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The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice

2014; Nature Portfolio; Volume: 20; Issue: 5 Linguagem: Inglês

10.1038/nm.3542

1546-170X

Hitesh Deshmukh, Yuhong Liu, Ogechukwu Menkiti, Junjie Mei, Ning Dai, Claire E. O’Leary, Paula M. Oliver, Jay K. Kolls, Jeffrey N. Weiser, G. Scott Worthen,

Neonatal and Maternal Infections

Here, Hitesh S. Deshmukh et al. report that in neonates, establishment of the intestinal microbiota is associated with neutrophil development. Antibiotic-treated and germ-free mice have reduced numbers of neutrophils and are susceptible to Escherichia coli K1 and Klebsiella pneumoniae sepsis. Reconstitution of the intestinal microbiota promotes interleukin-17 production by innate lymphoid cells and increases plasma granulocyte colony–stimulating factor levels, granulocytosis and host resistance to sepsis. 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 antibiotics1. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of late-onset sepsis (LOS)2, a disorder controlled by neutrophils3. 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.