Human microbiota and effectiveness of cancer chemotherapy

Shvets Yu.V.*1, Lukianova N.Yu.2, Chekhun V.F.2

Summary. This review presents up-to-date information on the effects of microbiota on the individual chemotherapy sensitivity in cancer treatment. Recent studies have shown that a fine balance between the intestinal microbiota and the immune system is crucial for maintaining an efficacy of cancer chemotherapy. A number of antitumor drugs have complex mechanisms of action involving not only direct effects but also the activity of the intestinal microbiota and the immune system. A unique combination of these factors contributes to the individual chemotherapy sensitivity.

Submitted: May 10, 2020.
*Correspondence: E-mail: julia73_shvets@ukr.net
Abbreviations used: 5-FU — 5-fluorouracil; ALL — acute lymphoblastic leukemia; CDDL — cytidine deaminase long form; GF — germ free; ICI — immune checkpoint inhibitor; ROS — reactive oxygen species.

DOI: 10.32471/exp-oncology.2312-8852.vol-42-no-2.14611

The outbreak of Covid-19 infection makes us think again about the fact that there are individual features of the infectious process. Similarly, the individual characteristics of the macroorganism determine the predisposition to the development of malignant neoplasms, the effectiveness of chemotherapy, radiotherapy and immunotherapy. Recently, more and more attention is paid to the microbiota of the human body as a key factor that determines the individual features of metabolism and functions of vital body systems: digestive, immune, hormonal, nervous.

Individual sensitivity of patients to therapeutic influences is a key problem in the treatment of any human pathology, including cancer, and is caused mostly by the genetic and epigenetic characteristics of a particular individual. However, apart from these, there are other important factors. Today it is known that the human body is a “superorganism” or “holobiont”, i.e. is a whole ecosystem inhabited by trillions of bacteria, protozoa, viruses, which generally form the microbiota of each individual macroorganism [1–4].

The microbiota of bacterial origin is one of the most studied and influential. In modern research projects Human Microbiome Projects 1 and 2, the species diversity of bacteria that inhabit the human body has been studied, and the impact of microorganisms on human health and pathology has been determined [5, 6]. According to recent estimates, the number of bacterial cells in the human body slightly exceeds the number of own cells of the macroorganism (the ratio of bacterial cells to eukaryotic cells of the human body is 1.3/1) [7]. The microbiota of the human body accounts up to ~ 2000 species of bacteria, ~ 800 of which are inhabitants of the intestine. The intestinal microbiota is the most numerous and has a tremendous effect on metabolic processes in the human body. All representatives of the intestinal microbiota belong to ~ 30 phyla, but the largest number of bacteria belongs to only 5 phyla: Firmicutes (Clostridia, Bacilli, Lachnospiraceae, Ruminicoccaceae, Veillonellaceae), Bacteroidetes (Bacteroidaceae), Actinobacteria (Bifidobacteria), Proteobacteria (Enterobacteriaceae), Verrucomicrobia (Akkermansia muciniphila) [8, 9] (Fig. 1). The most abundant are two phyla — Firmicutes and Bacteroidetes. The composition of the microbiota changes during human life and depends on many factors [10, 11] (see Fig. 1).

 Human microbiota and effectiveness of cancer chemotherapy
Fig. 1. Taxonomic distribution of human intestinal microbiota by phyla and the key factors influencing composition of microbiota

It was estimated that in the total number of genes of the holobiont, the genes of the human body make up only 1%, while 99% account for the set of genes of the human microbiota, which is called the microbiome. The microbiome encodes a wide variety of enzymes that carry out the biodegradation of various substances, foods and drugs that enter the human body [12–14]. Sometimes the human microbiota is called a “metabolic organ” and some scientists even use the term “forgotten organ” because the value of the microbiota in human health and pathological conditions has long been underestimated [15].

To date, it has been investigated that bacterial cells may be present in various organs and systems that were previously considered sterile. Bacteria are the components of the microenvironment of many types of tumors: tumors of the gastrointestinal tract, lungs, reproductive system, breast. The activity of these bacteria may be one of the causes of tumor development, as well as partially determine the resistance of the tumor to chemotherapy [16, 17]. It is also necessary to recognize that the effects of microbiota on cancer chemotherapy are mostly realized through various physiological systems of the host, especially, the immune system.

To study the effect of microbiota on the effectiveness of cancer chemotherapy, the animals that are born and live in germ-free (GF) conditions or the animals, in which the microbiota is eliminated by the use of broad-spectrum antibiotics, are being used. Both systems have their advantages and disadvantages. For example, in GF animals, all organs and systems develop in the complete absence of microorganisms. Therefore, the immune system of such animals is significantly underdeveloped, both structurally and functionally. Since the effectiveness of chemotherapy depends largely on the activity of the immune system, the GF model of animals, in this sense, is not adequate. When using animals in which the microbiota is eliminated­ by antibiotics, it should be understood that antibiotics, like any chemotherapy, have a number of toxic side effects on those organs and systems whose normal activity is important for the effectiveness of antitumor chemotherapeutics. Studies using GF animals have shown that the use of antitumor drugs in such animals with grafted tumors is not effective. The effectiveness was restored when these animals were contaminated by some microbiota representatives [3].

In the case of studying the effect of microbiota on the effectiveness of cancer chemotherapy in humans, special attention is paid to the study of those cases where chemotherapy occurs simultaneously with antimicrobial therapy.

