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Abstract The human microbiome consists of trillions of microbial cells that interact with one another and the human host to play a clinically significant role in health and disease. Gut microbial changes have been identified in cancer pathogenesis, at disease diagnosis, during therapy, and even long after completion of treatment. Alterations in the gut microbiome have been linked to treatment-related toxicity and potential long-term morbidity and mortality in children with cancer. Such alterations are plausible given immune modulation due to disease as well as exposure to cytotoxic chemotherapy, infections, and antibiotics. The following review presents our current scientific understanding on the role of the gut microbiome in pediatric cancer, identifies gaps in knowledge, and suggests future research goals. The human gut microbiome consists of a complex community of trillions of micro-organisms that play an important role in human metabolism, with diverse functions ranging from biosynthesis of vitamins to neurological signaling (1). The interactions of such micro-organisms with their host affect general health and homeostasis in addition to playing a role in disease pathogenesis, including malignancy (2). Alterations of the gut microbiota, known as dysbiosis, potentiate the development of disease, likely through depletion of health-enhancing microbiomes or increases in pathogenic bacteria (3). Factors that contribute to microbial dysbiosis include host genetic features, immune response, diet, medications, infections, chronic disease, and environmental exposures (3,4). Many of these factors overlap with pathogenesis and treatment of pediatric cancer. Underlying immune dysregulation, the use of cytotoxic chemotherapy, and exposure to infections and antibiotics make this population vulnerable to alterations in the gut microbiome (Figure 1). Figure 1. Open in new tabDownload slide A variety of factors can lead to alterations in the gut microbiome, known as dysbiosis. Dysbiosis may play a role in pediatric cancer disease pathogenesis, therapy related toxicity, and late effects seen in survivors. Figure 1. Open in new tabDownload slide A variety of factors can lead to alterations in the gut microbiome, known as dysbiosis. Dysbiosis may play a role in pediatric cancer disease pathogenesis, therapy related toxicity, and late effects seen in survivors. The pathogenesis of how the gut microbiome and its metabolites contribute to disease development is an active area of research that has yet to be fully elucidated. Identifying the driving factors that result in these alterations may allow for earlier disease diagnosis, preventative treatments, and supportive care strategies. Although researchers have found associations between gut microbial dysbiosis and malignancy, data are limited on how gut microbiome alterations interplay with oncologic processes at diagnosis, throughout the course of treatment, and even after. Microbiome and Cancer Disease Pathogenesis The composition of the gut microbiome has been implicated in the pathogenesis of several different types of cancers. The mechanisms of how microbial dysbiosis may lead to cancer include increased inflammation, avoidance of immune destruction, proliferative signaling, and genomic instability resulting in mutations (5). Several studies have demonstrated that in colorectal cancer patients, there is a high prevalence of Fusobacterium and Porphyromonas as well as decreased levels of Ruminococcus compared with controls (6–9). Other studies have identified increases in Selenomonas and Leptotrichia in colorectal cancer tissue (5). Scientists at the University of Michigan further supported these findings by colonizing germ-free mice with microbiota from mice with colorectal cancer and observed increased tumorigenesis. The use of antibiotics decreased both the number and size of tumors within the murine models, further supporting the relationship between gut microbial dysbiosis and cancer development (10). Other studies have also demonstrated associations with the microbiome and cancer epidemiology in adults, including breast, esophageal, gastric, prostate, pancreatic, and head and neck cancers (5). However, many of these studies include small sample sizes and have varying methodologies, making interpretation and causation more challenging. The gut microbiome composition may play a role perhaps in the development of the most common childhood cancer, acute lymphoblastic leukemia (ALL). ALL may be potentiated through exposure to specific microbiota, which could alter immune system modulation during infancy (11). Caesarian deliveries have been associated with an increased risk of developing ALL, because newborns who are born via C-section are not exposed to maternal microbiota like vaginally delivered children. Breastfeeding during infancy for a minimum of 6 months has been linked with a 10–20% reduced risk of developing ALL, with these findings replicated in many case-control and meta-analytical studies (11). It is proposed that breast milk aids in immune modulation through maternal transfer of specific nutrients, antibodies, anti-inflammatory molecules, oligosaccharides, and lactoferrin (12). This allows