microbiota regulates neutrophil homeostasis.pdfVIP

The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice Hitesh S. Deshmukh, M.D., Ph.D. 1,2 , Yuhong Liu, B.S. 1 , Ogechukwu R. Menkiti, M.D. 1,2 , Junjie Mei, Ph.D. 1 , Ning Dai, M.S. 1 , Claire E. O’Leary, B.S. 3 , Paula M. Oliver, Ph.D. 3 , Jay K. Kolls, M.D. 5 , Jeffrey N. Weiser, M.D. 2,4 , and G. Scott Worthen, M.D 1,2 1 Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA 2 Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 3 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 4 Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 5 Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA Abstract Acquisition of microbes by the neonate, which begins immediately during birth, is influenced by gestational age and mother’s microbiota and modified by exposure to antibiotics 1 . In neonates, prolonged duration of antibiotic therapy is associated with increased risk of sepsis after 4 days of life, known as late-onset sepsis (LOS) 2 , a disorder critically controlled by neutrophils 3 , but a role for the microbiota in regulating neutrophil behavior in the neonate has not been described. 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 of microbes in the intestine, altered the structure of intestinal microbiota and changed the pattern of microbial colonization. These changes were associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage restricted progenitor cells in the bone marrow. Antibiotic-exposure of dams attenuated the postnatal granulocytosis by reducing the number of interleukin (IL) 17-producing cells in intestine and consequen