When considering the interaction of microbiota and cancer chemotherapy, three logical areas of research could be identified: the effect of chemotherapy on the microbiota, the effect of microbiota on the effectiveness of cancer chemotherapy and the effect of microbiota on toxic side effects of chemotherapy. Also extremely attractive is the idea of ​​changing the composition of the microbiota for increasing the effectiveness of chemotherapy and decreasing its toxicity. What are the natural ways to correct the microbiota? Isn’t dietary therapy the safest and most environmentally friendly approach to such task?

The effect of chemotherapy on the species composition of the microbiota

Chemotherapeutic anticancer agents are divided into certain categories depending on their structure and mechanisms of action. Thus, the key groups are: alkylating drugs, antimetabolites, cytotoxic antibiotics, protein kinase inhibitors, topoisomerase inhibitors, cell division spindle blockers, antihormonal drugs. The effect of some drugs on the composition and translocation of the intestinal microbiota has been studied (Table).

Table. Effect of anticancer agents on microbiota in experiment
Chemotherapeutic drug Effect on the microbiota and the immune system
Cyclophosphamide Induction of dysbacteriosis, reduction of intestinal microbiota diversity, bacterial translocation;Firmicutes ↑1, Bacteroides ↓1;

Decrease in the number of Treg, increase in the number of CD8+ T cells, Th1 та Th17 in vivo

Cisplatin Induction of dysbacteriosis, bacterial translocation;Firmicutes ↓1, Lactobacillus ↓1, Ruminococcusgnavus ↓1, Bacteroidaceae ↑1, Erysipelotrichaceae ↑1, Helicobacter ↑1, Lactobacillus ↓2, Coprococcus ↓2, Escherichia ↑2, Bacteroides ↑2, Clostridium ↑2
5-FluorouracilMethotrexate Induction of dysbacteriosis;Clostridium ↓2, Lactobacillus ↓2, Streptococcus ↓2, Enterococcus ↓2, Staphylococcus ↑2

Induction of dysbacteriosis;

Lachnospiraceae ↑1, Ruminococcaceae ↓1, Bacteroidales ↓1

DoxorubicinMitomycin C Induction of dysbacteriosis of oral cavity and intestines in humans, Firmicutes/Bacteroidetes ↓1, Lachnospiraceae ↓1, Clostridium_IV↓1, Roseburia ↓1, Clostridium_XlVa↓1, Oscillibacter1, Butyricicoccus ↓1, Clostridiales ↓1, Akkermansia ↑1Induction of dysbacteriosis;

Pseudomonas aeruginosa ↓3, Escherichia coli ↓3, Klebsiella pneumoniae ↓3, Enterobacter cloacae ↓3

Irinotecan Induction of dysbacteriosis;Escherichia spp. ↑2, Clostridium spp. ↑2, Enterococcus spp. ↑2, Serratia spp. ↑2, Staphylococcus spp. ↑2, Proteus spp. ↑2, Clostridium spp. ↑2, Peptostreptococcus ↑2;

Bacillus spp. ↓2, Bifidobacterium spp. ↓2

Notes: 1data confirmed in experiments using mice; 2data confirmed in experiments using rats; 3results of in vitro studies.

Cancer chemotherapeutics are usually administered parenterally and orally. In the case of parenteral administration, from the first minutes > 90% of the chemotherapeutic agent is in circulation and acts directly on the cells of various organs and systems, including tumor tissue [3]. When administered parenterally, xenobiotics undergo the first stages of metabolism in the liver, then enter the small intestine through the bile ducts, where they are subjected to secondary metabolism with the participation of microbiota and then reabsorbed in the intestine. When administered orally, the drugs are first metabolized by the enzymatic systems of the intestinal microbiota, and then, after absorption in the intestine and transport through the portal vein, undergo metabolic transformations in the liver. It is believed that only ~ 10% of the active form of the drug enters the circulation and acts on the tumor and other tissues of the body when administered orally.

The results of clinical observations of patients undergoing chemotherapy indicate that most patients develop dysbacteriosis of the intestine, oral cavity, and vagina [18]. A number of antitumor drugs have a proven adverse effects on the intestinal microbiota [19–21]. Moreover, chemotherapy induces the changes not only in intestinal microbiota but also in microbiota of tumor tissue.

It is known that representatives of the human intestinal microbiota belonging to different species possess different sensitivity to the action of antitumor drugs [21]. Mitomycin C has been shown to be effective against opportunistic gram-negative bacteria: Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae [20]. In in vitro studies, the sensitivity of bacteria in the human intestinal microbiota belonging to 34 species to 12 most commonly used antitumor chemotherapeutics have been examined [21]. The sensitivity of bacteria belonging to the genera Lactococcus, Lactobacillus, Bifidobacterium, Bacteroides, Blautia, Slackia and representatives of the species Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Faecalibacterium prausnitzice and Serratiamarcescens was studied [21]. The studied bacteria were shown to be resistant to taxoids, docytaxel and paclitaxel, the drugs that disrupt the eukaryotic cell division spindle. Drugs such as erlotinib, gefitinib, and afatinib, which are inhibitors of EGF-R-dependent tyrosine kinase pathways, exerted different effects on the studied bacteria. It is believed that in this case, cross-reactivity of chemotherapeutics is possible due to the similarity of target proteins between pro- and eukaryotic cells. Most of the bacteria studied were resistant to so-called prodrugs such as irinotecan and capecitabine. These drugs are converted into active therapeutic forms only if they are metabolized by enzymes in the human body. Lactobacilli were resistant to cyclophosphamide. However, it was shown that lactobacilli and bifidobacteria were sensitive to 5-fluorouracil (5-FU), doxorubicin, gemcitabine and pemetrexed.

