pylori (Taremi et al., 2005; Sanders et al., 2013; Russo et al., 2014; Khoder et al., 2016; Rasouli et al., 2017). By triggering immune activity, probiotics, as functional dietary supplements, may mitigate neoplastic predisposition and development of GI cancers (Liong, 2008; Zuccotti et al., 2008; Kumar et al., 2010; De Preter et al., 2011; Zhang et al., 2011).
Clinical Overview on GI Neoplasms
Carcinogenesis is a multistage process characterized by genetic mutations (Nowell, 1976; Yuasa, 2003; Vogelstein and Kinzler, 2004). In the past, initiation and progression of tumors were considered as distinct processes. A critical observation that led to the multistage hypothesis was that neoplasm was clonal, with each neoplastic cell originating from a single progenitor (Nowell, 1976; Cahill et al., 1999). This model implied that genetic mutations required for neoplastic transformation did not occur at once, but rather progressively. With each stage in this process, the transforming cell obtained a new mutation that promoted cell survival or proliferation.
A cell clone was developed with all of the necessary aspects for neoplastic transformation through evolution or natural selection. Selection is a critical element of this process because mutations are random events; thus, only rare mutations result in activation of cell survival and growth-promoting pathways or inactivation of apoptotic pathways or tumor suppressors (Ponder, 2001). These mutations impart a selective survival and growth dominance to that cell and its progeny. This leads to the expansion of that cell into a clonal population. Further mutations that occur in cells of that clonal population provide a few rare cells with new superiority. These daughter cells are subjected to an additional round of clonal expansion. This process continues, building on round after round of clonal expansion, till a mass is generated, and neoplastic transformation has taken place (Nowell, 1976; Cahill et al., 1999).
The specific number of somatically acquired gene mutations necessary for neoplastic transformation is dependent upon which genes and tissues are targeted. In common solid tumors, such as those derived from the colon or pancreas, an average of 33–66 genes displays subtle somatic mutations that would be expected to alter their protein products. About 95% of these mutations are single-base substitutions (such as C > G), whereas the remainder are deletions or insertions of one or a few bases (such as CTT > CT). Of the base substitutions, 90.7% result in missense changes, 7.6% result in nonsense changes, and 1.7% result in alterations of splice sites or untranslated regions immediately adjacent to the start and stop codons (Vogelstein et al., 2013).
Typically, benign dysplastic intermediates develop before GI neoplasm. Indeed, they do not originate from normal tissues directly, and the dysplastic lesions are characterized by their morphology and categorized based on certain pathological indicators (Said, 2012). For example, in the colon, the adenoma–carcinoma pattern shows this promotion from normal mucosa to invasive carcinoma via dysplastic intermediates. This pattern has been well supported by many pathological and animal studies (Kim and Lance, 1997; Lynch and Hoops, 2002).
The same multistep pattern from normal tissue via dysplastic intermediates to malignancy has been shown for human pancreatic, esophageal, and gastric cancers (Hruban et al., 2001; Yuasa, 2003; Hruban et al., 2004; Lin and Beerm, 2004). Cancer always emerges in a dysplastic precursor lesion that is histologically or grossly apparent. Current models have shown that the sequence of events prior to intestinal gastric cancer is as follows: atrophic gastritis, intestinal-metaplasia, and adenomas, which develop into carcinomas (Yuasa, 2003). Precursor lesions that lead to pancreatic cancer have been formally agreed upon, and the characteristics necessary for their classification have been established (Hruban et al., 2001; Hruban et al., 2004). These criteria classify the pancreatic lesions for both scientific and clinical uses.
The concept of cancer stem cells highlighted new perspectives in understanding this disease. Although it is tempting to explain tumor formation and metastasis by the presence of stem cells, after almost a decade of intense research, it seems that cancer stem cells fail to explain how neoplasia evolves. It seems most likely that this population of cells is not a defined group of cells resting in a niche and populating the tumor with amplifying cells, but rather, that few or maybe multiple cells within the tumor can function as cancer stem cells if induced, yet also revert to the state of a “normal” cancer cell. In general, cancer stem cells resulting from mutations in stem/progenitor cells most likely undergo uncontrolled proliferation (Li and Neaves, 2006; Abdul Khalek et al., 2010; Welte et al., 2010).
