A gut instinct for childhood leukemia prevention: microbiome-targeting recommendations aimed at parents and caregivers

Abstract

Childhood leukemia accounts for 30% of all pediatric cancer cases with acute lymphoblastic leukemia (ALL) being the most common subtype. Involvement of the gut microbiome in ALL development has recently garnered interest due to an increasing recognition of the key contribution the microbiome plays in maintaining the immune system's homeostatic balance. Commensal gut microbiota provide a first line of defense against different pathogens and gut microbiome immaturity has been implicated in ALL pathogenesis. Several environmental factors such as nutrition, mode of delivery, breastfeeding and, early social or livestock contacts are known to alter the composition of the gut microbiota. Variations in these factors influence the risk of childhood leukemia onset. This review aims to elucidate the risk factors influencing microbial composition in the context of childhood ALL. The link between gut microbiome diversity and childhood ALL offers the opportunity to develop risk-reducing strategies that can be communicated to a broad target population of (future) parents and caregivers for childhood leukemia prevention. Here, we summarize evidence on how promoting a diverse gut microbiome in newborns through simple measures such as increasing social contacts early in life may decrease the risk of developing ALL in these children later on.

Keywords: childhood leukemia; gut microbiome; prevention; public health; recommendations; risk factors.

Figure 1

ALL age distribution and the “two hit and delayed infection model” of ALL pathogenesis. (A) ALL age distribution in the USA from 2012 to 2016, with a peak at 1–4 years. Incidence per 100,000 cases is shown (2). (B) The “two-hit theory” suggests that ALL occurs in a two-step process (3). The first one involves a genetic mutation, e.g., the t_(12,21) translocation, which arises in-utero predisposing the child to leukemia (~1–5% of healthy newborns) (9). However, the acquisition of additional mutations is crucial for leukemia onset (3). These mutations are primarily driven by oncogenic deletions occurring in ~1% of genetically predisposed children likely due to a dysregulated immune response upon exposure to one or more common infectious agents (3). This is especially critical for those children who were raised in an exaggerated hygienic environment, pointing to a potential association between the gut microbiome and ALL development (10). Hence, other factors affecting gut microbiome diversity, including maternal diet, mode of delivery, breastfeeding, vaccination, social, and livestock contacts are also thought to be implicated (10, 24). Figure was created on BioRender.com.

Figure 2

Factors that can influence the composition and function of the human gut microbiota, and alter ALL risk. Many external (drugs, exercise, geography, birth mode, vaccinations, diet, breastfeeding, and animal contact) and intrinsic factors (host genetics, disease, and aging) impact microbiome composition. The etiology of ALL is not yet fully understood, but causal connections to many factors accepted to influence the microbiome are also known to impact the risk of ALL development (factors represented by two-colored circles) (10). Figure was created on BioRender.com.

Figure 3

Prenatal and postnatal factors influencing microbiome diversity and immune system maturity of children. (A) In-utero, the presence of microbial-derived metabolites and maternal microbiota educates the immune system on how to confront postnatal microbes, affecting especially innate immune system cells (monocytes and neutrophils). (B) At birth, a neonate's immune system relies on maternal protection for its first encounter with living pathogens. (C) Breastfeeding plays an essential role in sustaining this protection by aiding in epithelial barrier formation and passive immunization. (D) Afterwards, increased microbiome diversity is followed by further evolvement of mucosal and adaptive immunity. Figure adapted from Kalbermatter et al. (17). MAITc, mucosal-associated invariant T-cells; HTLc, helper T lymphocyte cells; NKTs, natural killer T cells; iLCs, innate lymphoid cells; Tregs, regulatory T cells; iNKTs, invariant natural killer cells; DFEA1, alpha defensin 1; mo-DCs, monocyte-derived dendritic cells; TRMc, tissue -resident memory T cells. Figure was created on BioRender.com.

Figure 4

Risk factors for childhood leukemia and potential protective measures. Schematic view of accepted childhood leukemia risk factors (left) and preventive measures (right) which assure intestinal diversity and a mature immunity, able to prevent the switch from preleukemia toward overt leukemia, in genetically predisposed children. Figure was created on BioRender.com.

Figure 5

Simple measures toward childhood ALL prevention. Six ways parents and/or other caregivers can contribute in reducing the risk of childhood ALL development. Figure was created on BioRender.com.