It was shown that the use of cisplatin in C57BL/6 mice with grafted ovarian carcinoma led to the development of dysbacteriosis [22]. In the feces of mice, there was observed an increased content of bacteria from the families Bacteroidaceae (eg, Bacteroides uniformis) and Erysipelotrichaceae and significantly decreased content of bacteria of Ruminococcus gnavus. This study also showed that the administration of cisplatin to animals led to the destruction of the epithelial cells of the ileum and colon with the subsequent development of mucositis. In another study, when C57BL/6/J mice were injected with cisplatin, in the intestinal microbiota a significant decrease of Firmicutes phylum bacteria (by 27%), including members of Lactobacillus genus, and an increased Helicobacter counts were observed [23]. The use of cyclophosphamide in mice reduced the diversity of intestinal microbiota, decreased the content of Bacteroidetes phylum and increased the content of Firmicutes phylum [24].

Disturbed intestinal epithelial integrity along with the development of tissue inflammation was also observed in BALB/c mice after methotrexate administration [25]. The use of methotrexate led to the development of mucositis and intestinal dysbacteriosis in mice — decreased number of members of the family Ruminococcaceae, and increased number of bacteria of the family Lachnospiraceae. There was also observed a significant decrease of the counts of bacteria from genus Bacteroidales, especially bacteria of the key to the human intestine and mice species Bacteroides fragilis. It is known that the bacterium B. fragilis has tolerogenic effect on local immune response. In this study, the authors also showed that B. fragilis promoted the reduction of the polarization of macrophages in the direction of the proinflammatory M1 phenotype. The use of metronidazole, an antibiotic to which B. fragilis is sensitive, disrupted the tolerogenic effect of these bacteria and exacerbated the development of inflammation of the intestinal mucosa in response to methotrexate [25]. Therefore, the introduction of the cytostatics, in addition to a direct toxic effect on the cells of the intestinal epithelium, also exerted the effect mediated by the microbiota, which leads to increased inflammation.

In a study performed on rats, administration of cisplatin at therapeutic concentrations to these animals resulted in a reduction in the number of bacteria belonging to the genera Lactobacillus and Coprococcus and an increase in the number of bacteria belonging to the genera Escherichia, Oscillospira, Paraprevotella, Bacteroides, Clostridium, Desulfovibrio and Mucispirillum [26].

The use of 5-FU led to the development of intestinal dysbacteriosis in rats [27]. It has been shown that after chemotherapy with the use of 5-FU in the small intestine of animals the number of members of the genera Clostridium, Lactobacillus and Streptococcus decreased and the number of members of the genus Escherichia increased. In the large intestine of rats, 5-FU caused a decrease in the number of members of the genera Enterococcus, Lactobacillus and Streptococcus. In these animals the development of mucositis was also observed, which was accompanied by disruption of mucosal cells and mucus secretion [27].

Administration of doxorubicin to rats resulted in a decrease in the Firmicutes/Bacteroidetes ratio in their intestines. Also, there was observed a decrease in the number of representatives of Lachnospiraceae, Clostridium IV, Roseburia, Clostridium XlVa, Oscillibacter, Butyricicoccus, and an increase in the number of members of the genus Akkermansia [28].

Neoadjuvant polychemotherapy using doxorubicin, cyclophosphamide and taxotere led to an increase the number of bacteria of the genera Pseudomonas and Streptococcus and a decrease in the genus Prevotella in the tissue of breast tumors in female patients [29]. It was shown that in healthy breast tissue the content of P. aeruginosa yields up to ~ 5% of the microbiota, in breast tumors — 20%, while neoadjuvant chemotherapy caused such a redistribution of microbiota that the content of P. aeruginosa was 85% [29]. In an in vitro study, doxorubicin was shown to promote the formation of P. aeruginosa biofilms [30]. It is known that the formation of biofilms is among adaptations of bacteria to survive in adverse conditions.

The study of the intestinal microbiota in pediatric patients with acute lymphoblastic leukemia (ALL) showed that the microbiota of ALL patients differs from that of healthy children from the control group [31]. Thus, in children with ALL, Bacteroidetes accounted for 64% of the intestinal microbiota and Firmicutes — 31%, while in healthy children, the content of Bacteroidetes was twice lower (30%), and Firmicutes — 54%. After chemotherapy course, the ratio of bacteria of the key phyla changed toward normalization (close to the indexes of healthy children) — 42% for Bacteroidetes phyla representatives and 48% for Firmicutes [31].

The use of a number of chemotherapeutics, such as doxorubicin and 5-FU caused the development of mucositis in the oral cavity of patients. It has been shown that oral mucositis is also associated with dysbacteriosis. A decrease in the number of members of the genera Streptococcus, Actinomyces, Gemella, Granulicatella and Veillonella, which are associated with a healthy state of the oral microbiocenosis, and an increase in the number of Fusobacterium nucleatum, a bacterium associated with the development of pathological conditions of the oral cavity and intestine, has been shown [18].

