Sørum Maria Ebbesen, Boulund Ulrika, De Pietri Silvia, Weischendorff Sarah, Enevold Christian, Rathe Mathias, Als-Nielsen Bodil, Hasle Henrik, Pamp Sünje, Stokholm Jakob, Müller Klaus
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark.
Blood Adv. 2025 Apr 8;9(7):1508-1521. doi: 10.1182/bloodadvances.2024013986.
Delayed neutrophil recovery during acute lymphoblastic leukemia (ALL) treatment increases the risk of infection and causes delay in chemotherapy. Emerging evidence implicates 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 samples were monitored until day 29 during ALL induction treatment. Fecal sequencing using 16S ribosomal RNA revealed an overall significant reduction in bacterial diversity and Enterococcus overgrowth throughout the induction treatment. Prolonged neutropenia (ANC <0.5 × 109 cells per L at day 36) and elevated chemokine levels were associated with a 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 was unrelated to microbiota changes. Overall, this study revealed that a diminished abundance of specific intestinal commensals and Enterococcus overgrowth is associated with delayed neutrophil reconstitution and increased chemokine signaling, indicating that disruption of the microbiota may contribute to prolonged neutropenia. These findings lay the groundwork for future investigations into the mechanisms underlying these associations and their clinical implications for developing gut-sparring strategies to minimize the impact of gut dysbiosis on immune recovery.
急性淋巴细胞白血病（ALL）治疗期间中性粒细胞恢复延迟会增加感染风险并导致化疗延迟。新出现的证据表明肠道微生物群与化疗后中性粒细胞重建有关。我们在51例新诊断的ALL儿童中探讨了肠道微生物群与中性粒细胞动态变化之间的相互作用，包括中性粒细胞趋化因子。在ALL诱导治疗期间，每日监测绝对中性粒细胞计数（ANC）、每周血浆趋化因子（CXCL1和CXCL8）、粒细胞集落刺激因子（G-CSF）以及粪便样本，直至第29天。使用16S核糖体RNA进行粪便测序显示，在整个诱导治疗过程中，细菌多样性总体显著降低，肠球菌过度生长。延长的中性粒细胞减少症（第36天ANC<0.5×10⁹个细胞/L）和趋化因子水平升高与瘤胃球菌科和毛螺菌科属的丰度降低、韦荣球菌属减少以及从诊断开始直至整个诱导治疗过程中的肠球菌过度生长有关。G-CSF因中性粒细胞减少症而上调，但与微生物群变化无关。总体而言，本研究表明特定肠道共生菌丰度降低和肠球菌过度生长与中性粒细胞重建延迟和趋化因子信号增加有关，这表明微生物群的破坏可能导致中性粒细胞减少症延长。这些发现为未来研究这些关联的潜在机制及其对制定保护肠道策略以最小化肠道生态失调对免疫恢复影响的临床意义奠定了基础。
