Gut microbiota substantially impacts pathogenic and normal immune responses and is associated with common chronic diseases. Moreover, it has a considerable effect on the efficacy of cancer therapy. Variant gut microbiota is linked with immune checkpoint inhibitors, chemo drugs, and radiotherapy resistance. Therefore, a comprehensive interpretation of the interactions between microbiota and cancer therapies is required to encourage researchers to develop new cancer prevention strategies and weaken the consequences of the different cancer therapies. This review discusses the modulating role of gut microbiota that impacts the efficacy of cancer therapies and focuses on its influence on each treatment method, in addition to delivering an overview of the gut microbiota’s role and forming relationships between bacteria, inflammation, and cancer therapies. Highlighting the mechanism of action of probiotics, antibiotics, fecal microbiota transplantation, and prebiotics promotes cancer therapies’ efficacy. Consequently, this makes the gut microbiota essential as a new adjunct augmenting the cancer therapeutic response.
1. Introduction
Cancer is one of the top causes of death worldwide [1, 2]. Patients with cancer have a lower quality of life and a shorter lifespan [2]. Cancer was still the second most significant cause of death worldwide in 2018 [3]. Many effective anticancer treatments have been used throughout the years, such as radiotherapy (RT) (used with 50% of patients with cancer), immunotherapy, chemotherapy, and surgery [2–6]. Most anticancer treatments are (a) cytotoxic drugs that lack selectivity between normal and cancer cells, leading to undesirable side effects and (b) limited due to acquired resistance [2, 6]. Chemotherapy and RT induce necrosis and apoptosis in natural tissues and oxidative stress and inflammatory responses in other tissues, resulting in various side effects, including alopecia, gastrointestinal toxicity, hepatotoxicity, mucositis, nephrotoxicity, myelosuppression, cardiocytotoxicity, and neurotoxicity [7–11]. Also, immunotherapy might cause adverse autoimmune effects in some people, resulting in attacks on healthy cells. Like recombinant interleukin-2 (IL-2) treatment, many immunotherapies generate vascular leak syndrome and cytokine release disorder, which results in acute renal failure, hypotension, fever, and other life-threatening side effects [12–15].
The gut microbiota can reduce the side effects of anticancer therapy and improve treatment efficacy [6]. Gut microbiota is composed of 100 trillion microorganisms that colonize the gastrointestinal system [16]. These microbes weigh 1%–3% of total body weight, with nearly 1000 kinds of them, and because of this variety, each individual has a unique gut microbiota profile [2, 6] (Figure 1). Healthy people have mostly five types of bacteria: Proteobacteria, Actinobacteria, Firmicutes, Fusobacteria, and Bacteroides [2, 17]. Many factors affect gut microbiota composition, such as intestinal luminal conditions, diet, age, pancreatic enzymes, lifestyle, stress, and drugs. Also, inflammatory bowel disease (IBD), asthma, colon cancer, obesity, and psychiatric disorders are all known to influence the changes in these bacteria [16]. Gut microbiota has several functions: providing vitamins and nutrients, absorption of food, epithelial mucosa homeostasis, immune system enhancement, resistance to infection, influencing the host nervous system, and significantly modifying immune responses, both innate and adaptive. It is also believed that gut microbiota substantially impacts pathogenic and normal immune responses and is associated with common chronic diseases [6, 18–20]. Metabolites biosynthesized by microbiota may play an essential role because of their anti-inflammatory and antioxidant characteristics, management of gut barrier function, vitamin synthesis, and as a form of energy [21]. Gut dysbiosis is an imbalance in the gut microbiota composition that can alter the immune response to the tumor microenvironment (TME) [6, 21]. Many therapeutic techniques are currently being used to improve the gut flora, such as probiotics, prebiotics, antioxidants, fecal microbe transplantation (FMT), and antibiotics [21]. The gut microbiota has gotten much attention from researchers over the last two decades. Cell culture was used in preclinical and clinical experiments to discover the specific role of gut microbiota in modulating cancer treatment [6]. The role of microbiota in improving the efficacy of cancer therapies is discussed in this review. (Figure 2).
The gut microbiota colonizes the gastrointestinal system with thousands of types, and because of this variety, each individual has a unique gut microbiota profile.
Interaction between gut microbiota and immune system. Gut microbiota metabolites and dietary factors constitute the main antigen load of the GIT. Macrophages (CXCR1 +) and dendritic cells (DCs) are stimulated, and T regulatory (Treg) cells are activated by metabolic products such as short-chain fatty acid (SCFA). Follicular T cells activate B cells, inducing the production of IgA antibodies.
2. Potential Effects of Cancer Therapies on the Gut Microbiota
The gut microbiota and cancer medications interact so that cancer therapies can affect the microbiome, leading to dysbiosis, and those disruptions can alter the efficacy of the cancer therapies [5] (Figure 3). Radiation induces considerable deviations in the quantity and diversity of that microbiome, according to Kim Y, Kim J, and Park [22]. In another clinical investigation, the entire gut microbiota makeup was remodeled after pelvic radiation [23]. RT and chemotherapy negatively influence the gut microbiota by enhancing Bacteroides and Enterobacteriaceae and reducing Clostridium cluster XIVa, Faecalibacterium prausnitzii, and Bifidobacterium [24].
Gut dysbiosis is an imbalance in the gut microbiota composition that can alter the immune response to the tumor microenvironment.
Chemotherapy is one of the most commonly used cancer treatments and the mainstay of treatment for cancer patients in the early and metastatic stages. It works by inhibiting cancer cell proliferation by targeting cellular division pathways. Several chemotherapeutic drugs lack the selectivity to target tumor cells only, resulting in undesirable side effects across the body, such as cognitive impairment, fatigue, GI-related comorbidities, and immune suppression [25]. Chemotherapy causes GI-related comorbidities and systemic inflammation induced by prominent alterations in GI microbial communities [26].
In a study published in 2011, Zwielehner et al. quantified bacteria in patients following various chemotherapy regimens using molecular techniques. They discovered a substantial drop in overall microbiota and a decrease in Lactobacillus, Clostridium cluster IV, and Bifidobacterium spp. Faecalibacterium prausnitzii decreases considerably after chemotherapy, from 0% to 9% [27]. This study also showed the presence of unknown bacteria before chemotherapy, which might indicate a danger of infection from these species to the patient [26]. Chemotherapy disrupts the microbial community, resulting in alterations in the quantity of many microorganisms and a decrease in microbial diversity [28]. Fijlstra et al. found that myeloablative treatment for non-Hodgkin lymphoma patients resulted in an increase in Proteobacteria abundance but a drop in Firmicutes and Actinobacteria [29]. Also, fluorouracil (5-FU) as chemotherapy causes a dysbiosis of microorganisms and mucositis throughout the gastrointestinal system with just one intraperitoneal injection [30]. This increases the susceptibility of the mucosal tissues to ulcers and infections [31]. The associated inflammation raises the mucositis of the gut and can cause sepsis and bacteremia [32]. A nonspecific cell cycle medication, cisplatin, demonstrates some degree of cytotoxicity [33]. It can harm the structure of the cell membrane and the mucosal barrier and prevent tumor cells from replicating their DNA, which may result in infection [33]. According to Wu et al., D-methionine’s antioxidant and antioxidant properties can promote the proliferation of probiotics (lactobacilli and pine plants), minimize the disruption of the gut microbiota brought on by cisplatin, and keep intestinal homeostasis [34].
