Antibiotic treatment limits survival of peripheral and bone marrow B cell populations

Prolonged or broad-spectrum antibiotic courses are associated with intestinal dysbiosis and cytopenias, and depletion of hematopoietic progenitor populations following antibiotics is associated with loss of peripheral immune cells, leading to increased susceptibility to systemic infections. We evaluated the bone marrow hematopoietic compartment in a murine model of antibiotic exposure. Single-cell RNA sequencing revealed a substantial and previously unrecognized 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, yet fecal microbiota transfer did not rescue both peripheral and bone marrow B cells to a greater degree than natural recovery from antibiotic treatment. Antibiotic-mediated loss of B cell progenitors was secondary to enhanced apoptosis and occurred independent of disrupted systemic type I and II interferon signaling, previously implicated in the maintenance of other hematopoietic compartments. Instead, the depletion of pro-survival MYC signaling was implicated in the depletion of circulating lymphocytes and bone marrow B cell progenitor populations during antibiotic treatment. Further, in vitro exposure of bone marrow cells to antibiotics demonstrated significantly decreased viability of B cells. We conclude that both microbiota depletion and cytotoxic effects of prolonged broad spectrum antibiotic treatment disrupt cytokine and cell survival signaling critical for 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 antibiotic treatment.