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Accepted (AM)Open Access (License Unspecified), Open
Journal article
The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice
Nature medicine, v 20(5), pp 524-534
01 May 2014
PMID: 24747744
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice
- Creators
- Hitesh S Deshmukh - Children's Hospital of PhiladelphiaYuhong Liu - Children's Hospital of PhiladelphiaOgechukwu R Menkiti - Children's Hospital of PhiladelphiaJunjie Mei - Children's Hospital of PhiladelphiaNing Dai - Children's Hospital of PhiladelphiaClaire E O'Leary - University of PennsylvaniaPaula M Oliver - University of PennsylvaniaJay K Kolls - University of PittsburghJeffrey N Weiser - University of PennsylvaniaG Scott Worthen - Children's Hospital of Philadelphia
- Publication Details
- Nature medicine, v 20(5), pp 524-534
- Publisher
- Springer Nature
- Grant note
- P30 DK034987 / NIDDK NIH HHS 5R01AI038446 / NIAID NIH HHS R01 AI105168 / NIAID NIH HHS R01 AI093566 / NIAID NIH HHS 5R01HL105834 / NHLBI NIH HHS 5P60AA009803 / NIAAA NIH HHS 5R01HL062052 / NHLBI NIH HHS 1R01AI105168 / NIAID NIH HHS R01 AI099479 / NIAID NIH HHS R01 AI038446 / NIAID NIH HHS R01 HL105834 / NHLBI NIH HHS 5T32HD060556 / NICHD NIH HHS 5R01AI093566 / NIAID NIH HHS 3R37HL079142 / NHLBI NIH HHS 1R01AI099479 / NIAID NIH HHS T32 HD060556 / NICHD NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000335710700024
- Scopus ID
- 2-s2.0-84902996531
- Other Identifier
- 991021838271404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Medicine, Research & Experimental