title: The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice.
abstract: Neonatal colonization by microbes, which begins immediately after birth, is influenced by gestational age and the mother's microbiota and is modified by exposure to antibiotics. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of late-onset sepsis (LOS), a disorder controlled by neutrophils. A role for the microbiota in regulating neutrophil development and susceptibility to sepsis in the neonate remains unclear. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number and composition of microbes in the intestine of the neonates. This was associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage-restricted progenitor cells in the bone marrow of antibiotic-treated and germ-free neonates. Antibiotic exposure of dams reduced the number of interleukin-17 (IL-17)-producing cells in the intestine and production of granulocyte colony-stimulating factor (G-CSF). Granulocytopenia was associated with impaired host defense and increased susceptibility to Escherichia coli K1 and Klebsiella pneumoniae sepsis in antibiotic-treated neonates, which could be partially reversed by administration of G-CSF. Transfer of a normal microbiota into antibiotic-treated neonates induced IL-17 production by group 3 innate lymphoid cells (ILCs) in the intestine, increasing plasma G-CSF levels and neutrophil numbers in a Toll-like receptor 4 (TLR4)- and myeloid differentiation factor 88 (MyD88)-dependent manner and restored IL-17-dependent resistance to sepsis. Specific depletion of ILCs prevented IL-17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis in neonates.
authors.affiliation: 1] Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Hitesh S
authors.initials: HS
authors.lastname: Deshmukh
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ogechukwu R
authors.initials: OR
authors.lastname: Menkiti
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Mei
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Dai
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: O'Leary
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Oliver
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: 1] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [2] Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
authors.affiliation: 1] Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006706:Homeostasis; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D051379:Mice; D064307:Microbiota; D009504:Neutrophils / Q000382:microbiology / Q000473:pathology*; D011247:Pregnancy; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D020381:Interleukin-17; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016179:Granulocyte Colony-Stimulating Factor
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