Microbiomul intestinal – aliat sau obstacol în tratamentul afecțiunilor oncologice pediatrice?

Introduction

The gut microbiome, recognized as a key player in a variety of physiological and pathological processes, encompasses trillions of microorganisms living in the human intestine, thus representing one of the largest and most complex ecosystems. It begins to form during the intrauterine period, a process that continues in extrauterine life^(1-3).

Recent research suggests that its formation is influenced by maternal eubiosis or dysbiosis during the preconception period. The origin of the population that forms the gut microbiome is found in the placenta, umbilical cord blood, amniotic fluid and meconium; then, of course, it is continued and influenced by the following stages: birth, the first three years of extrauterine life, and external factors, such as the type of nutrition in the first six months, diversification and the use of antibiotics, which significantly impact the intestinal microbiome ecosystem⁽⁴⁾ (Figure 1).

The type of birth is important for the colonization of the gut microbiome; it has been shown that vaginal delivery mainly exposes the fetus to Prevotella and Lactobacillus, while caesarean delivery favors the newborn’s exposure to microorganisms typical of the skin environment: Propionibacterium, Staphylococcus and Corynebacterium⁽⁴⁾.

Numerous mechanisms mediate the relationship between the organism and the microbiota, but by far, the immune system is the foundation of this interaction. Through Toll-Like Receptors (TLR) and NOD-Like Receptors (NLR), pattern recognition receptors, interaction occurs with the conserved molecular structures of microorganisms (MAMPs), an interaction that can shape the immune response through the production of cytokines and chemokines⁽⁵⁾.

The role of the gut microbiome in modulating the adaptive system is numerous; thus, it influences the function and differentiation of various immune cells essential in the immune process – B cells, T cells, dendritic cells and macrophages. The gut microbiome can influence PD-1 and PD-L1 expression on immune and tumor cells, and Bifidobacterium species enhance the antitumor immune response by promoting dendritic cell maturation⁽⁴⁾.

Dysbiosis, defined as an imbalance between the host and the intestinal microbiome, according to research, is involved in the etiology of various types of cancers, in tumor progression, as well as in their response to therapeutic management, especially in the case of immunotherapy and chemotherapy⁽⁶⁾.

Probiotics – defined since 2001 by the World Health Organization and the Food and Agriculture Organization as live microorganisms which, when administered in adequate amounts, confer a benefit to the health of the host – have received increasing attention in recent decades from health researchers, and their beneficial effects are becoming increasingly well known on a large scale⁽⁷⁾.

Prebiotics, a concept introduced in 1995, are defined as an indigestible food ingredient that has a beneficial effect on the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, thereby improving the host’s health. With beneficial properties for the state of eubiosis of the gut microbiome, they act on health through their degradation products, short-chain fatty acids, and at a distance, not just at the level of the gastrointestinal tract⁽⁸⁾.

Postbiotics, defined as preparations of non-living microorganisms and/or their components that provide a benefit to the host’s health, are well known for their ability to optimize physiological functions^(9-11). Butyrate, the most representative and studied postbiotic in relation to pediatric oncological conditions, exerts its role depending on its concentration level; at low doses, it improves barrier integrity and reduces permeability, while at high levels, it induces apoptosis and decreases viability. Dysbiosis is associated with a reduction in the number of butyrate-producing bacteria, as well as with impaired intestinal barrier function and the onset of inflammation^(11,12).

The purpose of this narrative analysis is to investigate the impact of diversity and changes in the gut microbiome in pediatric patients with oncological conditions, due to the dual interest, both in maintaining physiological processes and because of the risk of systemic infections through the disruption of intestinal barriers.

The analysis presents the relationship between disturbances in the gut microbiota and clinical effects, the risk of morbidity and mortality due to oncological therapeutic management under dysbiosis.

The studies were selected from PubMed, ScienceDirect and Google Scholar, using the following keywords: gut microbiome, dysbiosis, pediatric oncology patients, eubiosis.

Only articles that addressed the influence of the gut microbiome and the consequences of microbial changes on treatment outcomes in pediatric oncological conditions were included, with the aim of identifying the main probiotic species that can protect the body from oncological diseases, as well as those that have beneficial effects in the management of oncological treatment.

Following the analysis of approximately 30 studies focused on the role of the gut microbiome, we identified the main classes of bacteria that make up the microbiota, with effects both in the prevention of malignant pathologies and with beneficial effects as adjuvant therapy in oncological management (Table 1).

Main bacteria classes in the fight against malignancy

Bifidobacterium, an anaerobic species, has demonstrated the ability to inhibit the growth of cancer cells by selectively colonizing tumor tissue. It has also been shown to act on the entire tumor tissue, not targeting it like conventional therapies do^(13,14). Kimura and colleagues demonstrated the ability of Bifidobacterium species to localize and proliferate in the tumor mass of mice⁽¹⁵⁾.

By its ability to target the tumor mass, Bifidobacterium has been used as a carrier for various types of antitumor therapy⁽¹⁴⁾. Bifidobacterium can act as an anticancer agent through various mechanisms – production of short-chain fatty acids, immune modulation and a role in cancer cell apoptosis^(16-19).