As shown in 5-FU and cisplatin, Cyclophosphamide (CTX) modifies the location and makeup of gut bacteria [35, 36]. In the mucosa of mice exposed to CTX, researchers found a drop in the phylum Firmicutes, which is spread throughout Clostridium cluster XIVa, Coprococcus, Lachnospiraceae, and Roseburia, as well as a decrease in lactobacilli and enterococci [37]. Yang et al. consistently found that giving mice CTX increased intestinal permeability and the number of potentially harmful bacteria, including Enterobacteriaceae, Pseudomonas, Escherichia coli, and enterococci [35]. Another medication that has been found to affect the gut microbiota is gemcitabine. Panebianco et al. examined the impact of gemcitabine treatment on the microbiota composition of pancreatic cancer xenografted mice [38]. In the stomach of mice given gemcitabine, the bacterial profile was changed to favor two additional phyla, Proteobacteria (especially E. coli) and Verrucomicrobia (especially A. muciniphila), which are minor members of the gut microbiota [38, 39]. Firmicutes and Bacteroidetes were under-represented in these mice’s guts [38, 39]. In the end, additional research supports the alterations in the gut microbiota after the administration of chemotherapy medications for malignant tumors, promoting the proliferation of harmful bacteria [33, 37].
The findings also show that the gut microbiota interacts bidirectionally with cancer radiation therapies. RT is known to alter the gut flora, which affects tumor radio sensitivity and toxicity, leading to a range of adverse effects. RT can disrupt the gut microbiota, resulting in decreased abundance and diversity, increased harmful microbiota (Fusobacteria and Proteobacteria), and decreased beneficial microbiota (Bifidobacterium and Faecalibacterium) [40, 41]. According to El Alam et al., the composition of the gut microbiome altered significantly following pelvic chemotherapy and radiation therapy (CRT). This change was accompanied by an increase in Bacteroides species and a decrease in Clostridiales [42]. Furthermore, radiation-induced gut microbiota imbalance contributes to mucositis, diarrhea, and tiredness in cancer patients undergoing pelvic RT [43, 44] due to the alteration of microorganisms responsible for producing short-chain fatty acids (SCFAs), leading to modifications in SCFA levels and the development of various disorders, including intestinal radiation injuries [41].
Studies have shown that pelvic RT can alter the gut microbiota’s community composition, which may mainly cause diarrhea due to the reduction of the possible protective effects of Clostridium cluster XIVa, Bifidobacterium, and Faecalibacterium as well as increasing levels of Enterobacteriaceae and Bacteroidetes [24, 45]. Concomitantly, The gut microbiota has been linked to radiation enteritis (one of the most serious and common intestinal complications), prompting an increased focus on the pathophysiology of this condition following RT [46]. The pathogenesis of radiation-induced gastrointestinal mucositis is believed to be caused by altered gut microbiota through regulating the inflammatory response, oxidative damage, permeability of the intestine, the composition of the mucus layer, the epithelial repair mechanism, and the stimulation and release of immune effector cells [47]. Xiao et al. obtained stool samples and a multidimensional fatigue self-report scale from head and neck cancer patients before and 1 month after RT. There were substantial variations in gut microbiota patterns among individuals with varied degrees of impairment over time. SCFA producers are underrepresented in the high-fatigue group, whereas inflammation-related taxa are common [48]. Eventually, radiation enteritis induced by altered gut microbiota causes tissue damage, leading to increased inflammation. Gut microbiota participates in this process through two mechanisms: translocation and dysbiosis. Radiation damages the gut barrier and mucus layer, causing bacterial translocation and inflammatory reactions. Radiation causes dysbiosis, which impacts both local and systemic immunological responses. In addition, the damaged epidermis allows microbiological agents to enter through, aggravating ulcers and inflammation [5].
On the other hand, in immunotherapy, there are often notable changes in the gut microbiome’s structure in mouse models [49]. Vetizou et al. found that stool samples taken from rats that had received a single injection of antibody against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (Ab) showed a notable impact on the composition of the microbiome, increasing the number of Clostridiales and rapidly decreasing the number of Bacteroidales and Burkholderiales. Additionally, the findings showed that the small intestinal mucosa had a relative enrichment of Bacteroides uniformis and Bacteroides thetaiotaomicron (Bt) bacteria, while the bacteria in feces were less abundant [50]. The gut microbiota and its metabolites appear to have a significant impact on the effectiveness of immunotherapy in people with cancer [51]. Gopalakrishnan et al. demonstrated that the feces of 112 patients with melanoma receiving PD-1 inhibitor treatment discovered that failure to respond had a higher concentration of Bacteroides, and respondents had a higher concentration of Faecalibacterium and Ruminococcus [52]. A connection between the particular gut microbiota and the effectiveness of immunotherapy in liver cancer was also disclosed by Zheng et al. According to Zheng et al., the gut microbiota of patients with hepatocellular carcinoma that receive antibodies against programmed cell death 1 (PD-1) inhibitor treatment showed a higher presence of Ruminococcus and Akkermansia in responders [53]. The gut microbiome promotes the efficacy of various therapeutic approaches [5], such as surgery, androgen deprivation therapy, chemotherapy, RT, and immunotherapy. Probiotics and prebiotics can restore the gut microbiota, which can help prevent psychophysiological impairments in young cancer survivors [54] and improve cancer therapies’ efficacy (Table 1).
Table 1.
A summary of previous studies explains the variations in the gut microbiome and its effect on RT, chemotherapy, and surgery.
N = 9/35–63 years/gynecologic cancer (cervix and endometrium)
Pelvic Radiotherapy
They noticed variations in the gut microbiome in cancer patients administered to radiation. The numbers of Fusobacterium and phyla Firmicutes were reduced by 10% and increased by their percent after treatment (p < 0.045) [23].
The patients had changes in counts of fecal bacteria after radiotherapy. In addition, after the initial radiation exposure, the intestinal microbiota is considerably reduced [55].
The variety of the gut microbiome dropped steadily after chemoradiation treatment (CRT), with the most significant drop occurring at Week 5. Patients with severe toxicity demonstrated differences in Clostridia species [58].
Twenty-eight patients with non-Hodgkin’s lymphoma/age, years, median 55 [45–62]
Chemotherapy (carmustine, etoposide, aracytine, and melphalan)
They discovered that feces samples taken after chemotherapy showed substantial reductions in the amount of Actinobacteria (p = 0.002) and Firmicutes (p = 0.0002) and marked raises in the amount of Proteobacteria (p = 0.0002) in comparison to samples taken before treatment [59].