There is another important aspect of the effect of anticancer chemotherapeutics on the organism as a whole. After all, drugs that directly or indirectly disrupt bacterial DNA activate the SOS signaling response in bacteria [32]. “Low-precision” DNA polymerases are involved in this reparative response, leading to a significant increase in mutations in the bacterial genome. Such processes underlie the development of drug resistance in bacteria. Therefore, during repeated courses of chemotherapy, microbiota often develops resistance to antibiotics, especially rifampicin and fluoroquinolones. In addition, the activation of the SOS response in bacteria activates the processes of horizontal gene transfer involving mobile genetic elements. Many mobile genetic elements encode pathogenic factors (e.g., toxins). Therefore, the action of cytotoxic anticancer agents leads to an increase in the pathogenic potential of the microbiota. These events are extremely undesirable in an organism with an immune system weakened by chemotherapy [33]. The combined use of antitumor chemotherapy and antibiotic therapy may increase the risk of infection caused by multidrug-resistant bacterial strains.

It is known that representatives of key species of intestinal microbiota exert colonization resistance, i.e. prevent the colonization of mucosa by bacteria of opportunistic and pathogenic species. In addition, many commensal bacteria are active in restoring the mucin layer and mucosal epithelial cells, as well as suppressing inflammatory processes in the intestine. For example, representatives of the species Faecalibacterium prausnitzii and Clostridium cluster XIVa, produce butyrates, which help to restore the epithelial cells of the intestine and maintain the integrity of the mucosa. Representatives of the species Bacteroides thetaiotaomicron and Bifidobacterium infantis exert anti-inflammatory activity suppressing signaling pathways that lead to the activation of NF-kB [33].

Thus, the mucous membrane of the human body and representatives of the microbiota exist in a state of certain mutually beneficial interaction and balance. Violation of one of the components of this balance by certain factors leads to a violation of this complex system as a whole. Thus, changes in the microbiota caused by chemotherapy can be mediated by biochemical changes in the microbiotope where bacteria live, namely: destruction of the epithelium, the development of inflammation in the epithelial tissue and changes in the activity of local immune factors [18].

The microbiota of the mouse, rat and human body changes its composition in response to chemotherapy. As can be seen from the above data, the number of bacteria with positive properties for the macroorganism usually decreases and the number of opportunistic pathogens increases. However, whether the effects of chemotherapy are direct or indirect remains an open question.

The effect of microbiota on the effectiveness of cancer chemotherapy

Scientists have proposed a number of mechanisms by which the microbiota exerts its influence on the effectiveness of cancer chemotherapy. The authors of one study referred to these mechanisms as “TIMER” (Translocation, Immunomodulation, Metabolism, Enzymatic degradation, Reduced diversity) [34]. To these mechanisms, one could can add the effect of the microbiota on the signal transduction pathways, which change the sensitivity of tumor cells to the action of drugs. All mechanisms are closely interconnected. Let’s shortly review the main of these mechanisms.

Translocation. The intestine is an organ most densely populated with bacteria. In a healthy state, the intestinal mucosa is impermeable to most bacteria. However, under certain physiological conditions, the “translocation” of the intestinal microbiota may occur through the mucosa outside the organ into the underlying tissues and bloodstream. Such translocation occurs in the absence of any pathologies and is not accompanied by the development of inflammation [17, 35]. For example, during lactation in women, representatives of the intestinal microbiota are subjected to physiological translocation to the breast with subsequent excretion with milk. The mechanisms of physiological translocation of bacteria are now being actively studied. In pathological processes, the translocation of the intestinal microbiota becomes abundant and leads to the development of local and systemic inflammation.

It is known that the barrier functions of intestinal tissues are provided via several mechanisms: 1) close contacts between cells of the monolayer intestinal epithelium (tight junctions), 2) a dense layer of mucus produced by goblet cells, 3) colonization resistance of microbiota that suppress growth of pathogenic and opportunistic microorganisms, and 4) mechanisms of immune protection of the mucosa (primarily, mechanisms of natural immune protection). Violation of any of these mechanisms leads to defects in the protective function of the mucosa.

Intestinal mucosal tissue, due to the high degree of vascularization and the presence of actively dividing stem cells, is one of the most vulnerable to intravenous chemotherapy. For example, the doxorubicin induces apoptosis of intestinal mucosal cells, leading to the development of mucositis. This effect was observed in both mice with microbiota and GF animals [36]. Violation of the morphology of the intestinal mucosa was detected in mice 48 h after administration of doxorubicin or cyclophosphamide [37]. Violations of the depth and number of crypts were less pronounced in GF animals compared with animals with microbiota [36]. This suggests that chemotherapy, in addition to direct action, also has microbiota-mediated mechanisms of its cytotoxic effects. However, the recovery of damaged tissues occurred faster in animals with microbiota. Therefore, the microbiota also affects the processes of tissue regeneration. It should be noted that apoptotic death of epithelial cells leads to the destruction of the mucosa with the concomitant development of the inflammatory process — mucositis [38]. In mucositis, a condition such as “leaky gut” is observed [35, 39]. In this case, non-degraded nutrients from the intestinal contents, toxic substances, as well as bacteria and their metabolites, can be transferred through the mucosal layer to the submucosal tissues [35, 40, 41] (Fig. 2). The translocation of intestinal microbiota is the main reason of endogenous infections. Further, an inflammatory process involving macrophages and neutrophils developed in the tissues.

 Human microbiota and effectiveness of cancer chemotherapy
Fig. 2. Mechanisms of mutual influence of microbiota and chemotherapy. 1 — mechanism of direct action of chemotherapy on tumor tissue, 2 — mechanism of indirect action involving the intestinal microbiota; M — myeloid cells, Mph — macrophages, Nph — neutrophils, ROS — reactive oxygen species, T — T cells, TNF-α — tumor necrosis factor α, Th17 — T-helpers 17

In an experiment using mice with grafted ovarian tumor, the use of cisplatin leads to the translocation of bacteria of the genera Eubacteria, Lactobacillus, Prevotella and Ruminococcus from the intestine into the circulation [22].

