Gut microbiota changes are associated with prolonged neutropenia after induction treatment of childhood acute lymphoblastic leukemia

Abstract

Prolonged neutrophil recovery during acute lymphoblastic leukemia (ALL) treatment increases infection risk and delays chemotherapy. Emerging evidence implicates the gut microbiota in neutrophil reconstitution after chemotherapy. We explored the interplay between the gut microbiota and neutrophil dynamics, including neutrophil chemoattractants, in 51 children with newly-diagnosed ALL. Daily absolute neutrophil count (ANC), weekly plasma chemokines (CXCL1 and CXCL8), granulocyte colony-stimulating factor (G-CSF), and fecal samplings were monitored until day 29 during ALL induction treatment. Fecal sequencing by 16S rRNA revealed an overall significant reduction in bacterial diversity and Enterococcus overgrowth throughout the induction treatment. Prolonged neutropenia (ANC < 0.5x10⁹ cells/L at day 36) and elevated chemokines levels were associated with decreased abundance of genera from the Ruminococcaceae and Lachnospiraceae families, decreased Veillonella genus, and Enterococcus overgrowth from diagnosis and throughout induction treatment. G-CSF was upregulated in response to neutropenia but unrelated to microbiota changes. Overall, this study reveals that diminished abundance of specific intestinal commensals and Enterococcus overgrowth are associated with delayed neutrophil reconstitution and increased chemokine signaling. These findings enhance our understanding of the mechanisms behind the huge variability in neutrophil reconstitution post-chemotherapy, emphasizing the need for gut microbiota-sparing strategies to minimize the impact of gut dysbiosis on immune recovery.