Sixty-one patients with advanced/esophageal cancer
Chemotherapy (receiving 5-FU, cisplatin, and docetaxel)
After chemotherapy, Lactobacillus bacteria decreased significantly, but enterococci and Clostridium difficile bacteria rose. As a result, chemotherapy altered the gut microbiota’s composition [60].
Following surgery, six different types of obligate anaerobes were dramatically reduced. On the other hand, Enterococcus, Enterobacteriaceae, Pseudomonas, and Staphylococcus increased markedly [61].
3. Cancer Therapies and Gut Microbe as an Immune Booster
Several studies have shown that drugs such as bacilli-taxel PTX harm the immune cells, involving natural killer (NK) cells, dendritic cells (DCs), T lymphocytes, macrophages, and B lymphocytes, together with their clinical applications [62]. Interestingly, there are chemotherapeutic drugs that have two actions. Positively, they promote antitumor immune responses against a wide range of neoplasms (Figure 4). Conversely, they can suppress immunological responses by regulating lymphocytes [63].
On the other hand, RT is a double-edged sword used as a frontline therapy for roughly 60% of all new cancer patients in the curative, adjuvant, or palliative setting [64, 65], aside from tumor cells. Moreover, it can influence the TME elements, including immune cells and tumor blood arteries, harming endothelial cells and triggering inflammation. Damaged arteries activate immunosuppressive pathways by preventing CD8+ T lymphocytes from penetrating tumor cells. This leads to the formation of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) with the M2 phenotype [66]. Studies have shown that MDSCs can suppress NK cell functions and effector T cells, promoting the growth of Tregs, which inhibit the role of other immune cells [67]. RT affects the host immune system directly. An observational study was performed at the University of Minnesota and Bastyr University under Institutional Review Board–approved protocols on 14 women with breast cancer. Results have shown a significant decrease in WBC count. They could not return to normal 6 weeks post-RT [68]. Furthermore, radiation is well-known in both normal and malignant tissue as the inducer of the active form of transforming gross factor-beta (TGF-ß) [69]. This cytokine has several suppressor functions against inflammation [70]. Conversely, it impairs DCs’ function in activating T cells; consequently, they cannot be differentiated into effector cells [71]. Thus, increasing levels of those immunosuppressed cytokines by RT can affect immune response negatively.
Some studies suggest using the gut microbiota as an immune booster due to their impact on cancer immunity. It has an immunomodulating capability to affect cancer throughout all its stages, such as elimination, equilibrium, and escape [72]. During elimination, exotic epitopes like Cyclin-A1 trigger an immunological response in which T cells kill cancer [73]. Intestinal homeostasis and inflammation inhibition are maintained through the interactive relationship between the host’s adaptive and innate immune systems and gut microbiome [74]. Furthermore, gut microbial metabolites impact inflammatory signals by interacting with host immune cells directly or indirectly [75]. Complex carbohydrates are digested by bacteria such as Roseburia intestinalis, Faecalibacterium prausnitzii, and Anaerostipes butyraticus via fermentation, making SCFAs [76, 77]. Colonocytes use SCFAs as a carbon source and aid in controlling host immunological cells [78].
Also, they play a critical function in preserving intestinal barrier integrity, lowering intestinal inflammation, and safeguarding it from pathogenic pathogens by activating G-protein-coupled receptors (GPCRs). Moreover, they can influence genes that decrease the activity of histone deacetylases (HDACs) [79, 80]. SCFAs, the most prevalent in the gut lumen, and other microbiota-derived metabolites have a solid potential to control immune cells. SCFAs, for instance, can stimulate and differentiate DCs, neutrophils, T-lymphocytes, and macrophages. Inducing anti-inflammatory effects on host immune cells, SCFAs can control the production of the central proinflammatory cytokines, interleukin-12 (IL-12), interleukin-6 (IL-6), and tumor necrosis factor (TNF-), through the activation of DCs and macrophages [81]. According to recent research, gut microbiota has dramatically affected the development of the peripheral immune system [82]. Indeed, gut microbiota could activate innate immune cells by producing soluble factors translocated to the bloodstream, such as microbiota-derived peptidoglycan, which defeats the opsonophagocytic activity of neutrophils, resulting in improved protection against pneumococcal sepsis [83]. Moreover, systemic T cell deficiencies and germ-free (GF) mice’s T helper (TH1/TH2) imbalance can be corrected by moon colonization with B. fragilis and the bacterium’s unique capsular polysaccharide, which activates DC IL-12 production [84]. Finally, studies have shown that gut dysbiosis, caused by cancer treatments like chemotherapy and RT, can induce immune response malfunction, leading to oxidative stress, inflammation, and insulin resistance [74] (Figure 5).
The gut-brain axis. It comprises the central nervous system (CNS), immune system, endocrine system, and peripheral nerves. All these components interact homogenously.
4. Mechanisms of the Gut Microbiome Modulate Different Cancer Therapies
4.1. Chemotherapy
During chemotherapy drugs, gut microbes affect the host’s reaction [85]. They can also act as normal and pathologic immune responses to cancer therapies [5]. Several variables influence the community composition of gut microbiota during anticancer therapy, including host environment and nutrition, surgical procedure, adjuvant medicine (antibiotics) usage, and the effectiveness of chemotherapy delivered [86]. Many of those causes induce dysbiosis, which disrupts the microbial population and affects the symbiotic connection with the host [78]. Thus, it has been suggested that the gut microbiota plays a crucial role in regulating and adjusting the therapeutic efficiency of chemotherapy medicines.
4.1.1. Platinum-Based Chemotherapy Agents
Antineoplastic medicines based on platinum, like cisplatin and oxaliplatin, destroy tumor cells by preventing DNA replication and concentrating on mitochondria and cellular membranes [87]. Reactive oxygen species (ROS), which led to DNA damage in tumor cells and eventual tumor degeneration, were produced by invading myeloid tumor cells and were responsible for the impacts of oxaliplatin on tumor development. Because of this, Iida et al., in terms of chemotherapy, have found that oxaliplatin does not affect tumor-bearing mice that are GF or whose gut flora has been altered by antibiotics. This can be explained by the commensal microbiota of mice, which may create Toll-like receptors (TLR) agonists that encourage the development of an oxidative stress environment and tumor cell death. Because of this, there is less microbiota-dependent ROS generation without a healthy gut microbiota, which results in a less potent chemotherapeutic response [78]. So a study done on lung cancer mice treated with cisplatin and antibiotics consistently showed that they lived shorter and developed larger tumors, contrary to mice treated with cisplatin coupled with probiotics like lactobacilli; the process includes the activation of proapoptotic genes inside the tumor mass as well as the increase the immune response of the host [76].