In Balb/c mice, cyclophosphamide led to the development of dysbacteriosis with an increase in the number of opportunistic pathogens of the genera Pseudomonas, Enterococcus and Escherichia coli  [42]. Cyclophosphamide has also been shown to induce disorders of expression of the proteins involved in tight junctions in intestinal epithelial cells: occludin, zonulin-1 and E-cadherin [42].

The use of chemotherapeutic regimen FEC60 (6 cycles of fluorouracil, epirubicin and cyclophosphamide) in the adjuvant mode in patients with breast cancer of stages II–III led to a violation of the integrity of the intestinal mucosa [43].

In patients with colon cancer, DNA of Bacteroides fragilis and Candida albicans was detected in the peripheral blood, indicating translocation of the intestinal microbiota [44].

The effects of chemotherapy lead to the translocation of intestinal microbiota into the circulation and mesenteric lymph nodes, which can further lead to the development of septicemia and systemic inflammation. It is known that the development of severe systemic infections is one of the serious side effects of chemotherapy. The situation is further complicated by the fact that chemotherapy has a significant suppressive effect on the formation of cells in the bone marrow and patients often develop severe neutropenia. Moreover, neutrophils are key cells that provide natural antibacterial protection of the macroorganism. According to statistics, systemic infections lead to the death of ~ 10% of cancer patients [33].

Immunomodulation. Some antitumor chemotherapeutics, in addition to direct cytotoxic activity, have immunomodulatory activity. One such drug is cyclophosphamide [45]. The use of this drug in low concentrations leads to a decrease in the number of CD4+ FoxP3+T reg cells with suppressive activity and an increase of the activity of CD8+ cytotoxic T cells [45]. Recently, studies have emerged that have partially deciphered the immunomodulatory effects of cyclophosphamide. It was shown that in C57BL/6 and DBA 2 mice with established P815 mastocytoma, cyclophosphamide resulted in the translocation of Gram-positive intestinal microbiota into secondary lymphoid organs (spleen and mesenteric lymph nodes). After chemotherapy from the secondary lymphoid organs of mice there were isolated such representatives of Gram-positive bacteria as Lactobacillus johnsonii, Lactobacillus murinus and Enterococcus hirae. This translocation process stimulated the generation of T helpers 17 (Th17) and T helpers 1 (Th1) [37]. Significantly lower levels of Th17 production were observed in GF animals and animals in which Gram-positive intestinal flora was eliminated by antibiotics. Tumors of these animals were resistant to cyclophosphamide. Adoptive transfer of Th17 cells restored the antitumor activity of the chemotherapeutic agent. Subsequent studies have shown that translocation of Gram-positive bacteria E. hirae of the small intestinal microflora led to an increase in the level of CD8/Treg cells in tumor tissue. Gram-negative bacteria of the species Barnesiella intestinihominis, which are commensals of the large intestine, contributed to the infiltration of IFN-γ-producing γδT cells into tumor tissue [46]. Both microorganisms had a systemic effect on the antitumor activity of the immune system. All the described above reactions were caused by the administration of cyclophosphamide. These facts indicate the existence of complex mechanisms of action of antitumor drugs involving the microbiota and the immune system.

The microbiota is required to maintain resident myeloid cells in tissues. It is proved that the optimal response to chemotherapy requires an intact microbiota, which mediates its effect by affecting the myeloid cells of the microenvironment of tumor tissue. One study showed that the efficacy of oxaliplatin was in part dependent on the production of ROS by myeloid cells in the tumor microenvironment. The use of a complex of antibiotics (vancomycin, imipenem and neomycin) led to a violation of the antitumor activity of oxaliplatin and cisplatin in C57Bl/6 mice with colon carcinoma MC38 and lymphoma EL4, respectively [47]. Disorders of the oxaliplatin response were also observed in GF mice with EL4 compared to animals with intact microbiota. The study of the mechanisms of this association showed that in the tumor tissue of animals treated with antibiotics, there is a decrease in the expression of genes that are associated with the inflammatory process: Nox1, Cybb, NOS2, Sod1, Sod2. ROS production by tumor myeloid cells also decreased after the use of antibiotics. These experiments showed that the efficacy of oxaliplatin was due in part to the production of ROS by myeloid cells in the tumor microenvironment.

The number of formed DNA adducts induced by platinum-containing drugs was the same in control and antibiotic-treated animals. However, the overall level of DNA damage was lower in animals treated with antibiotics. The reduction in DNA damage further initiated significantly weaker signals for the induction of p53-dependent apoptosis in tumor cells. This could explain the increased resistance of animals with microbiota disturbed by antibiotics to cancer chemotherapy.

In animals with defects in TLR4 and MyD88 genes, the antitumor activity of oxaliplatin was also impaired. This suggests that the activation of signaling pathways from the receptors for the recognition of bacterial molecular patterns is necessary to implement the toxic effects of antitumor drugs.

These studies have led to an idea of “oncomicrobiotics” — immunogenic bacteria-commensals which essentially influence interrelation between an organism and a tumor [68]. And such a drug as cyclophosphamide, in this sense, is attractive for use in combination with immune checkpoint inhibitors (ІСІ) or “oncomicrobiotics”, bacteria with proven antitumor activity [43].

Therefore, the translocation of the intestinal microbiota has an important immunomodulatory effect, which partially implements antitumor activity.

