Antibiotics Impair Murine Hematopoiesis By Depleting Intestinal Microbiota

Background: Bone marrow suppression is an adverse effect associated with many antibiotics, especially when administered for prolonged treatment courses.

Methods: Recent advances in our understanding of steady-state hematopoiesis have allowed us to explore in detail the effects of antibiotics on hematopoietic progenitors in a murine model.

Results: Antibiotic treated mice exhibited leukopenia, anemia and thrombocytosis. Analysis of leukocytes with flow cytometry revealed pronounced pan-lymphopenia, with reduction of the CD4:CD8 T cell ratio. Bone marrow progenitor analysis revealed severe depletion of multipotent progenitors across all subtypes. In contrast, hematopoietic stem cells were stable during antibiotic therapy, based on both phenotypic analysis and bone marrow transplant assays. Despite severe suppression of lymphoid cells in the periphery and their precursors in the marrow, naïve CD8⁺ T cells were increased in bone marrow. Reductions in progenitor activity were not observed when cells were directly incubated with antibiotics, suggesting that these effects are indirect. Given the known interactions between the intestinal microbiome and hematopoiesis, we investigated its role in antibiotic-associated effects. Hematopoietic changes were associated with a significant reduction of the fecal microbiome, and were partially rescued by fecal microbiota transfer. Further, mice raised in germ-free conditions had hematopoietic abnormalities similar to those seen in antibiotic-treated mice, and antibiotic therapy of germ-free mice caused no additional abnormalities.

Conclusion: Our findings suggest that antibiotics suppress hematopoiesis not through direct toxic effects on progenitors, but by depleting intestinal microbiota. Methods to preserve the microbiome may help reduce the incidence of antibiotic-associated bone marrow suppression.