Probiotic and Cancer Therapy
Advances have been made over the last century to develop anticancer drugs that lead to drastically reducing of the side effects of medications (Falzone et al., 2018). However, the beneficial effects of probiotics on metabolic profiles and biomarkers of inflammation and oxidative stress were previously reported (Asemi et al., 2012a; Asemi et al., 2012b; Tajadadi-Ebrahimi et al., 2014; Bahmani et al., 2016). Modifying the intestinal microbiome with oral probiotics has been applied to decrease side effects associated with drugs. The adverse effects caused by anticancer treatments mainly include mucositis and diarrhea. Among the advantages of probiotics are their low cost and general safety (Rondanelli et al., 2017). Probiotic application in clinical practice has displayed a wide range of advantages, such as improving antibiotics and Clostridium difficile-related diarrhea and respiratory tract infections (Rondanelli et al., 2017). Populating the gut microbiota in cancer patients with probiotics re-establishes both the functionality and quantities of commensal bacteria, which are reduced after treatments (Zitvogel et al., 2018). Nonetheless, probiotic administration in several clinical trials has been shown to re-establish healthy intestinal microbiota composition and to diminish diarrhea and other treatment-related damages to the gut, such as mucositis (Mego et al., 2013). Consistently, Lactobacillus containing probiotics prevent diarrhea and mucositis in individuals, who received chemotherapy/radiotherapy for pelvic malignancy (Gianotti et al., 2010; Lalla et al., 2014).
The specific mechanism associated with the antitumor properties of probiotics remains unclear. Gut microbiota affect a variety of pathways, which are considered to play a central role in this process. Primarily, probiotic bacteria play an essential role in the preservation of homeostasis, thus maintaining sustainable physicochemical conditions in the colon. Reduced pH causing inter alia by the excessive presence of bile acids in feces may be a direct cytotoxic factor affecting colonic epithelium leading to colon carcinogenesis. Regarding their involvement in the modulation of the pH and bile acid profile, probiotic bacteria, such as L. acidophilus and B. bifidum, have shown efficacy in cancer prevention (Biasco et al., 1991; Bernstein et al., 2005; Jia et al., 2018).
Probiotic strains are also responsible for maintaining the balance between the quantity of other participants of natural intestinal microflora and their metabolic activity. Putrefactive bacteria, such as Escherichia coli and Clostridium perfringens, naturally present in the gut, have been proven to be involved in production of carcinogenic compounds using enzymes such as β-glucuronidase, azoreductase, and nitroreductase (Górska et al., 2019).
Another cancer-preventing strategy involving probiotic bacteria, such as chiefly Lactobacillus and Bifidobacillus strains, has been linked to the binding and degradation of potential carcinogens. Mutagenic compounds associated with the increased risk of colon cancer are commonly found in unhealthy food, especially fried meat. Ingestion of the Lactobacillus strain by human volunteers alleviated the mutagenic effect of diet rich in cooked meat, which resulted in decreased urinary and fecal excretion of heterocyclic aromatic amines (HAAs) (Lidbeck et al., 1992; Hayatsu and Hayatsu, 1993; Górska et al., 2019).
Many beneficial compounds produced and metabolized by gut microbiota have been demonstrated to play an essential role in maintaining homeostasis and suppressing carcinogenesis. A specific population of gut microbiota is dedicated to the production of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate as a result of the fermentation of fiber-rich prebiotics. Except for their principal function as an energy source, SCFAs have also been proven to act as signaling molecules affecting the immune system, cell death, and proliferation as well as intestinal hormone production and lipogenesis, which explains their crucial role in epithelial integrity maintenance (Garrett, 2015; Requena et al., 2018; Górska et al., 2019).
Figure 1 shows both the advantages and potential disadvantages of probiotic administration as adjuvants during cancer treatments. The figure highlights show probiotics’ regulation of the gut’s subtle equilibrium, from microbial imbalance (dysbiotic) to functional and healthy microbiota.
FIGURE 1. Risks and benefits of probiotics associated with cancer treatment. Schematic depiction of healthy gut microbiota in humans, occupied by symbiotic bacteria (top left box) against tumor-affected microbiota and dysbiosis of the gut (top right box). Anticancer treatment may negatively influence gut microbiota, leading to dysbiotic unbalance (bottom right square). Probiotic administration may re-adjust the dysbiotic conditions mediated by tumor growth and treatment. Probiotics may improve gastrointestinal therapy–related side effects, so they re-establish the intestinal symbiosis (bottom left square). The application of probiotics in anticancer therapy has benefits and risks (central bottom box).