Metabolism and enzymatic degradation of antitumor drugs by microbiota. Chemotherapy affects the microbiota of various organs and systems changing its balance and leading to the development of dysbiotic disorders. Drug resistance of a tumor of a particular patient is a complex phenomenon. There is no doubt that the mechanisms of resistance develop directly in tumor cells. Recently, however, there is growing evidence that in the context of a macroorganism, the tumor tissue itself or the intestinal microbiota perform metabolic transformations of chemotherapeutics that render cytostatics ineffective. If such metabolic properties are characteristic for the tumor microbiota, it leads to a significant reduction in the concentration of the drug in the tumor tissue, compared with other tissues.

The microbiota is involved in the biodegradation of many drugs. Modern scientific approaches to sequencing make it possible to determine at the genetic level the presence of enzymes of microbiota that are involved in the biodegradation of various chemical compounds. Advances in this field have led to the development of the concept of pharmacomicrobiomics [13, 48]. One study showed [12] the ability of bacteria belonging to 76 key species to metabolize 271 drugs commonly administered orally. The selected drugs belonged to all known classes of drugs. The study showed that approximately 2/3 of the drugs used are metabolized by bacteria of selected species.

For example, in a model of colon cancer in mice, it was shown that tumor resistance to treatment with gemcitabine could be achieved by contamination of animals with bacteria Escherichia coli that had the enzyme cytidine deaminase long form (CDDL) involved in metabolism of this cytostatics. The activity of the enzyme CDDL led to a violation of its effectiveness. The use of the antibiotic ciprofloxacin for elimination of CDDL-positive E. coli led to the restoration of the sensitivity of the transplanted tumor to therapy with gemcitabine [49]. Gemcitabine is used for the treatment of patients with cancer of pancreatic ducts. The authors of the study [49] have shown that in 86 of 113 (76%) tumor samples there were present the representatives of the microbiota, which mainly belonged to the families Enterobacteriaceae and Pseudomonaceae. At the same time, only in 3 cases out of 20 (15%) in the study of pancreatic tissue without pathology, microbiota was detected. The authors of the study suggest that the activity of the detected bacteria may be one of the factors of the resistance of pancreatic tumors to chemotherapy.

In the study [50], the authors screened a collection of human intestinal microbiota isolates for their ability to inactivate doxorubicin. Representatives of microbiota such as Raoultella planticola, Escherichia coli, Klebsiella pneumoniae have been shown to possess enzymatic systems that perform metabolic transformations and inactivation of doxorubicin.

Another study showed that members of the genus Bacteroides cleave the antiviral drug sorivudine, which was used concomitantly with 5-FU. In this case, sorivudine was converted to a derivative of bromovinyluracil, which inhibited the metabolism of 5-FU, which further led to the accumulation of the chemotherapeutic agent in the blood and increase its toxicity [51].

The species of Bacteroides and other bacteria that produce the enzyme β-glucuronidase, such as Faecalibacterium prausnitzii and members of the genus Clostridium, convert the inactive metabolite SN-38G into a toxic active metabolite SN-38 in the intestine, leading to diarrhea [27]. Concomitant use of irinotecan with β-glucuronidase inhibitors reduced the toxic effects of the drug in the intestine [68].

Influence of microbiota on apoptotic signal pathways in cells of intestinal epithelium. Represen­tatives of the microbiota directly or through the production of soluble metabolites are in constant contact with the cells of the macroorganism. First, bacterial cells contain certain bacterial antigens (microorganism associated molecular patterns or pathogen associated molecular patterns) that are absent in the human body. These antigens interact with certain cell surface receptors (pattern recognition receptors). This system of antigens and receptors that recognize them remains extremely conservative in the process of evolution. After all, the development of all multicellular macroorganisms without exception has always been accompanied by symbiosis with microorganisms, which requires recognizing and distinguishing between commensals and pathogens. The ability to directly interact with bacterial antigens is characteristic for epithelial cells (because the microbiota primarily interacts with the epithelium of the skin and mucous membranes) and the immune system as a key system that recognizes antigens and implements reactions to ensure homeostasis at the body level.

Second, due to metabolic activity, bacterial cells produce certain substances that can be absorbed into the blood and act systemically. Substances such as vitamins K and B, deconjugated secondary bile acids, short-chain fatty acids, trimethylamine N-oxide, indole and indole-containing compounds act on the relevant receptors of sensitive cells of the whole macroorganism.

The relation between bacteria of a certain type and resistance to certain antitumor drugs is shown. For example, it has long been known that microbiota of patients with colon cancer is characterized by an increased content of Gram-negative bacteria Fusobacterium nucleatum. A number of molecular mechanisms by which this microorganism can induce tumor development has been studied [52]. In addition, in vitro and in vivo experiments have recently shown that F. nucleatum induces the expression of the antiapoptotic protein BIRC3 (a member of the inhibitors of apoptosis family) in colon tumor cells [53]. It was shown that the changes induced by F. nucleatum provide resistance of tumor cells to apoptosis induced by 5-FU (Fig. 3).

 Human microbiota and effectiveness of cancer chemotherapy
Fig. 3. The mechanism of influence of F. nucleatum on the apoptosis signaling pathways initiated by the action of antitumor drugs

Deciphering the molecular mechanisms of bacterial action showed that F. nucleatum activates a TLR4/NF-κB-dependent signaling cascade in target cells, which induces the expression of the antiapoptotic protein BIRC3. This protein inhibits the activity of caspase-3 (the key apoptotic caspase), which provides resistance of cells to 5-FU-dependent apoptosis [54].

