Abstract
Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS). However, few studies have examined the mechanisms involved. We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exposure at birth. Neonatal mice were transiently exposed to broad-spectrum antibiotics from birth for either 3- (SE) or 7-days (LE) and were examined at 14-days-old. We found that mice exposed to either SE or LE showed persistent expansion of Proteobacteria (2 log difference, P < 0.01). Further, LE mice demonstrated baseline translocation of E. coli into the liver and spleen and were more susceptible K. pneumoniae-induced sepsis. LE mice had a significant and persistent decrease in type 3 innate lymphoid cells (ILC3) in the lamina propria. Reconstitution of the microbiome with mature microbiota by gavage in LE mice following antibiotic exposure resulted in an increase in ILC3 and partial rescue from LOS. We conclude that prolonged exposure to broad spectrum antibiotics in the neonatal period is associated with persistent alteration of the microbiome and innate immune response resulting in increased susceptibility to infection that may be partially rescued by microbiome reconstitution.
Highlights
Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS)
The neonatal period is a critical time for colonization of the intestine and even transient antibiotic exposure could disrupt the normal pattern of microbiome acquisition
Since we demonstrated that LE mice transitioned into an altered microbiota at 2 weeks of life, had an increased susceptibility to LOS and decreased IL-17A-producing ILC3, we hypothesized that facilitating colonization with normal microbiota would rescue the LEinduced phenotype
Summary
Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS). We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exposure at birth. We conclude that prolonged exposure to broad spectrum antibiotics in the neonatal period is associated with persistent alteration of the microbiome and innate immune response resulting in increased susceptibility to infection that may be partially rescued by microbiome reconstitution. Several clinical studies have demonstrated that exposure to transient early antibiotics in the NICU can increase the risk for development of late-onset sepsis (LOS)[1,2,4,5]. Alteration of the intestinal microbiome and innate immune response may play an important role in increasing the risk for LOS in preterm infants. The role of ILC3 in neonatal host defense is emerging as crucial in mouse models and warrants further investigation
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