Mihai Cipleu

Background: Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy in childhood.¹ ALL is a cancer of the bone marrow and blood that results from the unchecked proliferation of immature B or T lymphoid progenitors (lymphoblasts).¹ While the current long-term survival rate is 90%, bloodstream infection (BSI) is a commonplace life-threatening complication and cause of mortality.^2,3 It has been indicated that bacterial translocation from the gut results in BSI in ALL, however, despite their importance, microbiota alterations are under-explored in controlled leukemia models.³ Modulation of the gut microbiota may be a target for leukemia therapy that can decrease susceptibility to infection.

Objective: In this literature review, I explored how alterations in the gut microbiome and gut-associated lymphoid tissue (GALT) contribute to increased susceptibility to BSI in leukemic animals.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2025 using the following keywords: “Precursor Cell Lymphoblastic Leukemia-Lymphoma”[Mesh], “microbiome,” “dysbiosis,” “intestinal barrier,” “infectious complications.”

Results: Genetic predisposition to precursor B-cell ALL through Pax5 heterozygosity or ETV6-RUNX1 fusion led to a gut microbiome composition that was distinct from WT mice.² Moreover, those with heterozygous Pax5 deletion showed a depletion of B220+ B cells in Peyer’s patches – specialized lymphoid tissues within the GALT that are essential for maintaining intestinal barrier integrity.² Bacterial microbiota compositional differences in leukemic mice included a decrease in commensal bacteria and an increase in pathogenic bacteria.³ In the intraepithelial lymphocytes of the GALT, IL-2 expression levels showed a significant decrease indicating that loss of immune cells in the GALT could be mediated by IL-2 suppression.⁴ 20(S)-Ginsenoside Rh2, an anti-cancer compound that has been investigated in ALL cells, also affects the microbiota and intestinal barrier in T-ALL mice such that homeostasis is restored.⁵ Specifically, cecal contents of T-ALL mice treated with 20(S)-GRh2 showed a decrease in abundance of pathogenic bacteria and an increase in abundance of protective bacteria including Verrucomicrobia, Akkermansia, Lactobacillus, and Lachnospiraceae_NK4A136_group.⁵ The five phyla and genera were positively associated with immune factors IL-2 and INF-γ, which are involved in the recruitment of T-cells, as well as with NK cells, which play a role in controlling viral infections.⁵ 20(S)-GRh2 administration ameliorated disordered epithelial cells in the colons of T-ALL mice and increased expression levels of tight junction regulating molecules ZO-1, occludin, and claudin-1, indicating enhanced intestinal integrity.⁵ Significant differences in microbiota composition were found between samples from pediatric ALL patients that suffered infectious complications and those that did not, corroborating the animal studies showing that a distinct microbiome composition is involved in BSI.⁶

Conclusions: Studies have shown that shifts in microbiome composition contribute to elevated risk of BSI in both animal models and patients with ALL. In animal studies, BSI was mediated by an increase in pathogenic bacteria, decrease in commensal bacteria, and a loss of immune cells in the GALT by IL-2 suppression. Therapies like 20(S)-GRh2 that increase protective bacteria and restore epithelial integrity may offer a promising strategy to reduce BSI in leukemia.

Works Cited:

1. Pagliaro L, Chen SJ, Herranz D, et al. Acute lymphoblastic leukaemia. Nat Rev Dis Primers. 2024;10(1):41. Published 2024 Jun 13. doi:10.1038/s41572-024-00525-x
2. Vicente-Dueñas C, Janssen S, Oldenburg M, et al. An intact gut microbiome protects genetically predisposed mice against leukemia. Blood. 2020;136(18):2003-2017. doi:10.1182/blood.2019004381
3. Song Y, Gyarmati P. Microbiota changes in a pediatric acute lymphocytic leukemia mouse model. Microbiologyopen. 2020;9(3):e982. doi:10.1002/mbo3.982
4. Song Y, Gyarmati P. Bacterial translocation in acute lymphocytic leukemia. PLoS One. 2019;14(4):e0214526. Published 2019 Apr 1. doi:10.1371/journal.pone.0214526
5. Xia T, Zhang B, Li Y, et al. New insight into 20(S)-ginsenoside Rh2 against T-cell acute lymphoblastic leukemia associated with the gut microbiota and the immune system. Eur J Med Chem. 2020;203:112582. doi:10.1016/j.ejmech.2020.112582
6. Nearing JT, Connors J, Whitehouse S, et al. Infectious Complications Are Associated With Alterations in the Gut Microbiome in Pediatric Patients With Acute Lymphoblastic Leukemia. Front Cell Infect Microbiol. 2019;9:28. Published 2019 Feb 19. doi:10.3389/fcimb.2019.00028