Effects of Probiotics on Gastrointestinal Cancer Cells
Probiotics and Gastric Cancer
H. pylori-mediated inflammation is one of the potential factors in the induction of gastric cancer in infected populations (Moss, 2017). Evidence evaluating the anti-gastric cancer effects of probiotics has focused on H. pylori-induced pathophysiology of this type of cancer. Maleki-Kakelar and others reported that by mediating numerous molecular pathways, Lactobacillus plantarum (L. plantarum) caused significant inhibitory effects on the H. pylori growth rate. Upon downregulation of the AKT gene and upregulation of the phosphatase and tensin homolog (PTEN), Bcl-2–associated X (Bax), and toll-like receptor 4 (TLR4), L. plantarum significantly inhibited the proliferation of AGS and CRL-1739 human gastric cell lines (Maleki-Kakelar et al., 2020). Interleukin-8 (IL-8) is an inflammatory chemokine that plays critical roles in inflammatory pathways (Meniailo et al., 2018). In the human gastric epithelial cell line-1 (GES-1), Lactobacillus bulgaricus (L. bulgaricus) inhibited the production of IL-8. In addition, Lactobacillus acidophilus (L. acidophilus) and L. bulgaricus inhibited adhesion of H. Pylori to GES-1 cells that attenuated inflammation in these cells (Song et al., 2019). Lin et al. reported that supplementation with Lactobacillus fermentum P2 (L. bacillus P2), L. casei L21, L. rhamnosus JB3, or their combination in H. pylori-infected mice reduced the expression level of interferon gamma (IFN-γ) along with interleukin-1 beta (IL-1β). Besides, H. pylori concentrations in the stomach of infected mice were decreased after probiotic supplementation (Lin et al., 2020). Another study demonstrated that L. acidophilus, L. plantarum, and L. rhamnosus supplementation significantly attenuated H. pylori-induced inflammation in vivo (Asgari et al., 2020). As mentioned earlier, most of the anti-gastric cancer studies have been directed at the inhibitory effects on H. pylori infection. Further experimental studies are needed for evaluating the effects of probiotic on gastric cancer inhibition mechanistically.
Ornithine decarboxylase is a crucial enzyme in the polyamine biosynthesis pathway and is responsible for catalyzing the decarboxylation of ornithine into putrescine (Svensson et al., 2008). Ornithine decarboxylase is a neovascularization agent in tumoral cells and has been overexpressed in tumors of epithelial origin including colorectal, prostate, and gastric cancers (Ma et al., 2007). Russo and others demonstrated that treatment with L. rhamnosus GG homogenate and cytoplasm extracts significantly decreased the activity of ornithine decarboxylase, reducing the polyamine content of HGC-27 human gastric cancer cells. Furthermore, in comparison with the untreated control group, probiotic treatment considerably increased the ratio of Bax/Bcl-2 (Russo et al., 2007). Xie and others reported that 8-day postoperative probiotic supplementation in gastric cancer patients significantly reduced diarrhea occurrence. Furthermore, in probiotic-induced patients, the expression level of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α) was significantly decreased compared with that in patients in the control group (Xie et al., 2018).
The urokinase plasminogen activator (uPA) is an important serine proteinase enzyme which catalyzes the production of active protease plasmin from its proenzyme plasminogen (Pavón et al., 2016; Mahmood et al., 2018). The activation of the uPA is dependent on the expression of the uPA receptor (uPAR) in the cell surface. By increasing the activity of matrix metalloproteinases (MMPs), plasmin degrades extracellular matrix components, contributing to cancer metastasis and invasion (Beamish et al., 2019). Therefore, the activation of the uPA/uPAR system plays crucial roles in the induction of invasiveness and metastatic features in cancerous cells (Rubina et al., 2017). Rasouli et al. reported that treatment with Lactobacillus reuteri (L.reuteri), in AGS gastric cancer cells, downregulated the expression level of the uPA/uPAR gene (Rasouli et al., 2017). Table 1 provides a summary of studies on probiotics and gastric cancers. Nami et al. studied the anticancer effects of Lactobacillus plantarum species on human cancer cell lines (cervical, HeLa; gastric, AGS; colon, HT-29; and breast, MCF-7) and on a human normal cell line (HUVEC). The strain exhibited desirable probiotic properties and anticancer activity against the tested human cancer cell lines; no significant cytotoxic effects on normal cells were exhibited (Nami et al., 2014).