Akkermansia muciniphila, from the Verrucomicrobia phylum, has received significant attention from medical researchers in recent years, and its antitumor capacity has been demonstrated. The degradation of mucin plays a crucial role in maintaining the integrity of the intestinal mucus layer and thereby in limiting bacterial translocation^(20-22).

Lacticaseibacillus rhamnosus GG (LGG) is a strain known for its anti-inflammatory effects and modulation of the gut microbiota, thus contributing to the prevention of colorectal cancer development^(23,24). Thus, up to 99% inhibition of cancer cells in colorectal cancer was demonstrated 72 hours after the administration of 30 mg/mL LGG. Also, the combination of LGG with standard drug treatment in colorectal cancer, 5-FU, resulted in a stronger cytotoxic effect, according to Budu and colab., while in vivo, this combination led to the optimization of both innate and adaptive immune responses⁽²³⁾.

Ruminococcaceae, present in the gut microbiome of people with eubiosis, an obligate anaerobe, has shown a significant reduction in tumor mass in cases of pancreatic ductal adenocarcinoma, in combination with gemcitabine, from 39% to 17%^(25,26). The analysis of stool samples in patients undergoing oncological therapy showed an abundant presence of Ruminococcaceae in the samples of those who responded favorably to treatment⁽²⁷⁾.

Discussion

According to Lloyd-Price et al., maternal variables and postnatal factors have an important contribution to the formation process of the gut microbiome, which is necessary for modulating the immune system⁽³⁹⁾.

Maternal weight, antibacterial therapy and chronic conditions such as diabetes have also been identified in Miyoshi’s study as being associated with the formation of the future child’s gut microbiome and subsequently its effect on immunity^(2,4,28).

The relationship between the type of birth and the child’s gut microbiome is a heavily studied one, with numerous studies supporting the benefits of vaginal delivery in colonizing the newborn’s intestinal tract with Staphylococcus, Lactobacillus and Enterococcus. These bacteria, according to the research of Coelgo et al., appear within the first 24 hours postpartum, and they are responsible for immune processes, but also play a role in promoting anaerobic bacteria^(7,11,27,28).

Routy et al. support in their research the beneficial effect of Akkermansia muciniphila on immunotherapy in patients with oncological conditions⁽²⁹⁾.

Bacteria of the genus Fusobacterium promote inflammation and the proliferation of cancer cells, whereas bacteria of the genus Bifidobacterium provide protection against oncogenesis through their ability to stimulate immune activity, according to recent studies on ribosomal RNA sequencing from stool samples of healthy patients versus those with colon cancer^(4,30).

Fusobacterium can contribute to the development of oncological conditions, because it has a well-known role in periodontal disease and colitis. This species of bacteria, according to studies, could even be a tumor marker, due to the fact that significantly higher levels have been observed on the surface of tumor tissue compared to healthy tissue. Additionally, increased levels of Fusobacterium nucleatum have been associated with colorectal cancer⁽³¹⁾.

Butyric acid, produced by bacterial metabolism in the colon, with strong anti-inflammatory properties, through its ability to inhibit NF-kB, can inhibit or activate the production of proinflammatory cytokines. Through the production of mucus and the strengthening of tight junctions between epithelial cells, it helps prevent the translocation of toxins and bacteria into the bloodstream, thus having a well-established role in systemic well-being⁽⁴⁾.

Studies have shown the ability of Bifidobacterium and Lactobacillus species to enhance the antitumor activity of CD8 T cells⁽³²⁾. Bifidobacterium species have also been associated with enhanced antitumor responses and increased efficacy of anti-PD-L1 therapy⁽⁴⁾.

Experimental studies in mice, on murine models of ALL precursor B cells, support the ability of a state of eubiosis to protect individuals with a genetic predisposition to the development of acute lymphoblastic leukemia (ALL), whereas dysbiosis is associated as a promoting factor in the onset of ALL⁽³³⁾.

The analysis of the gut microbiome at the time of diagnosis, according to research, can predict future complications. Thus, high levels of Streptococcaceae or Enterococcaceae are associated with post-chemotherapy infections, and febrile neutropenia occurs more frequently in patients with elevated levels of Proteobacteria⁽³⁴⁾.

Intestinal dysbiosis, with increased levels of Enterococcus and a significant reduction in populations of Lachnospiraceae and Ruminococcaceae, is associated with delayed recovery of neutrophil count in children with ALL; thus, we can state that dysbiosis is a contributing factor to neutropenia⁽³⁵⁾.

Changes in the gut microbiome in pediatric oncology patients are being intensively studied; it has been observed that the abundance of Enterococcus and Lachnospiraceae species, alongside a reduction in alpha diversity, is found in children undergoing chemotherapy who develop systemic infections and a decrease in the number of enterocytes⁽³⁵⁾.

