Probiotics and Gut Microbiota as A Possible Adjuvant Therapy for Cancer

After heart disease, cancer ranks as the second biggest reason for death worldwide. The most common cancer treatments include chemotherapy, radiation, surgery, and hormone therapy. Combining treatments, depending on the stage of the cancer, can increase its efficacy. However, chemotherapy medications also have an impact on the healthy cells that surround cancer cells. Also during bone marrow suppression, immune cells, such as lymphocytes and leukocytes, which are needed to protect against tumor cells, are attacked. The condition can be made worse by a reduction in immune cells or activity. Utilization of immunomodulatory agents to enhance immune replication may be an alternative treatment for cancer. These therapies, along with other immunomodulatory agents, refer to "adjuvant therapy". Immunomodulatory substances, such as probiotics, aid in the fight against cancer by increasing cancer cell death and protecting against oxidative stress (1). Therefore, nowadays, the wide acceptance of natural therapies such as the use of probiotic supplements with therapeutic application has improved the quality of life of people. Probiotic supplements, that mainly include live microorganisms of the Bifidobacterium and Lactobacillus species, have been studied for a range of health advantages in recent years (2). The potential of probiotics to eliminate carcinogens has been linked to a number of various processes (3). Most probiotics are members of a sizable group of the most dominant bacteria in the gut microbiota. A few of these microbes are Lactobacillus bacterial strains, which have a low risk of causing disease in people and animals and have a long history of being utilised in food production without causing any negative consequences (4, 5). Apoptosis is the process of programmed cell death that can play an important role in the prevention and treatment of cancer (20, 21).The mechanism of probiotic-induced apoptosis, its impact on the immune system and the possible benefits of apoptosis induction during probiotic therapy are discussed. Also Probiotics have been found to cause physicochemical changes in the colon that contribute to the breakdown of carcinogens. Furthermore, research has shown that probiotics decrease microorganisms related to colorectal cancer, such as Fusobacterium (89). According to all known research, probiotics stimulate apoptosis in cancerous or altered cells but do not always induce cell death in normal cells (15). In this regard, a study showed that treatment with oligofructose maltodextrin-enriched Lactobacillus acidophilus, Bifidobacteria bifidum, and Bifidobacteria infantum controlled the gut microbiome and increased TLR2 expression while decreasing TLR4, caspase 3, COX-2, and β-catenin (22). Exopolysaccharides (EPS) from nine Lactobacillus strains promoted apoptosis and G0/G1 cell cycle arrest in the colon cancer (23). Lactobacillus and Bifidobacterium activate pro-caspases and pro-apoptotic Bax while inactivating anti-apoptotic Bcl-2 proteins, causing cancerous cells to apoptosis (24). Moreover, the gut microbiota plays a critical role in chemotherapy medication metabolism, reduces chemotherapy side effects, and modulates the anti-cancer activity of these treatments (90). Chemotherapy-induced diarrhea, gastrointestinal side symptoms were reduced in acute leukemia patients who took L. rhamnosus (45). Furthermore, research has revealed that L. rhamnosus reduces the detrimental effects of chemotherapy by modulating the immune system (46). Through increased expression pro-apoptotic BAX and suppressor anti-apoptotic BCL-2 proteins, prophylaxis administration of L. rhamnosus GG and L. acidophilus in conjunction with celecoxib diminished tumor size in a colon cancer mouse model (35). Celecoxib, in combined with Lactobacillus acidophilus and Lactobacillus rhamnosus GG, dramatically decreased the number of aberrant crypt foci (ACF) and the expression of beta-catenin, NF-kB, and COX-2 in DMH-induced preclinical colon cancer Available reports indicate major probiotic protection mechanisms for chemotherapeutic toxicity including cell cycle maintenance and activation of tumor suppressor genes (36, 37), inactivation of proinflammatory cytokines, and inactivation of angiogenesis by inhibiting beta-catenin and NF-kB nuclear transport (36). Fewer studies are available to confirm the