Antibiotic-mediated depletion of the gut microbiota limits survival of peripheral and bone marrow B cell populations

Though crucial for the treatment of life-threatening bacterial infections, long-term and broad-spectrum antibiotic therapy is associated with numerous adverse effects, including risk for bone marrow suppression. Single cell RNA sequencing revealed a substantial depletion of bone marrow B cells at all stages of development in antibiotic-treated mice, further confirmed by flow cytometric analysis. Depletion of the microbiota was associated with rapid changes in the peripheral B cell compartment, which could be rescued by fecal microbiota transfer. Mice raised in germ-free conditions phenocopied the B cell progenitor loss observed in antibiotic-treated animals. Antibiotic-mediated loss of B cell progenitors was secondary to enhanced apoptosis, which was independent of disrupted systemic type I interferon signaling implicated in maintenance of other hematopoietic compartments. Instead, the depletion of pro-survival MYC signaling, likely secondary to depletion of numerous microbiota-regulated cytokines, was implicated in the enhanced apoptosis and depletion of circulating lymphocytes and bone marrow B cell progenitor populations during antibiotic treatment. We conclude that microbiota depletion following antibiotics treatment disrupts cytokine and MYC signaling critical for B cell survival, leading to impaired B cell progenitor maintenance. These results contribute to our understanding of the compartment-specific mechanisms by which the microbiota maintains the hematopoietic system and suggest critical pathways for maintenance of bone marrow progenitors during prolonged antibiotics treatment.

尽管长期广谱抗生素疗法（long-term and broad-spectrum antibiotic therapy）在危及生命的细菌性感染治疗中不可或缺，但该疗法伴随诸多不良反应，其中包括骨髓抑制风险。单细胞RNA测序（single cell RNA sequencing）结果显示，经抗生素处理的小鼠骨髓B细胞在所有发育阶段均出现显著耗竭，这一发现进一步通过流式细胞术分析（flow cytometric analysis）得到验证。微生物群耗竭与外周B细胞亚群的快速变化密切相关，而粪便微生物群移植（fecal microbiota transfer）可逆转该变化。在无菌环境（germ-free conditions）中饲养的小鼠，其表型与抗生素处理动物中观察到的B细胞祖细胞丢失情况完全一致。抗生素介导的B细胞祖细胞丢失继发于细胞凋亡（apoptosis）增强，该过程并不依赖于此前被证实可维持其他造血亚群的系统性I型干扰素信号通路（type I interferon signaling）紊乱。与之相反，促存活MYC信号通路（MYC signaling）的耗竭（其可能由大量微生物群调控的细胞因子（cytokine）耗竭继发而来），与抗生素处理过程中细胞凋亡增强以及循环淋巴细胞和骨髓B细胞祖细胞群体的耗竭显著相关。本研究得出结论：抗生素治疗后微生物群耗竭会破坏B细胞存活所必需的细胞因子与MYC信号通路，进而损害B细胞祖细胞的维持能力。本研究结果有助于我们理解微生物群维持造血系统（hematopoietic system）的亚群特异性机制，并为长期抗生素治疗过程中骨髓祖细胞（bone marrow progenitor）的维持提供了关键调控通路。