TABLE 1. Probiotics and gastric cancer.
Probiotics and Colon Cancer
Probiotics and Colon Cancer in Human Studies
One of the important goals in treating colorectal cancer patients is improving their quality of life. The role of probiotics in decreasing the symptoms and improving the quality of life in colorectal cancer patients has been evaluated at different stages of the disease. Lacidofil supplementation for 12 weeks in patients with colorectal cancer reduced the frequency of bowel symptoms while promoted functional well-being scores compared with those of patients in the placebo group (Lee et al., 2014). Zonulin (haptoglobin 2 precursor) is a regulator of tight junctions and intestinal permeability in the wall of the digestive tract (Sturgeon and Fasano, 2016). The increased serum level of zonulin was associated with autoimmunity, inflammatory diseases, and gastrointestinal cancers (Mörkl et al., 2018). Supplementation for 16 days (6 days preoperatively and 10 days postoperatively) with an admixture of L. plantarum, L. acidophilus-11, and B. longum-88 in colorectal cancer patients caused significant reduction in serum concentrations of zonulin as well as the duration of postoperative pyrexia, antibiotic therapy, and infectious complications in comparison with those in the placebo group. In addition, probiotic intervention inhibited the p38 mitogen-activated protein kinase signaling pathway (Liu et al., 2012). Yang and others reported that probiotic intervention with an admixture of B. longum, L. acidophilus, and Enterococcus faecalis (E. faecalis) for 12 days (5 days preoperatively and 7 days postoperatively) reduced the number of days to first defecation, days to first flatus, and diarrhea in the probiotic-treated group (Yang et al., 2016). 5-Fluorouracil (5-FU) is one of the most effective drugs for chemotherapy in colorectal cancer patients (Fu et al., 2019). However, its use is associated with diarrhea (Cheng et al., 2020). In a recent study, 24-week supplementation with L. rhamnosus GG in colorectal cancer patients who received 5-FU, the frequency of diarrhea was significantly decreased (Osterlund et al., 2007). Aisu et al. reported that supplementation with a probiotic mixture containing Enterococcus faecalis T110, Clostridium butyricum TO-A, and Bacillus mesentericus TO-A in colorectal cancer patients (n = 75) significantly diminished the occurrence of superficial incisional infection compared with that in untreated patients (Aisu et al., 2015). Fusobacterium is an important bacterial pathogen, which causes overexpression of E-cadherin/β-catenin and subsequent colorectal cancer proliferation (Zhou et al., 2018). Using an admixture of B. longum, L. acidophilus, and Enterococcus faecalis (E. faecalis) in colorectal cancer patients (n = 11) for 5 days significantly altered mucosa-associated microbiota of the intestine. Furthermore, probiotic intervention reduced the secretion of taxon assigned to the Fusobacterium (Gao et al., 2015). The treatment of colorectal cancer patients (n = 84) with a combination of probiotics, which consisted of L. acidophilus, L. plantarum, B. lactis, and Saccharomyces boulardii (1 day preoperatively and 15 days postoperatively), significantly decreased pneumonia, surgical site infections, anastomosis leakage, and need for mechanical ventilation compared with those who did not receive probiotic supplementation (Kotzampassi et al., 2015). Other studies evaluating the properties of probiotics in colorectal cancer patients are summarized in Table 2.
TABLE 2. Probiotics and colon cancer in human studies.