4.1.2. Cyclophosphamide (CTX)
Cyclophosphamide is an alkylating drug that is commonly used in chemotherapy. Commensals are translocated into secondary lymphoid organs because of cyclophosphamide and because of the reduction in small intestine villus height and intestinal barrier breakdown [6]. Viaud et al. [36] found that CTX therapy effectively treated mice with subcutaneous malignancies. MCA205 sarcoma cells and B16F10 melanoma cells caused the enhancement of the gut mucosa permeability with subsequent translocation of different commensal bacteria (Lactobacillus murinus, Enterococcus hirae, and gram-positive Lactobacillus johnsonii) into the mesenteric lymph nodes (MLNs) and the spleen. Gram-positive bacteria can polarise CD4+ T cells towards IFN-γ, producing Th1 and Th17 “pathogenic” (pTh17, expressing both IFN-γ and IL-17) cells. They are essential effector cells regulating tumor progression [77]. Similarly, Daillere et al. found that proinflammatory T helper 17 (TH17) is converted when Cyclophosphamide is combined with oral bacterial administration (Enterococcus hirae and Lactobacillus johonsoni), increasing the effectiveness of cyclophosphamide in tumor-bearing mice [88] (Figure 6 and Table 2).
Mechanisms of anticancer microbiome modulation. (a) The gut microbiota primes tumor-infiltrating myeloid cells in a TLR4-dependent way for increased ROS generation in response to oxaliplatin therapy, resulting in tumor regression [78]. (b) CTX interferes with the function of the gut epithelial barrier, allowing microorganisms to enter the bloodstream. Some gram-positive bacteria (e.g., Barnesiella, Lactobacillus johonsonii, and Enterococcus hirae) can translocate to MLNs and spleen, which causes an elevation in the percentage of Th1 and Th17 to Tregs, resulting in immune-mediated cancer degradation (165). (c) The effectiveness of CTLA-4 and PDL1 antibody therapies depends on DC cell maturation induced by certain commensal bacteria (e.g., Bacteroides fragilis, Bifidobacterium species, and Burkholderia cepacia) [88, 89]. (d) Chemotherapy-induced lymphodepletion disrupts the intestinal epithelial barrier, allowing microorganisms to enter the bloodstream and activate myeloid and dendritic cells, causing an increased action of adoptively transplanted T-cells [90, 91].
Mechanisms of anticancer microbiome modulation. (a) The gut microbiota primes tumor-infiltrating myeloid cells in a TLR4-dependent way for increased ROS generation in response to oxaliplatin therapy, resulting in tumor regression [78]. (b) CTX interferes with the function of the gut epithelial barrier, allowing microorganisms to enter the bloodstream. Some gram-positive bacteria (e.g., Barnesiella, Lactobacillus johonsonii, and Enterococcus hirae) can translocate to MLNs and spleen, which causes an elevation in the percentage of Th1 and Th17 to Tregs, resulting in immune-mediated cancer degradation (165). (c) The effectiveness of CTLA-4 and PDL1 antibody therapies depends on DC cell maturation induced by certain commensal bacteria (e.g., Bacteroides fragilis, Bifidobacterium species, and Burkholderia cepacia) [88, 89]. (d) Chemotherapy-induced lymphodepletion disrupts the intestinal epithelial barrier, allowing microorganisms to enter the bloodstream and activate myeloid and dendritic cells, causing an increased action of adoptively transplanted T-cells [90, 91].
Mechanisms of anticancer microbiome modulation. (a) The gut microbiota primes tumor-infiltrating myeloid cells in a TLR4-dependent way for increased ROS generation in response to oxaliplatin therapy, resulting in tumor regression [78]. (b) CTX interferes with the function of the gut epithelial barrier, allowing microorganisms to enter the bloodstream. Some gram-positive bacteria (e.g., Barnesiella, Lactobacillus johonsonii, and Enterococcus hirae) can translocate to MLNs and spleen, which causes an elevation in the percentage of Th1 and Th17 to Tregs, resulting in immune-mediated cancer degradation (165). (c) The effectiveness of CTLA-4 and PDL1 antibody therapies depends on DC cell maturation induced by certain commensal bacteria (e.g., Bacteroides fragilis, Bifidobacterium species, and Burkholderia cepacia) [88, 89]. (d) Chemotherapy-induced lymphodepletion disrupts the intestinal epithelial barrier, allowing microorganisms to enter the bloodstream and activate myeloid and dendritic cells, causing an increased action of adoptively transplanted T-cells [90, 91].
Mechanisms of anticancer microbiome modulation. (a) The gut microbiota primes tumor-infiltrating myeloid cells in a TLR4-dependent way for increased ROS generation in response to oxaliplatin therapy, resulting in tumor regression [78]. (b) CTX interferes with the function of the gut epithelial barrier, allowing microorganisms to enter the bloodstream. Some gram-positive bacteria (e.g., Barnesiella, Lactobacillus johonsonii, and Enterococcus hirae) can translocate to MLNs and spleen, which causes an elevation in the percentage of Th1 and Th17 to Tregs, resulting in immune-mediated cancer degradation (165). (c) The effectiveness of CTLA-4 and PDL1 antibody therapies depends on DC cell maturation induced by certain commensal bacteria (e.g., Bacteroides fragilis, Bifidobacterium species, and Burkholderia cepacia) [88, 89]. (d) Chemotherapy-induced lymphodepletion disrupts the intestinal epithelial barrier, allowing microorganisms to enter the bloodstream and activate myeloid and dendritic cells, causing an increased action of adoptively transplanted T-cells [90, 91].
Table 2.
Summary of intestinal microorganism modulating the efficacy of chemotherapeutic drugs.
Bacteria
Chemotherapeutic drug
Mode of action
References
Lactobacillus species
Segmented filamentous bacteria
Cyclophosphamide
Indorse Th17 and Th1 cell responses while cyclophosphamide treatment
Gemcitabine is another anticancer medication that is an antimetabolite drug. The active metabolites gemcitabine diphosphate and monophosphate block ribonucleotide reductase and DNA synthesis, resulting in cancer cell death [93]. According to mass spectrometry tests and high-performance liquid chromatography (HPLC), interaction with the microbiota causes biotransformation of the medications [79]. It was shown that the microbiota could decrease the antitumor impact of gemcitabine. At the same time, in vivo, intratumor injection of E. coli increased the anticancer action of the prodrug CB1954 [80]. Moreover, one study demonstrated an overall increase in liver enzymes following gemcitabine therapy in a mouse model with pancreatic ductal adenocarcinoma (PDAC). However, low liver enzymes were seen when gemcitabine therapy was coupled with a high dosage of probiotics drug. Probiotics used in high doses alone reduced the PDAC and raised liver enzyme levels [94].
4.2. RT
In radiosensitivity, the function of the gut microbiome is a new notion that has sparked much curiosity. Ionizing radiation can cause DNA damage in surrounding cells that have not been irradiated, resulting in inflammatory and immunological reactivity and genomic disturbance [79]. Clinical research found that exposure to pelvic radiation alters the nature of the total gut flora [23], in addition to a study that used hematopoietic stem cell transplantation in a mouse model with complete body irradiation as a conditioning regimen. They discovered that the GF mice’s small intestines developed less radiation-induced fatal enteritis compared to mice with gut microbiota; axenic mice had fewer apoptotic endothelial cells in the intestinal mucosa and reduced lymphocyte infiltration, mediated by angiopoietin type 4 productions [95].
