Gut microbiome immaturity and childhood acute lymphoblastic leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Here, we map emerging evidence suggesting that children with ALL at the time of diagnosis may have a delayed maturation of the gut microbiome compared with healthy children. This finding may be associated with early-life epidemiological factors previously identified as risk indicators for childhood ALL, including caesarean section birth, diminished breast feeding and paucity of social contacts. The consistently observed deficiency in short-chain fatty-acid-producing bacterial taxa in children with ALL has the potential to promote dysregulated immune responses and to, ultimately, increase the risk of transformation of preleukaemic clones in response to common infectious triggers. These data endorse the concept that a microbiome deficit in early life may contribute to the development of the major subtypes of childhood ALL and encourage the notion of risk-reducing microbiome-targeted intervention in the future.

Fig. 1. Early development of the gut microbiome in healthy children.

The development of the gut microbiome during early childhood consists of four different stages (acquisition, developmental, transitional and stable) that are characterized by stereotypic changes in diversity and composition. a, During the first 3 years of life, the gut microbiome exhibits increasing richness and evenness within individual samples (α-diversity)^, and decreasing compositional differences compared with adults (β-diversity), followed by gross stabilization. Different early-life exposures can either advance or delay the maturation trajectories of the gut microbiome. b, Recent longitudinal studies of healthy children have also revealed evolutionary-conserved changes in the relative abundance of major bacterial phyla during the first 3 years of life^,. Depicted trends in different gut microbiome metrics are estimates on the basis of the results of three recently published studies (Supplementary Table 1).

Fig. 2. Case–control studies investigating differences in gut microbiome diversity between children with newly diagnosed acute lymphoblastic leukaemia and healthy children.

We systematically searched the MEDLINE and Embase databases from inception until 20 October 2022 to identify existing clinical studies examining the diversity and composition of the gut microbiome of children with newly diagnosed acute lymphoblastic leukaemia (ALL). The search strategy and the criteria for study selection are provided in Supplementary Table 2 and in Supplementary methods. Differences in α-diversity (top panels) and β-diversity (bottom panels) between children with ALL and healthy children at the time of diagnosis (de Pietri et al. 2020 (ref. ), Gao et al. 2020 (ref. ), Chua et al. 2020 (ref. ), Rajagopala et al. 2020 (ref. ), Bai et al. 2017 (ref. ) and Liu et al. 2020 (ref. )). Ab, antibiotics; HS, healthy sibling; NR, not reported; UHC, unrelated healthy children.

Fig. 3. Case–control studies investigating differences in gut microbiome composition at the level of phylum and genus between healthy children and children with newly diagnosed acute lymphoblastic leukaemia.

We systematically searched the MEDLINE and Embase databases from inception until 20 October 2022 to identify existing clinical studies examining the diversity and composition of the gut microbiome of children with newly diagnosed acute lymphoblastic leukaemia (ALL). The search strategy and the criteria for study selection are provided in Supplementary Table 2 and in Supplementary methods. Only for the study of Liu et al. (2020), we used publicly available participant-level data to analyse differences in relative abundance between study groups at the level of phylum and genus using linear discriminant analysis of effect size (LEfSE) as described in Supplementary methods. For all other studies, data were directly extracted as reported in individual publications (Gao et al. 2020 (ref. ), Chua et al. 2020 (ref. ), Rajagopala et al. 2020 (ref. ), Bai et al. 2017 (ref. ) and Liu et al. 2020 (ref. )). a, Differences in the relative abundance of different bacterial phyla between children with ALL at the time of diagnosis and healthy children. b, Selected bacterial genera showing consistent differences in their relative abundance in children with ALL compared with healthy children. Only genera with consistent differences between study groups across three or more independent studies are presented. The complete list of genera identified by all studies (including known developmental trajectories) is provided in Supplementary Fig. 2.c, Physiological changes in the relative abundance of the five identified genera in healthy children during early childhood as reported by Roswall et al.. Ab, antibiotics; FC, fold change; HS, healthy sibling; LDA, linear discriminant analysis score; NR, not reported; UHC, unrelated healthy children.

Fig. 4. The two-hit model of childhood B cell precursor-acute lymphoblastic leukaemia.

Proposed role of the gut microbiome in the two-hit model of childhood B cell precursor-acute lymphoblastic leukaemia (BCP-ALL) based on the results of currently available preliminary studies analysed in the present work. Chromosomal first hits are necessary events for the development of BCP-ALL, but are not sufficient to drive leukaemogenesis. The synergistic effect of adverse early-life exposures, such as caesarean section, reduced or absent breastfeeding, reduced dietary fibre^a, antibiotics^a, lack of older siblings and delayed entry into daycare, may lead to gut microbiome immaturity during a critical time in the development of the immune system. A deficiency in short-chain fatty acid (SCFA)-producing bacterial taxa can compromise gut microbiome-mediated immune priming leading to suppression of regulatory T (T_reg) cells and promotion of T helper 17 (T_H17)-dominated immune responses. SCFA deficiency can also compromise the integrity of the gut epithelial barrier and facilitate the systemic translocation of opportunistic pathogens, as well as increase susceptibility to viral infections. The resulting dysregulated pro-inflammatory immune responses against common infectious triggers can ultimately lead to an increased risk of leukaemic transformation in a small proportion (about 1%) of children with in utero-acquired preleukaemic clones. ETV6::RUNX1, ETS translocation variant 6::runt-related transcription factor 1. ^aThese variables have not been systematically evaluated as risk factors for ALL.