for increased amounts of bifidobacteria, considered beneficial to human health, and decreased amounts of Escherichia coli and Clostridium difficile (13). Effects of Cancer Diagnosis and Treatment on the Microbiome In children, alterations in the gut microbiome have been noted at the time of cancer diagnosis. Huang et al. demonstrated that the total amount of bacterial flora in children with ALL was 29.6 % less than in healthy controls (P < .01). More specifically, the amount of Bifidobacteria, Lactobacillus, and E coli were statistically significantly decreased in children with ALL (P < .05) (14). Rajagopala et al. studied the gut microbial composition of pediatric patients with ALL compared with matched siblings at diagnosis and at various time points throughout leukemia treatment. By examining the gut microbiome composition, the study showed that both groups had increased abundance of Bacteroides, Prevotella, and Faecalibacterium before therapy. However, the alpha diversity, or the differences in species between the two groups, was significantly different; children with ALL had decreased alpha diversity compared with their siblings (P < .01). Based on taxonomic classification, children with ALL had a decreased relative abundance of Anaerostipes, Coprococcus, Roseburia, and Ruminococcus2 at the time of diagnosis compared with their unaffected siblings (15). Changes in the gut microbiome are seen throughout cancer therapy as well. Huang et al. demonstrated decreased amounts of Bifidobacteria, Lactobacillus, and E coli as early as 3 and 7 days after chemotherapy in children with ALL. The most clinically significant change was after day 3 with some recovery by day 7 but still overall decreased compared with before chemotherapy (14). Rajagopala et al. reported that although microbial diversity in their sample of ALL patients was not statistically significantly different at the end of chemotherapy compared with before, gut microbiome diversity significantly increased in subsequent visits after the completion of chemotherapy (P < .01) (15). Alterations of microbial diversity are also seen in children with acute myeloid leukemia (AML) during therapy. In children with AML, there was a significantly decreased number of total bacteria in fecal samples collected from those undergoing treatment compared with samples from a healthy control (P < .01). Considerable variation in microbial composition was also seen during therapy in the AML arm. Bacterial diversity was partially restored between cycles of chemotherapy, and there was no difference in the total number of gut bacteria between both groups after completion of therapy (16). Such changes in microbial diversity during and after cancer therapy may be attributed to nutrition, use of antibiotics, direct effects of chemotherapy, and immune system modulation as a result of chemotherapy. Microbiome and Therapy-Related Toxicity The relationship between the gut microbiome and cancer goes beyond disease pathogenesis and compositional changes during treatment. It also likely affects comorbid conditions observed during therapy. Several adult studies suggest a relationship between gut microbiome composition, therapy-related toxicity, and impact on quality of life. For instance, microbial dysbiosis has been linked to increased gastrointestinal toxicity in the form of chemotherapy- and radiation-induced diarrhea (17,18). Loss of intestinal microbial diversity has also been associated with increased risk of serious infection in adults during induction therapy for AML (19). In mouse models, the perturbations in gut microbiota facilitate the development of chemotherapy-induced neuropathic pain. Neuropathic pain, measured using mechanical withdrawal to specific stimuli, is notably decreased in germ-free mice but then increased when microbiota were restored in this population (20). The gut microbiome may also play a role in the etiology of mental health disease through the gut-brain axis. Dysbiosis may contribute to the numerous children who suffer from anxiety, depression, and behavioral changes both during and after therapy (21,22). Changes in gut microbiota may affect neuronal and CNS signaling pathways, leading to depression and anxiety (23,24). The relationship between microbiota changes and subsequent neuropsychological effects likely has a clinically significant impact on quality of life. Much of this research has primarily been done in animal models with some work in adults. Although similar relationships have not been studied in pediatric patients, data from murine models and adult populations raise the possibility of parallel conditions in children with cancer. A growing body of evidence also indicates that the microbiome plays an instrumental role in the development of bacterial infections and graft versus host disease (GvHD) (25,26). This relationship underscores the impact of the interaction of the gut microbiome and host immune system induction, training, and function (27). Taur et al. demonstrated that in adults undergoing allogeneic Hematopoietic stem cell transplantation (HSCT), decreased gut microbial diversity is an independent predictor of mortality (25). Thus, research to directly target gut microbial perturbations is underway in an effort to