Probiotics and Colon Cancer in Animal Studies
Probiotics exert their effects via activation or inhibition of cellular and molecular pathways (Figure 2). TNF-α is a pro-inflammatory cytokine which is produced by macrophages and T-cells and has numerous immunological roles in the regulation of inflammation (Farajzadeh et al., 2017). Mi et al. reported that chemotherapy induced significant increases in the levels of interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and TNF-α expression in rats. In turn, treatment with Bifidobacterium infantis (B. infantis) decreased the level of the aforementioned cytokines. Furthermore, probiotic treatment reduced the expression of cytokines related to Th17 and Th1 cells, and these changes led to decreased chemotherapy-induced mucositis (Mi et al., 2017). Ras-p21 is an oncoprotein and plays critical roles in the induction of different cancers (Banys-Paluchowski et al., 2018). In rats with azoxymethane-induced colorectal cancer, Bifidobacterium longum (B. longum) administration significantly suppressed the tumor volume, tumor incidence, cell proliferation, and the expression of ras-p21 (Singh et al., 1997). Administration of L. plantarum and L. rhamnosus promoted the expression of anti-oxidant enzymes such as glutathione, superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in rats with 1,2-dimethylhydrazine-induced colorectal cancer. Furthermore, the treatment increased the concentrations of pro-apoptotic agents, such as p53, B-cell lymphoma 2 (Bcl-2), BCL2-associated X (Bax), caspase-9, and caspase-3, which are involved in the p53-mediated apoptotic pathway (Walia et al., 2018). Walia and others demonstrated that 16-week supplementation with L. plantarum and L. rhamnosus decreased the expression of cyclooxygenase-2 (COX-2). Therefore, it appears that suppressing COX-2 is a potential protective mechanism against colon cancer development, leading to decreased tumor volume and incidence (Walia et al., 2015). Ki-67 is a tumor proliferative marker that is associated with the upper proliferation rate in various types of cancers (Sun and Kaufman, 2018). An admixture of L. fermentum and L. acidophilus in the mouse model of colorectal cancer reduced tumor growth, survival, and proliferation and decreased the expression of Ki-67 compared with those of the placebo group. Concomitantly, probiotic supplementation had no significant effects on the expression of cleaved caspase-3, E-cadherin, and β-catenin in comparison with that of the other group (Kahouli et al., 2017). In the dimethylhydrazine-induced colon cancer model, the probiotic strain L. rhamnosus GG suppressed the expression of β-catenin, COX-2, and TNF-α. Moreover, probiotic supplementation upregulated the expression of pro-apoptotic proteins Bax, p53, and caspase 3 and downregulated the expression of Bcl-2 as an anti-apoptotic agent (Kumar et al., 2012). Agah and others compared the efficacy of L. acidophilus and B. bifidum probiotic strains against the azoxymethane-induced mouse model of colon cancer. The results showed that the colonic lesions incidence was decreased after probiotic intervention compared with that of the control group, and these effects were more potent for L. acidophilus than for B. bifidum. Serum concentrations of tumor markers CEA and CA19-9 were reduced after treatment with probiotics, while the expression of interferon gamma (IFN-γ), interleukin-10(IL-10), and the count of CD4+ and CD8+ cells were upregulated upon intervention (Agah et al., 2019a). Wang et al. evaluated the efficacy of 12-week probiotic VSL#3 supplementation on azoxymethane/dextran sulfate sodium-induced colitis-associated carcinogenesis (1.5 × 109 CFU). Compared with that of the untreated group, probiotic supplementation downregulated the expression level of IL-6 and TNF-α in a considerable manner. Furthermore, probiotic intervention decreased the Oscillibacter and Lachnoclostridium genera, coupled with increased presence of Bacillus and Lactococcus genera in the fecal microbial composition of mice samples (Wang et al., 2018a). The c-Jun NH2-terminal kinase (JNK) is a major protein kinase which belongs to the MAPK signaling pathway and plays pivotal functions in the regulation of cell proliferation, cell death, apoptosis, and other features of cancerous cells (Wu et al., 2019). Considering its interfering role in different molecular pathways including NF-kB, JNK has binary roles in cancer development/progression (Tournier, 2013). By inhibiting the phosphorylation of glycogen synthase kinase 3 beta (GSK3β), JNK has suppressive effects on the expression of β-catenin (Hu et al., 2009). Ali et al. reported that L. casei probiotic supplementation in mice with 1,2-dimethylhydrazine-induced colon cancer significantly reduced the number