title: Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota.
abstract: Bone marrow suppression is an adverse effect associated with many antibiotics, especially when administered for prolonged treatment courses. Recent advances in our understanding of steady-state hematopoiesis have allowed us to explore the effects of antibiotics on hematopoietic progenitors in detail using a murine model. Antibiotic-treated mice exhibited anemia, thrombocytosis, and leukopenia, with pronounced pan-lymphopenia as demonstrated by flow cytometric analysis of peripheral blood. Bone marrow progenitor analysis revealed depletion of hematopoietic stem cells and multipotent progenitors across all subtypes. Granulocytes and B cells were also diminished in the bone marrow, whereas the number of CD8+T cells increased. Reductions in progenitor activity were not observed when cells were directly incubated with antibiotics, suggesting that these effects are indirect. Hematopoietic changes were associated with a significant contraction 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. The effects of antibiotics were phenocopied in Stat1-deficient mice, with no additional suppression by antibiotics in these mice. We conclude that microbiome depletion as a result of broad-spectrum antibiotic treatment disrupts basal Stat1 signaling and alters T-cell homeostasis, leading to impaired progenitor maintenance and granulocyte maturation. Methods to preserve the microbiome may reduce the incidence of antibiotic-associated bone marrow suppression.
authors.affiliation: Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX; and.
authors.forename: Kamilla S
authors.initials: KS
authors.lastname: Josefsdottir
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO.
authors.forename: Megan T
authors.identifier: 0000-0002-7030-6131
authors.initials: MT
authors.lastname: Baldridge
authors.affiliation: Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX; and.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Kadmon
authors.affiliation: Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX; and.
authors.forename: Katherine Y
authors.identifier: 0000-0002-5093-6005
authors.initials: KY
authors.lastname: King
mesh_terms: D000740:Anemia / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069467:Fecal Microbiota Transplantation; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression; D005856:Germ-Free Life / Q000187:drug effects / Q000235:genetics; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis / Q000187:drug effects* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007970:Leukopenia / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013922:Thrombocytosis / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology / Q000628:therapy
chemical_list: D000900:Anti-Bacterial Agents; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human