The authors of the study, published in the journal Science Translational Medicine, built on previous human research into how conditions around birth affected newborn development – and specifically their intestinal bacteria.
“Previous epidemiological studies show that human infants whose mothers received frequent [antibiotics] before birth or who were delivered by caesarean section not only had altered intestinal commensal bacteria, but also had increased risk of developing pneumonia,” the authors wrote.
“This led us to hypothesise that early-life exposure to commensal bacteria promotes resistance to pneumonia in newborns,” they added.
To test this, the researchers gave a combination of the antibiotics (ABX) ampicillin, gentamicin, and vancomycin to pregnant mice, and then exposed their newborn mice to a variety of Streptococcus pneumoniae.
“This early-life ABX exposure not only reduced the total number of commensal bacteria but also disrupted the succession of bacterial species in the intestine of newborn mice,” the authors wrote.
Six hours after infection, the researchers saw an increased bacterial load in the lungs and bronchial fluid of the mice, compared to mice of the same age whose mothers were not given antibiotics.
Impact on inflammatory conditions
Given the association of disruption of intestinal bacteria at birth to inflammatory disorders later in life, the researchers also tested the longer-term effects of the disruption in mice.
“We found that increased susceptibility to pneumonia after early-life ABX exposure persisted beyond the neonatal period, until at least four weeks of age. This persistence in susceptibility contrasted with the transient susceptibility to infection that occurs in ABX-exposed adult mice, highlighting the critical nature of commensal exposure during early life,” the authors wrote.
The researchers then transferred intestinal contents from mice with antibiotic-free mothers to those affected by antibiotics.
“Reconstitution of intestinal commensal bacteria restored resistance to pneumonia in ABX-exposed and GF newborn mice. This protection against S. pneumoniae persisted beyond the neonatal period,” wrote the study’s authors.
“ABX-exposed mice that received intestinal contents during the early postnatal period likewise showed increased resistance to infection, at least, for as long as four weeks after birth compared to their littermates that did not receive intestinal bacterial reconstitution,” they added.
The researchers found having intestinal bacteria affected the mice’s expression of the interleukin-22 (IL-22) gene, which is critical to the ability of lungs to repair themselves. Antibiotic-affected mice showed decreased concentrations of IL-22 in bronchial fluid.
Confirmed in human newborns
“We confirmed these observations in human newborns, finding reduced concentrations of IL-22 in the [bronchial] fluid from human newborns exposed to prolonged duration of ABX,” the authors noted.
In their conclusion, they wrote: “Our data demonstrate the importance of commensal exposure in a defined developmental window during the newborn period in the development of pulmonary mucosal immunity in mice. … These data also potentially explain the association between caesarean delivery or widespread use of ABX and an increased risk of infections in newborn infants.
“Finally, similar mechanisms could influence the development of other pulmonary inflammatory disorders such as asthma, which is also associated with caesarean delivery and ABX use during early life, and lead to new therapeutic agents to mitigate the risk associated with early-life ABX exposure in children,” the authors added.
Source: Science Translational Medicine
Published online ahead of print, doi: 10.1126/scitranslmed.aaf9412
“Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection”
Authors: Gray, J; Oehrle, K; Worthen, G; Alenghat, T; Whitsett, J; Deshmukh, H