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.