In the case of pediatric patients with acute myeloid leukemia, a study observed that certain species only began to be detected after the start of therapy; for example, Klebsiella appeared after the first seven days of treatment and showed an increase until day 21, confirming that changes in the intestinal microbiome can influence the treatment response. Throughout the three stages of therapy in LAM, Firmicutes was the most abundant phylum, with no quantitative changes across the three stages; however, the internal composition seems to have undergone substantial changes. Compared to sepsis, at T2 the genera Streptococcus and Bacteroides were significantly higher⁽¹⁾.

Rattanathammethee et al. demonstrated a significant association between the rate of infectious complications in patients with ALL and the increased level of Firmicutes clade⁽³⁶⁾. Another study presents the significant association between BSI and bacterial translocation in patients with an abundance of Enterococcus and proteobacteria⁽³⁷⁾.

Probiotics and prebiotics are extensively studied as an adjuvant component in the therapeutic management of oncology patients, with the aim of reducing the adverse effects of chemotherapy through their ability to modulate the intestinal microbiome, as well as addressing the major risk of morbidity and mortality caused by bacterial and fungal infections resulting from chemotherapy-induced myelosuppression⁽³⁸⁾.

According to studies, diarrhea induced by irinotecan therapy was significantly reduced among patients who received probiotics⁽³⁸⁾. The most commonly used strains in the adjuvant treatment of pediatric oncology patients were L. rhamnosusGG and Lactobacillus acidophilus, over a minimum duration of six months, and most frequently in combination with strains from the species Bifidobacterium breve⁽⁴⁰⁾.

Bifidobacterium breve administered in pediatric patients with leukemia reduced the use of antibacterial therapy, episodes of fever, and the levels of Enterobacteriaceae in fecal samples⁽⁴¹⁾.

The administration of Lactobacilli in children with oncological conditions has been associated with better tolerance to drug therapy due to the fact that it reduced side effects such as nausea and vomiting⁽⁴²⁾.

The state of the gut microbiome is associated with the post-allogeneic hematopoietic stem cell transplant survival rate; thus, higher diversity has been associated with higher survival rates and a lower likelihood of abnormal graft-versus-host disease (GVHD). The group of patients with high levels of Oscillospiraceae and Ruminococcaceae had higher chances of survival compared to the group of patients whose gut microbiome was low in diversity and rich in Enterobacteriaceae and Enterococcaceae. The increased survival chance among patients with high levels of Oscillospiraceae and Ruminococcaceae can be explained by a higher number of SCFA-producing taxa⁽⁴³⁾.

Fecal microbiota transplantation (FMT), widely discussed in numerous inflammatory conditions of the gastrointestinal tract, has been shown to be beneficial in cancer patients⁽⁸⁾.

The benefits of FMT on intestinal GVHD have been highlighted by specialized studies, with six out of seven patients showing an improvement in the intestinal microbiome. According to studies, Bacteroides fragilis, Bifidobacterium spp., Escherichia coli and Faecalibacterium prausnitzii showed increased levels after FMT in both adults and children with GVHD^(44,45).

In the case of FMT, the side effects were mostly mild, regardless of the condition for which FMT was performed, but with recognized benefits. In patients with recurrent Clostridioides difficile infection (CDI), the cure rate was approximately 90% of cases, noting that 80% of patients needed only a single transplant⁽⁴⁶⁾. These success rates are also maintained in immunocompromised patients with CDI who have benefited from FMT⁽⁴⁷⁾.

Conclusions

Cancer is one of the leading causes of death worldwide among the adult population, but with an increasing incidence also among children. The treatment is complex, often with short- and long-term side effects, which is why adjuvant therapy is currently being intensively studied.

Research in recent decades has solidified the role of the gut microbiome in multiple physiological and pathological processes. The commensal members of the gut microbiome begin to form from intrauterine life and are influenced by a multitude of genetic and environmental factors. Birth by vaginal delivery, breastfeeding and reduced antibiotic consumption are the factors most often reported as promoting a state of dysbiosis.

This ecosystem, one of the largest and most important ecosystems of the body, plays an essential role in maintaining the intestinal barrier intact, thus preventing multiple systemic infections, a vital role in the case of pediatric patients, immunocompromised due to oncological diseases and the challenges of therapeutic management.

The administration of probiotics, as an adjunct therapy, is associated with favorable short- and long-term effects in children diagnosed with various types of oncological conditions. Bifidobacterium, Akkermansia, Lacticaseibacillus, Faecalibacterium and Lactobacillus are among the most recognized for these effects.

Fecal matter transplantation, extensively studied but still approached with caution, is associated with beneficial effects both in children with Clostridioides difficile infection and in those with CDI and oncological conditions.

We consider future, extensive studies on this subject necessary, due to the multiple beneficial effects of a state of eubiosis, both among the general population and among patients with pathologies in the oncological field. We also consider it useful for medical specialists to pay attention from the very beginning of intrauterine life and continue care after birth to maintain a state of eubiosis.  

Autor corespondent: Heidrun Adumi­tră­chioaiei E-mail: ad.heidi91@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.