preventative usefulness of probiotics than for other types of cancer, including colorectal cancer. Several reports are accessible regarding the antitumor action of probiotics in relation to breast cancer. Daily intake of lactic acid could decrease the incidence of breast cancer in women (38). Also Radiation-related toxicity, like radiation-induced diarrhea, can be reduced by Bifidobacterium (41). Consequently, Bifidobacterium also improves the ability of chemotherapy and immunological therapy to treat cancer and decreases the side effects of these treatments, as well as radiation therapy (11). Interestingly, Bifidobacterium species improved immune function and Bifidobacterium therapy decreased melanoma growth, according to the findings (80). Researchers also found that in patients with head and neck cancer who received 70 Grays/35 fractions of radiation therapy and cisplatin treatment, L. brevis CD2 lozenges reduced oral mucositis (25). On the other hand, in a colon cancer rat model administered with 5-fluorouracil, Bifidobacterium infantis reduced the expression of proinflammatory cytokines (e.g., IL-6, IL-1, TNF-α) and contributed to minimizing mucositis (50). Additional study even found L. Gasseri orally reduced the cardiotoxicity of cisplatin. Compared to animals subjected to cisplatin and an antibiotic cocktail (vancomycin, ampicillin, and neomycin), the longevity of lung cancer rats exposed to cisplatin and Lactobacillus bacteria was much reduced (74). Likewise, an antibiotic cocktail reduced oxaliplatin's anti-cancer activity in E4 lymphomas and cisplatin's anti-cancer activity in colon carcinoma and E4 lymphomas (75). The absence of a reactive oxygen species (ROS) producing enzyme was also found to be the cause of the reduced anti-cancer activity in this research. Microflora may cause anti-cancer action by increasing the production of reactive oxygen species (ROS), according to research (75). Additionally, some bacteria play a significant role in the efficacy and toxicity of newly emerging immunotherapy medicines. Immunotherapy targeting checkpoint blockers was first licensed for the treatment of various cancers, and there are now a number of monoclonal antibodies target PD-1, PDL-1, and CTLA4 on the market. Monoclonal antibodies are regarded to be proper and effective tumor-growth inhibitors. PD-1 antibodies have been approved for the treatment of a variety of malignancies. Pembrolizumab and Nivolumab are PD-1 monoclonal antibodies, were first approved for the treatment of melanoma (78, 79). While this is going on, multiple PDL-1 antibodies have also been given the go-ahead to treat various malignancies. For instance, atezolizumab, avelumab, and durvalumab were authorized for use in the treatment of urothelial carcinoma, non-small cell lung cancer, and small cell lung cancer as well as bladder, non-small cell lung, breast, and small cell lung cancer. Additionally, the CTLA4 antibody therapy iplimumab has been licensed for the treatment of colorectal, renal cell, and melanoma cancer (78). In a melanoma mouse model, a mixture of PDL-1 antibody plus Bifidobacterium therapy stopped tumor growth (80). In advanced NSCLC and renal cell carcinoma, antibiotic exposure decreased the efficacy of PD-1 and PD-L1 antibody treatment (81). Wang et al. recently investigated the role of probiotics in lowering the incidence of colitis caused by CTLA4 blockade and discovered that vancomycin therapy increased the severity of the beginning of colitis in mice given dextran sodium sulfate (DSS) and anti–CTLA-4. Moreover, this study found that by down - regulating various proteins like IL-6, KC, and CFS3, the injection of a commonly available probiotic, Bifidobacterium, restored the vancomycin-induced microbiota unbalanced and prevented the autoimmune relating to anti treatment (65). In this study, the aim was to determine how probiotics prevent cancer cell proliferation, and it was found that probiotics reduce cancer cell proliferation by inhibiting growth factor signaling and promoting mitochondrial-mediated apoptosis. Furthermore, a study indicates that probiotics decrease the deleterious effects of chemo, immunological, and radiation therapy by reducing proinflammatory cytokines. As a result more clinical research is required to identify the strongest and appropriate probiotic strain for the development of adjuvant therapy to complement chemo, immune and radiation therapy.