of aberrant crypt foci compared with that in untreated animals. Furthermore, by upregulating the expression of phosphorylated JNK-1, L. casei regulated the expression of β-catenin and phosphorylated GSK3β, leading to significant protective effects against colon cancer (Ali et al., 2019). Sakatani and others have demonstrated that a L. brevis-derived polyphosphate significantly promoted the activation of the ERK signaling pathway, expression of cleaved PARP, and the ratio of cleaved PARP/PARP in SW620 colon cancer cells and mice bearing SW620 tumor xenografts. These changes led to increased apoptosis and inhibition of colon cancer growth (Sakatani et al., 2016a). By increasing the level of various inflammatory cytokines including IL-18, TNF-α, and TGF-β1, the NLR family pyrin domain–containing 3 (NLRP3) inflammasome can trigger metastasis in colon and colorectal cancer samples (Shaima’a Hamarsheh, 2020). The results of a recent study demonstrated that probiotic supplementation with the E. faecalis strain caused inhibitory effects on the activation of caspase-1 and maturation of IL-1β in vivo. Furthermore, E. faecalis suppressed the activation of NLRP3 inflammasome, and thereby protected animals from intestinal inflammation in dextran sodium sulfate-induced colitis-associated colorectal cancer (Chung et al., 2019a). Two-week intervention with L. casei in 1,2-dimethylhydrazine dihydrochloride-induced colon cancer in mice reduced the occurrence of chemical-induced aberrant crypt foci and the activity of ornithine decarboxylase. As noted previously, by promoting the polyamine metabolism in tumoral cells, ornithine decarboxylase has a pivotal function in the induction of cell proliferation. Hence, suppression of this enzyme in vivo diminished colon cancer growth and proliferation (Irecta-Nájera et al., 2017a). Numerous investigations have demonstrated that the expression level of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) in colorectal cancer patients is associated with poor prognosis, chemoresistance, and increased invasiveness features (Shiratsuchi et al., 2011; Vigneri et al., 2015). Valadez-Bustos and others demonstrated that probiotic intervention with B. longum BAA-999 in the colorectal murine model reduced the expression level and activity of IGF-1/IGF-1R in a considerable manner. Furthermore, after probiotic supplementation, the expression level of insulin-like growth factor-binding protein-3 (IGFBP3) was normalized. Overall, the noted alterations led to reduction in the tumor volume and size (Valadez-Bustos et al., 2019). In a comprehensive in vivo investigation, Jacouton and others found that by decreasing the expression grade of IL-22 as a pro-inflammatory cytokine and upregulating the expression of caspase-7, caspase-9, and Bik, probiotic treatment with L. casei BL23 had significant anti-proliferative effects in the azoxymethane-induced colorectal cancer model (O'Mahony et al., 2001). Table 3 provides a summary of in vivo investigations on the efficacy of probiotics in colorectal cancers.
FIGURE 2. Physiological nonspecific mechanisms of probiotics for preventing and treating colorectal cancer (CRC). Probiotics produce short‐chain fatty acid (SCFA) and mediate apoptotic and anti-proliferative reactions in CRC cells. Produced SCAFs by probiotics protect the intestinal tract by preventing the histone deacetylases (HDACs) and overexpression of mucins, including MUC1, MUC3, and MUC4. SCFAs activate 5′‐adenosine monophosphate‐activated protein kinase. This is a critical factor in keeping the hypoxia‐inducible factor via SCAFs, which improves the epithelial duct’s survival and function. Probiotics elevate antimicrobial peptides, including defensin and (LL‐37) cathelicidin, from the intestinal mucosal layer. These peptides protect them against bacterial inoculation and invasion. Probiotics inhibit enzymatic activity of pathogenic bacteria, including enzymes such as nitroreductase, β‐glucuronidase, azoreductase, and β‐glucosidase. They also decrease the production of carcinogenic agents. Probiotics inhibit carcinogenic agents (N‐nitrous and heterocyclic aromatic amines [HCA]) by two mechanisms (deactivation and binding). They are potent mutagens and result in carcinogenic mutations in intestinal cells. Moreover, probiotics increase the antioxidant enzyme production and inactivate carcinogen‐deactivating agents, including glutathione reductase, glutathione‐S‐transferase (GST), superoxide dismutase (SOD), glutathione peroxidase, and catalase (CAT), and decrease their adverse effects. Besides, probiotics eliminate the risk of CRC development due to metabolites that have effects on the cytochrome p450. This figure is adapted from Eslami et al., (2019).
TABLE 3. Probiotics and colon cancer in animal studies.