Furthermore, recent research that examined 45 samples of feces collected from rectal cancer patients before concurrent chemoradiation (CR) found differences in microbiota structure and functioning between CR and non-CR participants. In non-CR patients, the microbiota was detected in greater quantity than in CR patients [96]. TLRs are capable of recognizing intestinal bacteria and their products. The interplay between gut bacteria and TLRs preserves the balance of intestinal immunity. Toll-like receptors-2 (TLR2) activating microorganisms in mice, such as Lactobacillus rhamnoses GG, have been demonstrated to drive cyclooxygenase-2-expressing cells from the intestinal villi to the bottom of the intestinal crypts and produce ROS to boost the cytoprotective nuclear factor erythroid-2-related factor 2(NRF2) system, protecting the intestinal mucosa from the toxicity of radiation treatment [97]. Some clinical studies have shown gut microbes to aid in preventing radiation-related enteropathy, autophagy regulation, fasting-induced adipose factor (FIAF) production, inflammation, SCFA synthesis, and circadian rhythms are other gut microbiome-related processes for controlling radiation response [5]. The gut microbiome contributes to autophagy regulation, and Fusobacterium nucleatum has been linked to colorectal cancer chemoresistance via autophagy activation. FIAF, also known as angiopoietin-like 4 (ANGPTL4), a microbiota-regulated, epithelial-derived, secreted protein, may be efficient as a gut radioprotector, according to one study [95]. Another study discovered Bt, Clostridium perfringens, Enterococcus faecalis, and E. coli to regulate FIAF production in colorectal cancer cell lines [98]. The gut microbiota regulates the response to and recovery of irradiation-induced damage.
4.3. Immunotherapy
Immunotherapy has proven to be quite effective in cancer treatment. Immunotherapies depend on T cell-mediated immunity to identify and destroy cancerous cells [6]. Immunotherapy has three main techniques: (a) immune checkpoint inhibitors (ICI) such as nivolumab (antibody against PD-1), pembrolizumab (antibody against PD-1 ligand (PD-L1)), ipilimumab (antibody against CTLA-4). Checkpoints (PD-1, PD-L1, and CTLA-4) inhibit and confine the T cell-mediated immunity, leading to tumor cells’ escape from the antitumor immunity; (b) CpG oligodeoxynucleotide (ODN) (such as TLR9 agonist), which leads to stimulation of the immune system and the body’s defense mechanism through signaling cascade transduction; and (c) adoptive T cell transfer specific to patient’s tumors [2, 6, 79]. Moreover, since this gut microbiota may control the immune system and regulate T cell growth and activity, it is believed that gut microbiota plays a crucial role in determining the efficacy of immunotherapy, for example, the Clostridium strain-induced CD4+ T regulatory cells differentiation [2, 99]. Antibiotic therapy reduced the efficiency of immunotherapeutic CpG ODN/anti-IL-10 within B16 subcutaneous melanoma and MC38 colon cancer in mice samples. This was explained by a drop in microbial load in the gut, which reduced monocytes and their production of proinflammation cytokines at the site of malignancy [1, 78].
Previous research has linked anti-CTLA activity to Bacteroides, whereas anti-PD-L1 activity is Bifidobacterium-dependent [2, 100]. In 2019, Tanoue et al. demonstrated that we can from the feces of a healthy human obtain 11 strains of bacteria, five Bacteroides spp., Parabacteroides spp., Fusobacterium ulcerans, Phascolarctobacterium faecium, Ruminococcaceae bacterium cv2, Eubacterium limosum, and Alistipes senegalensis, stimulated IFN-+CD8 T cell production in the gastrointestinal tract, increasing host resistance to pathogenic organism infection and improving the antitumor effects of ICIs [2, 101, 102]. Inosine is a gut microbe-derived metabolite released by A. muciniphila and Bifidobacterium pseudolongum bacteria in the upper gastrointestinal tract. Inosine administration during ICI treatment significantly increased intratumoral IFN- γ+ CD8+ and IFN- + CD4+ T cell infiltration, indicating enhanced effectiveness of ICIs [103, 104].
After administering anti-PD-1 to melanoma patients, gut microbiota composition changed; the patients who responded to the treatment had increased Ruminococcaceae and Clostridiales. On the other hand, the patients who did not respond to the treatment had increased Bacteroidales [2, 52]. Administration of Bifidobacterium, a health-associated microbial group, has been proven to improve the effectiveness of anti-PD-L1 as Bifidobacterium induces DC reactivation, which stimulates IFN- γ+CD8+T-cells and boosts their effect on the tumor [1, 103]. A. muciniphila can also improve anti-PD1 effectiveness by boosting IL-12 and gut-tropic CD4C T cells and promoting the chemokine receptor CCR9 in the mesenteric and tumor-draining lymph nodes tumor beds to act as an adjuvant to immunotherapy [6]. The anti-CTLA-4 treatment causes Clostridiales to proliferate but Bacteroidales to decrease, while Bacteroides fragilis remains the same. The anti-CTLA immunotherapy does not affect antibiotic-treated mice or GF mice; nevertheless, oral administration of Burkholderia cepacia, Bacteroides fragilis, or Bt can restore the immunotherapy effectiveness and reduce side effects following therapy via (a) evoking a Th1 cell response in lymph nodes draining the tumor, which is dependent on DC maturation and IL-12, and (b) activating the TLR2/TLR4 signaling pathways to induce immunoprotection [2, 105].
4.4. Surgery
Removing the tumor surgically can be the most effective therapeutic approach, specifically for early-stage solid tumors with no metastasis [2, 106]. Surgery and gut microbiota can both affect each other. Villeger et al. discovered in a meta-analysis that patients treated with oral antibiotics and preoperative mechanical bowel preparation (MBP) in elective colorectal surgical procedures have a lower risk of postoperative complications, mortality, morbidity, and anastomotic leak rates [1, 21, 107]. At the same time, researchers found that after cancer surgery, facultative anaerobic pathogens such as Staphylococcus, Pseudomonas, Enterococcus, and Enterobacteriaceae have increased. In contrast, certain obligate anaerobes intestinal bacteria are responsible for gut integrity. Clostridium B. fragilis, C. septum, coccoides, Atopobium, and Bifidobacterium have all declined [2, 108].
In a 91-patient double-blind, randomized clinical trial, the first group received 108 to 109 colony-forming units (CFU) from each of the following symbiotic: Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium, Lactobacillus casei, and 6 g of fructooligosaccharide (FOS) for 5 days before surgery and 14 days after surgery, while the second group received placebo. The symbiotic group had a 2% infection rate at the surgical site, while the placebo group had a 21.4% infection rate [21, 109, 110]. The anastomotic leak is the colorectal cancer surgery’s most serious complication, threatening the patient’s life. Over the last few decades, anastomotic leak rates have been between 1% and 19% [2, 111, 112]. Several studies show that rates of anastomotic leaks are significantly affected by the activity and composition of gut microbiota [21, 113]. Villeger et al. examined anastomosis tissue samples by 16S MiSeq sequencing. They revealed low microbial diversity was linked to anastomotic leak formation, a substantial percentage of the dominating Bacteroidaceae and Lachnospiraceae families, and decreased Prevotella oralis [1, 2, 114].