Certain bacteria are known to produce compounds that have cytotoxic activity. These compounds include antibiotics, bacteriocins, exotoxins, exoenzymes, nonribosomal peptides, which have in vitro proven antitumor activity. In vivo, such substances may act synergistically with chemotherapeutic anticancer drugs.

Antibiotics and antitumor chemotherapy

The use of cancer chemotherapy and antibiotics is a separate topic of study. In clinical observations of ~ 600,000 patients, the repeated use of antibiotics has been shown to increase the risk of developing malignancies [55]. For example, the use of penicillin (> 5 courses) led to an increased risk of gastric, esophageal and pancreatic cancer. The use of penicillin, cephalosporins and macrolides in repeated courses also increased the risk of lung cancer. The risk of developing breast cancer increased moderately with the use of sulfonamides. The use of antibiotics such as penicillin, quinolones, sulfonamides and tetracyclines increased the risk of urinary tract tumors.

In addition, it has been shown that the use of antibiotics is often associated with a decreased effectiveness of cancer chemotherapy. Clinical observations have shown that the use of antibiotics that disrupt the Gram-positive microbiota has reduced the efficacy of cyclophosphamide and cisplatin therapy in patients with chronic lymphocytic leukemia and lymphoma recurrence, respectively [56]. The use of cisplatin simultaneously with antibiotics that disrupted the intestinal microbiota in mice with experimental lung tumors led to a significant reduction in the effectiveness of cisplatin [57]. The life expectancy of animals was lower in the group where cisplatin was used concomitantly with antibiotics compared to animals treated with cisplatin alone [57].

In patients with locally advanced tumors of the head and neck (stages III and IV A/B), the use of antibiotics in two or more courses simultaneously with chemoradiotherapy led to an early disease progression and reduced overall survival. Chemotherapy was performed using cisplatin or carboplatin and 5-FU. For antibiotic therapy, penicillin and its derivatives, as well as macrolides and quinolones were used. Approximately half of patients with this pathology are prescribed antibiotics because of oral infections, dermatitis and mucositis. Recurrences of tumor process were related not to metastasis to distant locations, but to activation of the primary tumor lesion. This suggested that it is possible that changes in the microflora of the oral cavity have an impact on tumor progression [58].

The studies of intestinal microbiota were performed in children with acute myeloblastic leukemia who received high-dose chemotherapy (daunorubicin, etoposide, cytarabine) with the simultaneous use of broad-spectrum antibiotics [59]. Stool analysis showed that the diversity of bacterial species in the patients decreased, as well as the total number of intestinal bacteria decreased by several orders of magnitude. A more detailed study of the microbiota species composition showed that in the studied samples the number of anaerobes belonging to the genera Bacteroides, Bifidobacterium, Clostridium cluster XIVa, Fecalibacterium prausnitzii was reduced by 3000–6000 times. Six weeks after termination of the treatment, the number of representatives of Fecalibacterium prausnitzii and Clostridium cluster XIVa was restored, however, the number of representatives of the genera Bacteroides and Bifidobacterium still remained 10–300 times lower. After chemotherapy, the number of streptococci was reduced by 100–1000 times. The content of these bacteria in the intestine also did not recover in 6 weeks after therapy. However, in the intestinal microbiota of patients after therapy, the number of enterococci increased by 7–8 times [59].

Influence of microbiota on toxic side effects of chemotherapy

All anticancer drugs have severe toxic side effects. These effects are often associated with the development of intestinal dysbacteriosis and impaired activity of the immune system. To date, there is much evidence that the restoration of intestinal microbiota helps to reduce the side effects of cancer chemotherapy. There are different approaches to restoring the microbiota using probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation and diet.

The cardiotoxic effect of cisplatin in C57BL6 mice was mitigated by administration of Lactobacillus to animals [23]. In the heart tissue of animals, a decreased number of macrophages and a decreased expression of genes whose products are associated with the development of inflammation (Tnfa, Ccl2, Ccl3), were observed. Similar changes have also been reported in the adipose tissue of mice [23]. Another study also showed that the use of bacteria of the genus Lactobacillus concomitantly with cisplatin treatment significantly increased the effectiveness of cancer chemotherapy in mice. The overall lifespan of mice with lung tumors was the highest in the group of animals in which lactobacilli were administered simultaneously with cisplatin, and the lowest in the group of animals treated with cisplatin simultaneously with antibiotics. It was found that bacteria of the genus Lactobacillus administered simultaneously with cisplatin stimulated the expression of Ifn-γ, Prf1, Gzmb genes in CD8+ T cells isolated from the lymph nodes of experimental animals [57]. This study proved that the microbiota affects the development of both local and systemic antitumor immune responses.

The use of the autologous intestinal microbiota transplantation approach in mice with grafted ovarian tumors and treated with cisplatin resulted in microbiota recovery and rapid healing of damaged tissues of small and large intestines. Such recovery occurred much faster in animals of the group to which the intestinal microbiota transplantation approach was applied. Intestinal microbiota was obtained from animals prior to chemotherapy [22].

Administration of Bacteroides fragilis to BALB/c mice resulted in reduced inflammation and faster recovery of the intestinal mucosa after treatment with methotrexate [25].