Probiotics and Colon Cancer in In Vitro Studies
As mentioned earlier, caspase-3 is a pro-apoptotic factor and its decreased levels are associated with the shortened survival time in various types of cancers (Vince et al., 2018). Bacillus coagulans (B. coagulans) Unique IS2 exerted anti-proliferative and pro-apoptotic properties in the COLO 205 human colon cancer cell line. By activating the p-53-mediated apoptotic pathway, treatment with probiotics increased the expression of BAX, activation of caspase-3, cleavage of poly (ADP-ribose) polymerase, and release of cytochrome C. Furthermore, B. coagulans reduced the mitochondrial membrane potential and Bcl2 expression level (Madempudi and Kalle, 2017). Orlando and others reported that L. rhamnosus GG intervention in Caco-2, HT-29, and SW480 colon cancer cell lines upregulated the Bax/Bcl-2 ratio, increasing apoptosis in these cells (Orlando et al., 2016). The cyclin family is a group of cell cycle regulators. Their aberrant expression is associated with tumorigenesis (Wood and Endicott, 2018). Intervention with L. paracasei subsp. paracasei reduced the expressions of cyclin D1 and cyclin E1 X12 in HT-29 colon cancer cells. In addition, probiotic intervention upregulated the expression of p27 as a cyclin-dependent kinase (CDK) inhibitor (Huang et al., 2016). CKD inhibition represents a potential mechanism for suppressing over proliferation of cancer cells induced by aberrant regulation of the cyclin family (Sánchez-Martínez et al., 2019). PTEN (phosphatase and tensin homolog) has been demonstrated to be a prominent tumor suppressor gene, which plays critical roles in the dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) (Di Cristofano et al., 1998). The additional evidence indicated that downregulation of PTEN is associated with increased tumor growth and survival. Therefore, targeting PTEN inhibitors is one of the most effective means for decreasing the tumor incidence, tumor volume, and tumor growth rate (Lee et al., 2019a). Sambrani et al. demonstrated, in HT-29 colon cancer cells, that treatment with Saccharomyces cerevisiae (S. cerevisiae) caused a significant upregulation in the expression of PTEN and caspase-3, while the expression levels of Bcl-xL and RelA were markedly decreased after probiotic intervention (Sambrani et al., 2019). Pichia kudriavzevii AS-12 treatment showed considerable cytotoxic properties in HT-29 and Caco-2 cells compared with those in normal control cells. In addition, Pichia kudriavzevii upregulated the expression of pro-apoptotic agents including Fas-R, caspase-3, -8, and -9, and BAD protein, while the expression of anti-apoptotic Bcl-2 was decreased after yeast probiotic treatment in mentioned cell lines (Saber et al., 2017). Bacillus polyfermenticus treatment reduced ErbB2, ErbB3, cyclin D1, and E2F-1 transcription factor in HT-29, DLD-1, and Caco-2 colon cancer cells. These changes led to the suppression of over proliferation of cancerous cells (Ma et al., 2010). In another study, Lee et al. investigated the anti-cancer effects of the B. adolescentis-derived butanol extract in Caco-2, HT-29, and SW480 colorectal cell lines. The results showed that the butanol extract significantly promoted the activation of macrophages and upregulated the production of TNF-α and nitric oxide in tumor cells. These changes led to the induction of cytotoxic and anti-proliferative properties against colorectal cancer (Lee et al., 2008). Survivin is an anti-apoptotic agent, which has been reported to be a crucial agent in the inhibition of apoptosis and subsequent tumor growth, proliferation, metastases, and invasiveness in various types of cancer, especially in colorectal cancer (Hernandez et al., 2011). Tiptiri-Kourpeti et al. demonstrated that L. casei ATCC 393 administration (109 CFU/ml) in CT26 and HT29 colon carcinoma cells upregulated the expression of the ligand TRAIL, which was induced by TNF-mediated apoptosis. Furthermore, L. casei declined the level of survivin expression (Tiptiri-Kourpeti et al., 2016). By significantly decreasing the expression of Bcl-2 and remarkable up-regulation in the expression grade of pro-apoptotic agents Bak and Bax, probiotic intervention with L. paracasei K5 showed anti-proliferative effects in Caco-2 cells (Chondrou et al., 2018). In another investigation, Chen et al. reported that various strains of Lactobacillus genera in HT-29 colon cancer cells promoted the expression level of the Bax protein, while decreasing the expression of Bcl-2, leading to a notable increase in the Bax/Bcl-2 ratio. Furthermore, the increased lactate dehydrogenase activity and the ensuing degradation of the cell membrane of tumor cells were observed (Chen et al., 2017). A summary of mechanistic in vitro investigations on probiotics and colon cancer is summarized in Table 4.
TABLE 4. Probiotics and colon cancer (in vitro).