Furthermore, patients with anastomotic leak had lower microbial diversity and more mucin-degrading Bacteroidaceae and Lachnospiraceae groups [21, 113]. Also, Enterococcus faecalis helps anastomotic leak development through its high collagen-degrading property [21, 114, 115]. Following colorectal cancer surgery, oral probiotics have decreased tumor recurrence and protected the intestinal epithelium’s biological and physical barrier functions [5, 116, 117]. Combining Lactobacillus and Bifidobacterium, for example, can help avoid infections and improve surgical outcomes [118]. Eventually, these results demonstrated that more clinical investigations are mandatory to comprehend the mechanism of microbiota interactions with surgery.
5. Improving the Efficacy of Cancer Therapies
5.1. Probiotic
Intestinal dysbiosis is a side effect of cancer treatment. At the same time, dysbiosis may be the reason for various responses to therapeutic applications [6, 119]. A probiotic is defined by the World Health Organization (WHO) as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [1, 120, 121]. The use of probiotics to manage dysbiosis has become a widely researched topic [1, 122]. Bacillus coagulans, Lactobacillus, Saccharomyces boulardii, and bifidobacteria are the widely utilized microbiome constituents as probiotics [5, 123, 124] .It has been revealed that probiotics boost the count of CD8+ T, CD4+ T, and CD3+ T cells by stimulating transcription of nearly 760 genes in tumor-infiltrating DCs, including the Cd70 and Icam1 genes, which are responsible for CD8+ T cell stimulation, as well as Rab27a and Relb, which are responsible for antigen processing and cross-presentation, and DC maturation, respectively [2, 125]. Bifidobacteria can also enhance costimulatory molecule major histocompatibility complex-II (MHC-II) DCs within the tumor’s microenvironment. Bifidobacteria can activate the host’s immune system by promoting the IFN-g pathway [2, 89, 126]. Probiotics either increase NK cells or recover by stimulating monocytes/macrophages to create IL12. Still, there is also an unknown mechanism because NK cell activation did not stop entirely after IL12 neutralization [16].
5.1.1. Probiotic and RT
Probiotics can also protect patients from irradiation-induced toxicity, according to [1, 127]. Lactobacillus rhamnosus GG (LGG) (TLR2-activating microorganisms) was discovered to minimize irradiation-induced toxicity by stimulating cyclooxygenase 2-expressing cells to reposition from the intestine’s villi to the intestine’s crypts and producing ROS to facilitate the cytoprotective NRF2 system [1, 127]. Bifidobacterium spp., Lactobacillus, and Streptococcus make normal and GF mice more resistant to irradiation toxicity by promoting Angptl4 expression [6]. Also, in a study, the administration of eight different lactic acid-producing strains (VSL#3) was shown to minimize the occurrence of radiation-induced diarrhea in 490 patients [1, 21, 128]. Also, mucositis incidence decreased, treatment completion increased after CD2 lozenges, and Lactobacillus brevis oral therapy was given to patients receiving RT for head and neck cancer [6].
5.1.2. Probiotic and Immunotherapy
Bifidobacterium can diminish tumor development and improve antitumor efficacy by boosting ICIs (PD-L1 blockade and anti-CTLA-4) by stimulating DCs to release IL-12 tumor-specific CD8+ T cell differentiation and activation [2, 21, 129]. Also, administering genetically modified E. coli Nissle 197 helps T cells destroy cancer cells by creating nanobodies coupled with two anticancer targets, PD-L1 and CTLA-4 [102, 130]. Bacteroidetes fragilis administration diminished the incidence of colitis in GF mice after ipilimumab (anti-CTLA-4 immunotherapy), as the amount of Bacteroidetes was substantially lower in the patients who had ipilimumab-associated colitis than in the patients who did not develop colitis. The Bacteroidetes phylum stimulates and matures plasmacytoid DCs in MLNs, culminating in the activation and proliferation of ICOS C Treg cells in the lamina propria [6, 131].
5.1.3. Probiotic and Chemotherapy
One of the well-researched drugs in treating colorectal cancer is 5-FU. When Lactobacillus rhamnosus GG is combined with (5-FU), severe diarrhea and abdominal discomfort are reduced [6, 21, 132]. Researchers also discovered that antibiotic-treated and GF mice had reduced CTX-induced Th17 cell conversion and reduced tumor regression. CTX-mediated Th17 cell conversion was restored after antibiotic-treated mice were given Lactobacillus johnsonii and Enterococcus hirae to enhance T cells’ immunological response [1, 36, 88]. In a mouse model of nonmetastasizing sarcoma, the efficacy of cyclophosphamide (CP) was dependent on certain gram-positive bacteria. (Lactobacillus johnsonii, segmented filamentous bacteria, L. murinus, and E. hirae) [6]. After the administration of Clostridium species, the period of initial irinotecan therapy was shortened to the seventh day of recovery, although Lactobacillus and Bifidobacterium species were significantly reduced [6, 78]. Also, the intratumoral CD8/Treg ratio has been reported to enhance after E. hirae translocation, and in individuals with cancer-related cachexia, probiotics can help their weight improvement [6, 133]. Even though probiotics are generally beneficial, it was discovered that supplementing with Bacillus subtilis in patients with a highly impaired immune system was associated with septicemia. The delivery of Lactobacillus rhamnosus GG to critically ill patients was also associated with bacterial translocation from the gut to the blood. As a result, it is critical to proceed cautiously when using probiotics [103, 134, 135].
5.2. Fecal Microbiota Transplantation (FMT)
Healthy gut microorganisms are transplanted to ill patients through the upper or lower gastrointestinal tract in a procedure known as FMT. FMT is a cutting-edge process that seeks to reconstruct the gut microbiota of patients by restoring intestinal microbial diversity (Figure 7) (137, 138).
Fecal transplantation procedure. First, we prepare the bowel, and the patient is asked to ingest antibiotics and purgative (1). Then, sample dissolution and donor stool suspension (2). Fecal transplantation to the patient through nasogastric, nasoduodenal, or transcolonic infusion (3).
5.2.1. FMT and RT
Several FMT doses are an effective therapy for reducing radiation-induced toxicity and increasing irradiated mice’s survival rate. FMT can also help to restore intestinal epithelial integrity and improve gastrointestinal symptoms and function [5, 18, 136]. The small intestine tissues of saline-treated and FMT-treated mice were subjected to microarray analysis by Cui et al., which confirmed a substantial gap in the mRNA expression profile between the two groups, indicating that FMT conserves the bacterial communities, retaining the lncRNA and mRNA expressions [18].
