The Microbiome in Childhood Acute Lymphoblastic Leukemia

Abstract

For almost 30 years, the term “holobiont” has referred to an ecological unit where a host (e.g., human) and all species living in or around it are considered together. The concept highlights the complex interactions between the host and the other species, which, if disturbed may lead to disease and premature aging. Specifically, the impact of microbiome alterations on the etiology of acute lymphoblastic leukemia (ALL) in children is not fully understood, but has been the focus of much research in recent years. In ALL patients, significant reductions in microbiome diversity are already observable at disease onset. It remains unclear whether such alterations at diagnosis are etiologically linked with leukemogenesis or simply due to immunological alteration preceding ALL onset. Regardless, all chemotherapeutic treatment regimens severely affect the microbiome, accompanied by severe side effects, including mucositis, systemic inflammation, and infection. In particular, dominance of Enterococcaceae is predictive of infections during chemotherapy. Long-term dysbiosis, like depletion of Faecalibacterium, has been observed in ALL survivors. Modulation of the microbiome (e.g., by fecal microbiota transplant, probiotics, or prebiotics) is currently being researched for potential protective effects. Herein, we review the latest microbiome studies in pediatric ALL patients.

Antibiotics in early life and childhood pre-B-ALL. Reasons to analyze a possible new piece in the puzzle

“…Additional evidence supporting this fact is that also the supragingival plaque is less rich and less diverse in pediatric ALL patients at diagnosis comparted with healthy controls [ 109 ]. As described by Oldenburg et al at the onset of ALL, reduced diversity in the oral and gut microbiomes in ALL patients is already observed [ 110 ]. Further reduction of diversity occurs during treatment due to the administration of chemotherapeutics and antibiotics, with dominance of Enteroccocaceae being predictive of infections.…”

“…A state of dysbiosis with persistent low plasmatic LPS leves can induce loss of lymphoid differentiation in HSC and a myeloid shift. One may hypothesize that whereas a healthy, species-rich microbiome balances normal hematopoiesis, the depletion of the microbiome by antibiotics followed by a state of dysbiosis, with persistently low plasmatic LPS levels may contribute to a lymphoid-myeloid shift and the generation of a myeloid inflammatory microenvironment, predisposing pre-leukemic cells to progression to overt pB-ALL [110]. Further reduction of diversity occurs during treatment due to the administration of chemotherapeutics and antibiotics, with dominance of Enteroccocaceae being predictive of infections.…”

“…Further reduction of diversity occurs during treatment due to the administration of chemotherapeutics and antibiotics, with dominance of Enteroccocaceae being predictive of infections. Changes to the microbiome can be detected up to several years after completion of treatment, with possible implications for long-term health [ 110 ].…”

Enhanced tumor accumulation and therapeutic efficacy of liposomal drugs through over-threshold dosing

“…Nearly all chemotherapeutics are cytotoxic [ 1 – 3 ]; they kill both tumor cells and normal cells indiscriminately in vivo, which inevitably leads to various side effects during tumor treatment [ 4 – 6 ]. The delivery of as many drugs as possible to solid tumors at the same dose is the key to solving this problem.…”

Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense

“…The composition of the GIT microbiome impacts both the pathogenic development of cancer, as well as the efficacy of treatments ( Alexander et al., 2017 ; Geller et al., 2017 ; Chau et al., 2021 ; Nearing et al., 2019 ; Thomas et al., 2019 ; Huang et al., 2020 ; Lucafò et al., 2020 ; Rotz and Dandoy, 2020 ; Song et al., 2020 ). This relationship is bidirectional in that both the treatments of cancer, and the pathological state can influence the composition of the GIT microbiome ( Rajagopala et al., 2016 ; Helmink et al., 2019 ; Oldenburg et al., 2021 ). As such, dysbiosis can both cause, and be a result of, cancer.…”