Probiotics and Other Gastrointestinal Cancer
The mitogen-activated protein kinase (MAPK) signaling pathway has crucial roles in the induction of intracellular responses from extracellular signals in cells. Aberrant regulation of this pathway leads to numerous homeostatic and pathologic sequels, such as cancer (Chapnick et al., 2011). In the KB oral cancer cell line, probiotic intervention with L. plantarum reduced the expression of MAPK and caused significant upregulation in the expression of PTEN signaling transduction (Asoudeh-Fard et al., 2017). Zhang and others evaluated the properties of Lactobacillus salivarius (L. salivarius) REN supplementation in an animal model of 4-nitroquinoline-1-oxide-induced oral cancer. By decreasing the expression level of COX-2 and proliferating cell nuclear antigen (PCNA), L. salivarius intervention had significant inhibitory effects on tumor growth of oral cancer (Zhang et al., 2013). Another study demonstrated that Acetobacter syzygii and L. acidophilus (PTCC 1643) probiotic strains caused significant cytotoxicity and inhibitory effects against the KB cancer cell line (Aghazadeh et al., 2017). Barrett’s esophagus is a pathological condition in which the lining of the distal esophagus is damaged due to the exposure of the esophagus to stomach acid. In this situation, squamous epithelium of the esophagus is replaced by columnar epithelium (Spechler, 2013). Barrett’s esophagus plays a critical role in the induction of esophageal cancer and acts as an important risk factor for development of esophageal cancer (Conteduca et al., 2012). Mozaffari Namin et al. reported that B. longum and L. acidophilus treatment of Barrett’s esophagus cell lines downregulated the expression of CDX1 (caudal type homeobox 1), COX-2, TNF-α, and p53, while the expression level of IL-18 was enhanced after intervention of both probiotic strains (Mozaffari Namin et al., 2015). Table 5 provides a summary on the effectiveness of probiotics for oral, esophageal, and pancreatic cancer.
TABLE 5. Probiotics and other gastrointestinal cancers.
Conclusion
Owing to their effects on different aspects of host health, probiotics have been demonstrated to be important tools in clinical medicine. Various investigations using a plethora of experimental models, including in vitro, animal models, and human clinical studies, have shown that by inducing anti-carcinogenic properties, anti-mutagenic effects, producing short-chain fatty acids, activating the immune system of the hosts, inhibiting the bacteria-induced conversion of pro-carcinogens to carcinogens, and reducing intestinal pH (which results in reduced microbial activity), probiotics can assist in the prevention and treatment of gastrointestinal cancers. Nonetheless, to date, the benefits of probiotic strains as bio-therapeutic agents have not been adequately investigated against GI cancers. Moreover, the clinical efficacy of probiotics, especially on mortality, remains largely unexplored. Hence, more clinical studies with adequate follow-up durations are needed to obtain a clearer understanding on the potential utility of various strains and optimal doses for the administration of probiotics as pharmacological tools to combat GI cancers.
Author Contributions
HM and AS involved in conception, design, statistical analysis and drafting of the manuscript. AD, FF, ZB, HF, MA-K, and MA contributed in data collection and manuscript drafting. All authors approved the final version for submission. MT, MG, ORT, and VT, critically revised the manuscript. All authors approved the new authorship changes.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: probiotic, gastrointestinal disorders, cancer, pathology, therapy
Citation: Davoodvandi A, Fallahi F, Tamtaji OR, Tajiknia V, Banikazemi Z, Fathizadeh H, Abbasi-Kolli M, Aschner M, Ghandali M, Sahebkar A, Taghizadeh M and Mirzaei H (2021) An Update on the Effects of Probiotics on Gastrointestinal Cancers. Front. Pharmacol. 12:680400. doi: 10.3389/fphar.2021.680400
Received: 15 March 2021; Accepted: 26 November 2021;
Published: 21 December 2021.
Edited by:
Stefano Fiorucci, University of Perugia, ItalyReviewed by:
Dan-Lucian Dumitrașcu, Iuliu Hațieganu University of Medicine and Pharmacy, RomaniaVeronica Ojetti, The Catholic University of America, Rome Campus, Italy
Jose A. Uranga, Rey Juan Carlos University, Spain
Copyright © 2021 Davoodvandi, Fallahi, Tamtaji, Tajiknia, Banikazemi, Fathizadeh, Abbasi-Kolli, Aschner, Ghandali, Sahebkar, Taghizadeh and Mirzaei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Maryam Ghandali, ghandali.maryam@gmail.com; Amirhossein Sahebkar, amir_saheb2000@yahoo.com; Hamed Mirzaei, mirzaei-h@kaums.ac.ir, h.mirzaei2002@gmail.com