5.2.2. FMT and Immunotherapy
It has been demonstrated that FMT improves anti-PD-1 response by boosting the number of T cells that regulate the colon mucosa’s immune system and treat cancer immunotherapy side effects [102, 137, 138]. According to Villeger et al., after anti-PD-1 therapy, the patients were divided into responding and nonresponding. The fecal microbiota of each group was orally transplanted into GF mice with melanoma. They discovered that mice treated with responding FMT had one-sixth the tumor size of mice treated with nonresponding FMT after 28 days of treatment [1, 52]. According to Routy et al., patients who received antibiotics during anti-PD-1/PDL-1 antibody treatment did not respond adequately to the therapy. Still, sensitivity to immunotherapy was restored once the microbiota of patients who responded to treatment was transplanted and Akkermansia muciniphila to antibiotics treatment patients [21, 139]. Nevertheless, data from 2000 to 2020 revealed that FMT was associated with negative consequences in 19% of cases and severe side effects such as bacteremia in 1.4% of patients [140, 141]. As a result, the FDA has put decisive regulations regarding FMT, insisting that each FMT sample must be tested for potential drug-resisting bacteria, among other investigations, to certify its efficacy and safety [102].
5.3. Prebiotics
Prebiotics are substances that the host is unable to digest. These components work as food for gut microbiota, positively affecting it [142]. Prebiotics are carbohydrates, including xylooligosaccharides (XOS), galactooligosaccharides (GOS), FOSs, fructans, and inulin [21]. One of the main effects is increasing the number of particular bacteria, which improves the host’s health and may positively affect the antitumor treatment [1, 16]. It has been observed that FOS, XOS, GOS, and inulin increase the amount of Lactobacillus and Bifidobacterium, among others, resistant [121, 143]. Starch is another extensively used prebiotic that enhances probiotics’ biological activity, particularly Bifidobacterium, and improves immune responses [144]. Some animal models and cell culture studies suggest prebiotics can control colorectal carcinogenesis [21, 145, 146]. Inulin is one of the prebiotics found to limit colon cancer growth in a murine model survey [147]. However, the effectiveness of prebiotics is contingent on the host’s healthy gut microbiota. As a result, using prebiotics and probiotics (synbiotics) may show great results [1]. It has been found that using probiotics, prebiotics, and synbiotics before operations decreases infections and inflammations after procedures and decreases morbidity and hospital stay [148, 149].
5.3.1. Prebiotics and RT
In a recent placebo-controlled clinical trial, oligosaccharide supplementation was investigated in patients with gynecological malignancies who had radiation with a total dosage of 52.2 Gy after surgery [56]. Although radiation therapy has been shown to reduce Bifidobacterium levels and fecal Lactobacillus, this prebiotic supplement improved their recovery [150].
5.3.2. Prebiotics and Immunotherapy
It has been shown that a low variety of gut microbiota is linked to decreased immunotherapy efficacy in advanced melanoma patients [52]. According to the American Gut Project, individuals who consume 30 different plant species (many of which have prebiotic qualities) weekly have the healthiest and most diverse microbiomes [151]. According to a new study, 46 patients on anti-PD-1 medicine evaluated their diet and supplement use. Patients who indicated they ate a high-fiber diet were roughly five times more likely than those who stated they ate a low-fiber diet to respond to therapy [152]. Inulin-fed animals with inhibited colon cancer growth had the highest Akkermansia muciniphila. Moreover, A. muciniphila has been associated with therapeutic response in anti-PD-1/PDL-1 immunotherapy [139, 147].
5.3.3. Prebiotics and Chemotherapy
It has been proposed that manipulating the microbiome’s diet during cancer treatment could shield patients from the side effects of chemotherapy. Polysaccharides derived from squid ink of Ommastrephes bartramii after cyclophosphamide treatment affected the intestinal microbiota structure in mice [153]. It boosted the amount of Bifidobacteria while decreasing the amount of Bacteroidetes [85]. Prebiotics were evaluated in mice with cytotoxic drugs (cyclophosphamide, methotrexate, vincristine, cytarabine, doxorubicin, and 5-FU) [154]. Dietary supplementation with inulin and oligofructose increased the life span of mice with an intraperitoneal type of transplantable liver tumor, potentiating the impact of all six medications [155]. The inulin-doxorubicin combination keeps the response to therapy in vitro at lower dosages than doxorubicin alone [156].
5.4. Antibiotics
Using antibiotics affects and decreases the gut microbiome [157, 158]. Each antibiotic class has distinct characteristics and excretion mechanisms, resulting in diverse microbiome composition changes [159]. Antibiotics efficiently treat many infections and can be used to clear microorganisms that impair cancer therapy efficacy [1]. A study found that antibiotics like anisomycin, prodigiosin, and salinomycin stop colorectal cancer cells from growing by targeting various molecular processes [160–162]. However, antibiotics result in gut microbiota dysbiosis [1]. They have negative health consequences due to their lack of specificity.
Prophylactically, cancer patients receive long-term antibiotic treatment [163]. However, the widespread and prolonged use of broad-spectrum antibiotics to lower infection-related death and morbidity in cancer patients is probably a factor in the development of antibiotic resistance [164]. The rapid loss of antibiotic potency brought on by bacterial antibiotic resistance poses a serious risk to the effectiveness of cancer treatment [165]. Antibiotic resistance is defined as the ability of microorganisms to survive when exposed to antibiotics that usually kill them or prevent their growth [166]. Some mechanisms can lead to antibiotic resistance in 1 or 2 classes of antibiotics, whereas others result in multidrug-resistant (MDR) isolates [167, 168].
Antibiotic failure in cancer patients increases the frequency of sepsis, sepsis-related mortality, and sepsis-associated costs of care [59, 169–171]. In postchemotherapy infections, Teillant et al. discovered that 26.8% of microorganisms were resistant to antibiotics. According to that study, among patients undergoing chemotherapy for hematological malignancies in the United States, a 30%–70% decrease in antibiotic efficacy would lead to around 4000–10,000 extra infections and 500–1000 additional deaths annually [172]. In 109 patients with hematological diseases who were undergoing chemotherapy, in patients who had infections caused by MDR bacteria, survival was significantly lower compared with the survival of those who had infections caused by non-MDR isolates [173].
Antibiotic or chemotherapy administration can result in gut microbiota dysbiosis, altering the diversity of bacteria [59]. Dysbiosis in the gut microbiota can increase the risk of resistant bacteria [174], invasive infections, post-transplant complications, and reduced efficacy in cancer patients who are treated with immunotherapy [175]. Monitoring gut microbiota for its composition, administering protective commensal bacteria as probiotics and prebiotics to reduce antibiotic-resistant infections, and promoting a healthy microbiome could be promising approaches for preventing antibiotic resistance, minimizing antibiotic use, and leading to positive outcomes in cancer patients [176]. So, further research is required to reduce the harmful effects of antibiotic use during cancer treatment [1]. One of these studies suggests that probiotic coadministration during antibiotic therapy has some promising prospects [1].