improve transplant-related morbidity and mortality. The use of probiotics during HSCT may be used as a mechanism to preserve microbiota composition during therapy. Although probiotics have been used in several disease processes, its use during myeloablative therapy is limited, with a major concern being the risk of bacteremia related to specific probiotic bacteria in the setting of severe immunosuppression. A multidisciplinary panel suggested that probiotics should be avoided for prevention of C difficile infections in children with cancer and those undergoing HSCT. Due to limited available data, the panel was unable to conclude that probiotic use was not related to the incidence of invasive infection (28). However, Ladas et al. demonstrated that the use of Lactobacillus plantarum in pediatric patients receiving a HSCT was safe and feasible. Children and adolescents undergoing allogenic HSCT received L plantarum daily from the start of the conditioning regimen until day +14 posttransplant. This pilot study demonstrated that administration was feasible with 97% of participants receiving at least 50% of the targeted probiotic dose. Participants did not experience any serious adverse events, including bacteremia due to L plantarum. Results also suggest that there was no increased incidence of GvHD compared with data from other allogenic HSCT trials. These data must be interpreted carefully given the small sample size. Based on these findings, there is now an ongoing prospective randomized controlled study to further study the role of this probiotic in reducing GvHD in pediatric transplant patients (29). The safety of other species of probiotics in HSCT remains to be determined. The gut microbiome may also play a role in pulmonary immunity and lung damage. In murine models, gut microbial dysbiosis has been associated with alterations in the lung microbiota in what is known as the gut-lung axis. This may subsequently lead to lung damage that may be recovered by the use of probiotics (30). Understanding the implications of the gut-lung axis is in its infancy but may be important given the variety of different infections immunocompromised hosts are at risk for. Research has clearly demonstrated an association between the gut microbiome and obesity, which may help to further explain the increased prevalence of obesity in pediatric patients with ALL. In mouse models, distinct differences in bacterial phyla have been demonstrated between obese and lean mice (31). In addition, the transfer of intestinal microbiota from genetically engineered obese mice to germ-free mice has resulted in the development of obesity (32). In humans, adult and pediatric studies continue to support this potential relationship. Gut microbiome composition evolves during infancy and early childhood, and the relative abundance of Bacteroidetes in the gut microbiome of infants has been potentially associated with a 40% increased risk of obesity seen in children delivered via C-section (33). Riva et al. compared obese children to nonobese children and demonstrated microbial dysbiosis as evidenced by increased amounts of Firmicutes and decreased amounts of Bacteroidetes between the two populations (34). The importance of the Firmicutes to Bacteroidetes ratio has also been implicated in adult obesity studies. The mechanism underlying this association has yet to be fully understood but is likely multifactorial, involving alterations in fatty acid metabolism and proteins that control fat storage (35). The increased prevalence of obesity in survivors of pediatric ALL is well documented throughout the literature, with rates ranging from 29% to 69% after completion of therapy. In addition to obesity in this population, there is also evidence of a greater rate of change in BMI over time both during and after therapy. The exact pathophysiology of weight gain during this time is unclear and cannot be attributed to caloric intake alone. Many hypothesize that age at diagnosis, prolonged use of corticosteroids, biological mechanisms such as leptin levels, and exposure to cranial radiation likely play a role in the development of obesity after ALL therapy (36,37). Underlying microbial dysbiosis may be an additional contributing factor to the development of obesity in this population. Given the known relationship between microbial dysbiosis and obesity, further exploration is warranted to understand the role of the gut microbiome in the development of obesity in children with ALL. A multi-institutional pilot study currently enrolling children with ALL older than 5 years of age is attempting to assess the feasibility of a family-based nutritional intervention during the first 6 months of treatment while looking at secondary outcomes of weight gain and changes in gut microbial composition during this time (NCT03157323). The nutritional intervention is centered around the use of a low-glycemic index diet because high-glycemic index diets have shown to be strongly linked to the development of obesity and metabolic syndromes (38). Although obesity is an important health concern to monitor and address in patients undergoing active therapy and in survivors of pediatric ALL, there are also many other long-term side effects of cancer therapy that the