Doxorubicin has many toxic side effects on various organs and systems. It is known that the drug shows significant cardiotoxicity and induces damage to the intestinal mucosa. In addition, doxorubicin causes serious dysbiotic disorders in the intestines and oral cavity. The use of Zn2+ and curcumin complexes reduced the toxicity of chemotherapy and helped to reduce the level of intestinal epithelial destruction and intestinal dysbacteriosis in rats treated with doxorubicin [28]. The use of Zn2+ and curcumin maintained the number of A. muciniphila bacteria within the physiological range. Also, the use of this complex helped maintain the required number of goblet cells that produce mucus in the intestinal epithelium [28]. Another study used the flavonoid glabridin, which reduced doxorubicin-induced intestinal dysbiosis. The use of this substance in mice reduced the M1/​​M2 polarization of colon macrophages and the production of proinflammatory cytokines IL-1β and TNF-α and promoted the production of anti-inflammatory cytokines TGF-β and IL-10 in colon tissue [60].

Bacteria Lactobacillus plantarum NCU116, which are isolated from fruits, were administered orally to mice treated with cyclophosphamide. It has been shown that after the use of lactobacilli, the intestinal mucosa of animals recovered faster. The height and depth of the crypts, the number of goblet cells and mucin production, and the amount of short-chain fatty acids were normalized. In the intestinal microbiota of animals, the content of the genera Lactobacillus and Bifidobacterium was restored faster, and the number of representatives of the genus Pseudomonas and Escherichia coli decreased [61].

Many studies aimed at the reduction of the side effects of cancer chemotherapy have shown different approaches to restoring the microbiota in animals treated with anticancer drugs [62–64]. However, most studies have been performed on intact and tumor-free animals. Meanwhile, not only the reduction of side toxicity but the effectiveness of anticancer drugs per se is of particular interest in setting of interactions between chemotherapy and microbiota of tumor-bearing host.

CONCLUSION

The microbiota of the human body is represented by hundreds of species of bacteria that exist in stable associations with each other and in close symbiosis with the macroorganism. So, the systems of macroorganisms and microorganisms exist in a state of equilibrium [65, 66]. These symbiotic relationships have been honed over millions of years of evolution. The human body gives bacteria a comfortable ecological niche with lots of nutrients. Bacteria, in turn, exert colonization resistance and provide the human body with digestive enzymes, biologically active substances, stimulate the development of immune, nervous and metabolic systems. The microbiota of the human intestine is the most numerous and has a tremendous impact on human health. The composition of the intestinal microbiota is very individual, but it is possible to trace certain patterns. In one of the key studies, an attempt was made to determine the main enterotypes of the microbiota of the large intestine of healthy people [67]. Three key enterotypes with a predominance of bacteria of certain genera were identified: Bacteroides, Prevotella and Ruminicoccus. However, many scholars are inclined to believe that such a categorization is somewhat simplistic. So, the final answer to the question, what is a “healthy” microbiota, is missing yet. Each individual’s body is unique with its genotype and phenotype, which determines the composition of its own microbiota and the peculiarities of its interaction with the immune system. For example, each person has a certain set of glycosyltransferases, which determine the production of special types of glycosylated mucins, which are consumed by certain bacteria. The individual’s immune response is determined by the sets of humal leukocyte antigens molecules.

Cancer chemotherapy changes the composition and properties of the microbiota. According to experimental studies and clinical observations, the number of obligate anaerobes in the intestinal microbiota decreases and the content of opportunistic pathogens increases. There is also a redistribution of the content of representatives of key phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia. Under the action of cancer drugs in representatives of the microbiota the SOS signaling system can be activated, which leads to the development of antibiotic resistance. In addition, chemotherapy can stimulate the genetic mechanisms of spread of drug resistance genes and pathogenic factors in the microbiota.

In turn, the microbiota affects the effectiveness of antitumor chemotherapy via various mechanisms. Bacteria change the effectiveness of cancer chemotherapy via the activity of metabolic enzymes, the impact on the signaling pathways of tumor cells, the impact on the functioning of the immune system.

The use of chemotherapy in cancer patients is often associated with the use of antibiotics, which worsens the situation associated with the redistribution of the composition and properties of the microbiota.

Cancer develops at the background of gradual changes in the microenvironment of a particular tissue, including a range of factors: physiological, immune and microbial [65]. Because the microbiota is a kind of thin sensor that responds to any changes in the microenvironment, it also gradually changes along with the affected tissue. What is the primary factor in this relationship is an open question.

Many members of the intestinal microbiota (members of the genera Bifidobacterium, Lactobacillus, Akkermansia) have been shown to have a positive effect on improving the effectiveness of cancer chemotherapy, reducing side toxicity of drugs, restoring damaged healthy tissues, increasing antitumor activity of the immune system.

Today the influence of microbiota on the effectiveness of cancer chemotherapy is out of doubt. Therefore, many researchers suggest a personalized approach to treatment planning. In addition to such mandatory tests as detailed blood tests, blood biochemical parameters, researchers consider it necessary to determine the composition of key representatives of the intestinal microbiota.

The microbiota of the human body has a powerful potential for self-restoration. However, prolonged changes in the microbiota can lead to the extinction of certain types of bacteria. In this case, outside intervention is needed to improve the situation. Therefore, approaches to the recovery of intestinal microbiota using probiotics, prebiotics, synbiotics, allogeneic and autologous microbiota transplantation should be developed. However, one of the most effective and affordable factors influencing the microbiota is diet. And the famous thesis of Hippocrates “food should be medicine, and medicine should be food” in the light of modern knowledge acquires a new meaning. Thus, the study of the nutritional needs of microbiota with the subsequent application of the acquired knowledge to develop a diet for patients with malignant neoplasms is one of the most promising tasks of personalized therapy of the future.

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