Editors' ChoiceSepsis

A Maternal Microbial Gift for the Baby

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Science Translational Medicine  28 May 2014:
Vol. 6, Issue 238, pp. 238ec94
DOI: 10.1126/scitranslmed.3009411

Antibiotics are commonly prescribed medications in newborn intensive care nurseries. Indeed, empiric prolonged antibiotics in newborn infants during the first days of life have been used to prevent early-onset sepsis, especially in the case of mothers with concerns of intrauterine infection that have led to premature labor, premature rupture of membranes, and chorioamnionitis. However, such antibiotic use can also have negative consequences. In addition to contributing to antibiotic drug resistance and increased risk of invasive fungal infection, intensive broad-spectrum antibiotic use has been shown to result in increased mortality and morbidity for the neonate in the form of late-onset sepsis and necrotizing enterocolitis.

Distortions of the gut microbiota by antibiotics in preterm infants have been shown to be associated with late-onset sepsis, a neutrophil-mediated process; however, how antibiotic use leads to worse outcome is not clear. Recent work by Deshmukh et al. provides important mechanistic insights into the increased susceptibility of perinatal antibiotic use. They treated pregnant mice with broad-spectrum antibiotics in the drinking water in utero and after birth. Antibiotic treatment resulted in decreased transmission of maternal microbial load to the neonates, a simplification of the gut microbiota, and a particularly early abolishment of Gammaproteobacteria in the neonate observed in the first 3 days after birth. Perinatal antibiotic exposure altered the intestinal microbiome pattern and attenuated postnatal granulocytosis, as antibiotic-exposed neonates had decreased numbers of neutrophils and granulocyte/macrophage-restricted progenitor cells. This relative neutropenia in antibiotic-exposed neonatal mice resulted in increased mortality when they were infected with Gram-negative bacteria such as Escherichia coli or Klebsiella pneumoniae as compared with that of neonatal mice exposed to anitbiotics. The neutropenia and the susceptibility to infection could be rescued in antibiotic-exposed neonatal mice when given intestinal contents of control mice by oral gavage. Moreover, the authors determined that the microbiota-derived signals regulating postnatal granulocytosis were dependent on Toll-like receptor 4 (TLR4) signaling (through the recognition of the Gram-negative bacterial lipopolysaccharide), interleukin-17 (IL-17) production by group 3 innate lymphoid cells in the intestine, and induction of granulocyte colony-stimulating factor (G-CSF), which is important for granulopoiesis.

This work highlights the importance of the neonatal gut microbiota in infection. Microbes in the neonatal gut help promote neutrophils’ antibacterial function. Alteration of the neonatal gut micriobiome with perinatal antibiotics can impair this neutrophil function, making the neonate susceptible to bacterial sepsis, and this new work opens many areas of investigations, including finding a specific class of gut bacteria that can be used as probiotic treatment for newborns at risk for late-onset sepsis and, in scenarios in which antibiotics are needed to treat perinatal infections, finding specific microbial products or target restoration of the IL-17/ILC3/G-CSF axis to bypass the adverse effects of antibiotics. With the adage of “mother knows best,” we should pay careful attention to any alteration of the mother’s natural gut flora, as it can have profound effects on their young.

H. S. Deshmukh et al., The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014). [Full Text]

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