5.4.1. Antibiotics and RT
To determine if the gut microbiota may affect the antitumor immune response after radiation to nongut tissues, one group employed mice of melanoma B16-OVA and lung/cervical cancer TC-1 models. They discovered that the antibiotic vancomycin promotes the tumoricidal immune response induced by radiation and inhibits tumor growth [5]. This synergy is based on tumor-specific antigens cross-presentation to cytolytic CD8 + T cells and interferon-γ [177]. This research indicated that removing vancomycin-sensitive bacteria improved RT’s anticancer effect [18].
5.4.2. Antibiotics and Immunotherapy
Antibiotics are crucial in tumor immunotherapy; they can even influence the therapeutic effects of immunological drugs by modifying the gut microbiota composition. Researchers found that vancomycin-treated mice have improved the efficiency of CTLA-4 blockade as vancomycin decreases gram-positive bacteria, giving the gram-negative Burkholderiales and Bacteroidales a chance to increase [50]. Routy et al. found that when mice received antibiotics concomitantly with anti-PD1 mAb alone or in combination with CTLA-4 mAb, they had shorter life duration. In human patients, 69 out of 249 received antibiotic therapy (fluoroquinolones, macrolides, or b-lactam+/− inhibitors) concomitantly with PD-1/PD-L1 mAb, which resulted in shorter progression-free survival and overall survival. Furthermore, the detrimental effect of antibiotics on overall survival after PD-1/PD-L1 inhibition was endorsed by a validation cohort involving 239 patients [139].
Ahmed et al. used ICI to treat 60 patients with advanced cancer who had different microbiological infections; 17 of these patients received antibiotics both before and after the therapy. It is essential to keep in mind that when comparing the two groups, there was no difference in PD-L1 expression. Researchers discovered that patients’ response rates were lower in those who received systemic antibiotics within 2 weeks of starting their first medication dose. The explanation provided was that antibiotics—extensive spectrum antibiotics, have the power to modify the composition of the gut microbiota by reducing the number of microorganisms that trigger a suppressive immune response [178]. Petrelli et al. reported that 29% of patients got antibiotic therapy, which decreased the patients’ prognosis-free survival, and also, antibiotics have been connected to a higher risk of mortality [175].
5.4.3. Antibiotics and Chemotherapy
Iida et al. found that the anticancer impact is diminished in GF mice or animals that were given an antibiotic cocktail because altered microbiota activity results in decreased expression of the Nox1 and Cybb genes, which encode for the ROS-generating NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase 2 [78].
In mice treated with antibiotic or GF mice, the anticancer activity of cyclophosphamide (CP) was reduced, according to Viaud et al., when compared to gram-negative bacteria antibiotics; gram-positive bacteria antibiotics have much lower CP efficacy. In a sarcoma (nonmetastatic) mouse model, certain gram-positive bacteria (Lactobacillus johnsonii, segmented filamentous bacteria, E. hirae, and Lactobacillus murinus) were found to be required to modulate the anticancer activity of CP [36] Also, and antibiotic treatment reduces the recruitment of immune cells that play a crucial role in mediating tumor regression and their proinflammatory potential [6].
Conversely, antibiotics and chemotherapy may work in concert as Enterobacteriaceae (R. planticola) can biotransform doxorubicin to its metabolites, 7-deoxyrubicinol and 7-deoxyrubicinolone, through anaerobic conditions through a deglycosylation mechanism. This helps to mitigate the toxicity of chemotherapy to other organs, as well as the cytotoxicity of CB1954, fludarabine de phosphate, 5-fluorocytosine, gemcitabine, tretazicar, and 6-mercaptopurine-2-deoxyriboside, which is amplified when combined with E. coli, while L. welshimeri enhanced the effects of Fludarabine de phosphate and CB1954 alone. Additionally, the bacterial components of the gut microbiome release enzymes that aid in the detoxification of 5-FU [179].
6. Conclusion and Future Perspectives
Research-based evidence discovered the importance of gut microbiota in cancer therapies and suggests that restoring healthy bacteria can improve anticancer treatment efficacy and limit tumor growth [180]. Some bacterial species are fundamental for cancer therapy, whereas other species of bacteria reduce the effectiveness of cancer therapy by various mechanisms. To determine the most beneficial microbiota composition in treatment facilities, an extensive human database and detailed investigation of bacterial species’ association with clinical outcomes are necessary [79]. Disrupting the gut microbiota composition may contribute to disease progression and influence treatment strategies. After identifying the optimal microbiota composition for each clinical condition, the following phase is altering the patient’s microbiome to improve the efficacy of cancer therapies [79]. For instance, researchers provided bacteria strains as probiotics or performed the FMT techniques as new strategies to regulate microbiota composition accurately. So, the gut microbiota’s persistence and response to physiological, pathological, and environmental changes will make it a promising biomarker, diagnostic tool, and potential therapeutic target [181]. New developments in the use of trained machine learning techniques for assessing patient microbiota composition while accounting for regional and intercohort variation [182]. So, targeting the microbiota will hold promise for developing better cancer treatments that will lower mortality and enhance quality of life. It might be advantageous to use the microbiota as a trustworthy indicator to estimate how it affects the host physiology and how the patients will respond to cancer treatments. However, it is unclear which gut microbiota composition effectively promotes cancer therapy response, thoroughly tested in clinical trials. Other essential parameters for regulating the gut microbiota, such as adjusting antibiotic formulation, must also be discovered. A thorough knowledge of these pathways is required to better gut microbiota control and expand the options for immune surveillance and cancer therapy.
Nomenclature
CIA
chemotherapy-induced anemia
CNS
central nervous system
FMT
fecal microbe transplantation
HCC
hepatocellular carcinoma
IBD
inflammatory bowel disease
ICI
immune checkpoint inhibitors
RT
radiotherapy
SCFA
short-chain fatty acid
TGF-ß
transforming gross factor-beta
TLR2
Toll-like receptors-2
TNF
tumor necrotic factor
Ethics Statement
This is not required, as no human individuals were included in the study.
Consent
This is not required, as no human individuals were included in the study.
Conflicts of Interest
The authors declare no conflicts of interest.
Author Contributions
Study concept and design: Zeinab S. Sayed, Noha. S. Yasen, and Esraa N. Mohamed. Searching the literature: Hanan A. Elbary, Rawan. A. Altaf, Reem. A. Elsayed, Mostafa A. Madkour, Al-Hassan S. Wadan. Data collection: Zeinab S. Sayed, Mostafa A. Madkour, Noha S. Yasen, and Reem A. Elsayed. Manuscript drafting: Esraa N. Mohamed, Hanan A. Elbary, Al-Hassan S. Wadan, and Mohamed Toema. Manuscript revision: Mohamed Toema, Mohamed H. Nafady, Sanaa A. El-Benhawy, Ph.D. Supervision: Mohamed H. Nafady and Sanaa A. El-Benhawy, PhD. All the authors approve this version of the manuscript for submission.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
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