Gastrointestinal microbial populations can distinguish pediatric and adolescent Acute Lymphoblastic Leukemia (ALL) at the time of disease diagnosis

Abstract

BackgroundAn estimated 15,000 children and adolescents under the age of 19 years are diagnosed with leukemia, lymphoma and other tumors in the USA every year. All children and adolescent acute leukemia patients will undergo chemotherapy as part of their treatment regimen. Fortunately, survival rates for most pediatric cancers have improved at a remarkable pace over the past three decades, and the overall survival rate is greater than 90 % today. However, significant differences in survival rate have been found in different age groups (94 % in 1–9.99 years, 82 % in ≥10 years and 76 % in ≥15 years). ALL accounts for about three out of four cases of childhood leukemia. Intensive chemotherapy treatment coupled with prophylactic or therapeutic antibiotic use could potentially have a long-term effect on the resident gastrointestinal (GI) microbiome. The composition of GI microbiome and its changes upon chemotherapy in pediatric and adolescent leukemia patients is poorly understood. In this study, using 16S rRNA marker gene sequences we profile the GI microbial communities of pediatric and adolescent acute leukemia patients before and after chemotherapy treatment and compare with the microbiota of their healthy siblings.ResultsOur study cohort consisted of 51 participants, made up of matched pediatric and adolescent patients with ALL and a healthy sibling. We elucidated and compared the GI microbiota profiles of patients and their healthy sibling controls via analysis of 16S rRNA gene sequencing data. We assessed the GI microbiota composition in pediatric and adolescent patients with ALL during the course of chemotherapy by comparing stool samples taken before chemotherapy with stool samples collected at varying time points during the chemotherapeutic treatment. The microbiota profiles of both patients and control sibling groups are dominated by members of Bacteroides, Prevotella, and Faecalibacterium. At the genus level, both groups share many taxa in common, but the microbiota diversity of the patient group is significantly lower than that of the control group. It was possible to distinguish between the patient and control groups based on their microbiota profiles. The top taxa include Anaerostipes, Coprococcus, Roseburia, and Ruminococcus2 with relatively higher abundance in the control group. The observed microbiota changes are likely the result of several factors including a direct influence of therapeutic compounds on the gut flora and an indirect effect of chemotherapy on the immune system, which, in turn, affects the microbiota.ConclusionsThis study provides significant information on GI microbiota populations in immunocompromised children and opens up the potential for developing novel diagnostics based on stool tests and therapies to improve the dysbiotic condition of the microbiota at the time of diagnosis and in the earliest stages of chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2965-y) contains supplementary material, which is available to authoriz...

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“…In contrast, other Firmicutes families, including Clostridiaceae , Streptococcaceae , Lactobacillaceae , and Enterococcaceae significantly increased after chemotherapy . In addition, in the Rajagopala study, the increased differences of gut microbial communities were observed during the maintenance phase compared with prechemotherapy baseline …”

“…65 Rajagopala and collaborators extracted DNA from the stool samples of 28 pediatric and adolescent patients at diagnosis (before chemotherapy) and 23 matched healthy siblings to compare the gastrointestinal microbiota composition by 16S rRNA gene sequencing. 66 They demonstrated that, in both groups, microbiota profiles were dominated by members of the Bacteroidetes (genera Bacteroides and Prevotella) and Firmicutes phyla (genus Faecalibacterium), although with changes in the mean abundances (lower percentages of Bacteroides, and higher percentages of Prevotella, and Faecalibacterium in ALL). Major differences between the two groups occurred in the remaining less represented taxa with lower diversity in patients: genera Anaerostipes, Coprococcus, Roseburia, and Ruminococcus (Firmicutes phylum) had relatively lower abundance in the patient group.…”

“…Several studies highlighted the ALL‐induced gastrointestinal dysbiosis possibly due to an interaction between the immune system and host microbiota, in particular in the gut immunological niche . Rajagopala and collaborators extracted DNA from the stool samples of 28 pediatric and adolescent patients at diagnosis (before chemotherapy) and 23 matched healthy siblings to compare the gastrointestinal microbiota composition by 16S rRNA gene sequencing . They demonstrated that, in both groups, microbiota profiles were dominated by members of the Bacteroidetes ( genera Bacteroides and Prevotella ) and Firmicutes phyla ( genus Faecalibacterium ), although with changes in the mean abundances (lower percentages of Bacteroides , and higher percentages of Prevotella , and Faecalibacterium in ALL).…”

“…Major differences between the two groups occurred in the remaining less represented taxa with lower diversity in patients: genera Anaerostipes, Coprococcus, Roseburia, and Ruminococcus (Firmicutes phylum) had relatively lower abundance in the patient group. 66 In agreement with Rajagopala's results, Bai and coworkers 67 also found that the amount of Firmicutes decreased and that of Bacteroidetes increased in 10 children with ALL compared with 17 healthy controls: Lachnospiraceae, in particular Blautia genus, and Erysipelotrichiaceae families (Firmicutes) were less abundant in children with ALL; Bacteroidales (Bacteroidetes) were more abundant in children with ALL and Porphyromonadaceae (Bacteroidetes) and Enterococcaceae (Firmicutes) families were effective in distinguishing children with ALL from controls.…”

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“…While it was once believed that bacteria and humans simply co-existed in the same space, a wide body of evidence now suggests that host–microbial communication is more complex than ever imagined and the microbiome plays a critical role in maintaining host homeostasis. The microbiome is also altered in multiple disease states, including heart disease [2], cancer [3], and Clostridium difficile infection [4], with changes detectable in microbial composition, number, diversity, and virulence compared to healthy controls. While the majority of studies linking the microbiome to disease are associative, there is increasing evidence that the microbiome plays a crucial role in mediating the pathophysiology of multiple acute and chronic illnesses.…”