Potential Solution to Build Infection Immunity in Preterm Infants

Published on in Neonatology Update

One out of every 8 babies is born premature each year in the United States, according to the Centers for Disease Control and Infection. A study by CHOP researchers recently published in Nature Medicine offers a possible explanation as to why these infants are more vulnerable to serious infections than infants born at term. Ultimately, this research may lead to potential treatments to restore critically ill newborns’ resistance to common pathogens, such as E. coli., in the neonatal intensive care unit.

Within 12 to 24 hours after birth, human babies experience a burst in production of infection-fighting white blood cells, a process known as granulocytosis. The study found that neonatal mice have the same spike in white blood cells; however, this acceleration was lessened in mice that had been exposed to antibiotics, which contributed to increased susceptibility to E. coli K1 sepsis, a severe blood infection.

Though antibiotics are frequently prescribed in NICUs because signs of infection in preterm babies are difficult to interpret, counter intuitively, recent research shows that prolonged antibiotic use in preterm babies can give rise to late-onset sepsis. The Nature Medicine study suggests preterm babies exposed to antibiotics, either directly or through their mother, tend to get sicker because antibiotics hamper their natural buildup of granulocytes, as described in the mice models. This makes preterm babies more prone to infection and less able to resist sepsis.

The researchers found that regulation of postnatal granulocytosis likely lies within the gut microbiome, which is sterile at birth. Microbial colonization of the gut starts upon birth, initiating an immune response.

“When you interrupt this pattern of colonization, either by giving antibiotics or some other mechanism, you make babies more susceptible to infection,” suggests CHOP Neonatology Fellow Hitesh Deshmukh, MD, PhD, who co-authored the study.

It has been thought that antibiotics act on the bone marrow and decrease its ability to produce white blood cells. But the research team’s finding that germ-free mice, which are born in sterile environments and are not naturally colonized with microbiota, behaved similarly to the mice that were exposed to antibiotics, disproves that theory. “We think this is all mediated by the absence of microbes in the gut,” says Deshmukh. “If you were to replace some of those microbes, you’d restore the resistance of the newborn to the infection.”

To prove this, they took normal intestinal microbiota from mice that were not exposed to antibiotics and transferred them to mice that had received antibiotics. Restoration of normal microbiota increased the number of circulating and bone marrow neutrophils, plasma granulocyte colony stimulating factor (GCSF) levels, and IL17 transcripts, and restored the IL17-dependent resistance to infection.

Substantial research and safety testing must be done to determine which groups of microbes are beneficial for preterm infants and which are not. But once researchers pinpoint the good and bad bugs, they could isolate, purify, and manipulate certain bacterial components that could trigger postnatal granulocytosis.

The team is now focused on identifying bacterial components that could generate a new microbial community for preterm infants who need antibiotics and subsequently preserve or restore their resistance to infection. Their results could form a basis for future clinical studies for microbiota manipulation and transplantation to ameliorate antibiotic-induced microbiota dysbiosis and improve neonatal mortality.