gut microbiome may help us better understand. Microbiome and Survivorship The world of pediatric oncology has continued to see improvements in childhood cancer outcomes over the last several decades. According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, the 5-year survival rate of children diagnosed with cancer before the age of 20 years is 83% (39). However, such success does not come without intensive therapy that has a lasting impact on individuals. The Childhood Cancer Survivor Study analyzed information from more than 10 000 survivors of pediatric cancer and found that 62.3% had at least one chronic health condition and 27.5% had a severe or life-threatening condition. On the other hand, among siblings in the same study, only 36.8% reported a chronic health condition of which 5.2% had a severe life-threatening condition. Chronic health conditions included, but were not limited to, heart disease, secondary malignancy, endocrinopathies, and cognitive dysfunction (40). Many of these long-term ailments have been associated with microbial dysbiosis outside of the cancer population. Thus, the gut microbiome may be an important link between cancer therapy and long-term side effects seen in survivorship patients. Preliminary data support this idea because changes in the gut microbiome have been seen months to years after the completion of therapy in survivors of ALL when compared with sibling controls. In a pilot study comparing the microbial composition of survivors of ALL at a median of 24 months from the completion of therapy and their environmentally matched biologic siblings, a statistically significant difference in the beta diversity, or variation in species composition, of gut microbiota was noted between the two groups. Alpha diversity analysis demonstrated lower species evenness in patients with history of ALL compared with their healthy siblings but no statistically significant difference in species richness (R. Bhuta, J. Shapiro, unpublished data). This may indicate a more permanent change in the gut microbiome as a result of cancer therapy. Cozen et al. studied the gut microbiome between a small number of adolescent and young adult Hodgkin lymphoma survivors at an average 22.5 years from diagnosis and their unaffected twin. Cancer survivors had reduced gut microbiota diversity and, compared with their twin sibling, had decreased numbers of unique species-level operational taxonomic units (P = .015) (41). Although the sample size was small, such findings support the hypothesis that gut microbial changes are seen beyond the time of treatment. Future Directions Microbiota composition and its interaction with the host environment is complex and plays a clinically significant role in maintaining health and triggering disease. Advances in DNA sequencing and the development of metabolomic and proteonomic assays have allowed us to better understand the prevalence of specific microbiota and how they affect downstream development of metabolites and proteins that then play a role in disease pathogenesis. Pediatric cancer patients represent a unique population in which physicians and scientists continue to strive to improve survival rates and minimize toxicity both during and after completion of therapy. Although remarkable progress has been achieved over the last few decades, much has yet to be understood. Microbiome research in pediatric cancer patients is an area where gaps in knowledge exist and improvements in patient outcomes may be obtained. Large studies comparing the gut microbial composition of pediatric patients at the time of diagnosis, during therapy, and years after in comparison with healthy controls are imperative. Understanding the microbiome of this population will allow us to implement beneficial interventions in hopes of preventing comorbidities such as obesity, infection, GvHD, and late effects of therapy. As more insight and knowledge in this area are discovered, we can begin to identify specific microbiota that may be associated with clinically significant outcomes and thus target these microbial signatures with novel therapies. The gut microbiome is an exciting area of study, with a wealth of undiscovered potential in the field of pediatric oncology research. Notes Affiliations of authors: Division of Pediatric Hematology-Oncology, Hasbro Children’s Hospital, The Warren Alpert Medical School of Brown University, Providence, RI (RB); Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL (MN); Division of Hematology/Oncology/Stem Cell Transplant in the Department of Pediatrics (in Epidemiology and in the Institute of Human Nutrition) at the, Columbia University Medical Center, New York, NY (EL); Division of Oncology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA (TJ). Dr Michael Nieder is on the Speaker’s Bureau for Jazz Pharmaceuticals. He speaks about Defibrotide, which is the only FDA-approved drug used to treat severe posttransplant Veno-Occlusive Disease of the Liver. This activity is not related to any aspect of this manuscript. All other authors have no conflicts of interest. 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JNCI Monographs – Oxford University Press
Published: Sep 1, 2019
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