Going With the Gut to Build Preterm Infants' Immunity

At birth, infants move from a sterile environment to one full of microorganisms. They rapidly acquire alterations in their immune systems that help them to survive in this dirty world. Researchers at The Children’s Hospital of Philadelphia used mouse models to show that changes in microbial colonization of the gastrointestinal tract play a vital role in this transition.

Their findings published in Nature Medicine offer a possible explanation as to why human premature infants are more vulnerable to serious infections. 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. One out of every eight babies is born premature each year in the U.S., according to the Centers for Disease Control and Infection.

“Babies who are born preterm, in addition to them having less ability to fight infection, are more likely to get infected, either as a consequence of being born premature or exposure to microbes from the mother’s womb,” said Hitesh Deshmukh, MD, PhD, of CHOP’s division of neonatology and department of pediatrics, who co-authored the study.

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

“Usually a low white count is a harbinger of bad things,” Dr. Deshmukh said. “It means that your body does not have enough white cells to fight an infection, and you’re more likely to be sicker.”

Neonatologists frequently prescribe antibiotics in NICUs because signs of infection in preterm babies are difficult to decipher, Dr. Deshmukh said. Yet, counter intuitively, recent research shows that prolonged antibiotic use in preterm babies can give rise to late-onset sepsis.

The Nature Medicine study suggests a mechanism that explains why preterm babies exposed to antibiotics, either directly or through their mother, tend to get sicker. Perhaps antibiotics hamper their natural buildup of granulocytes, as described in the mice models, which makes the preterm babies more prone to infection and less able to resist sepsis.

Study senior author G. Scott Worthen, MD, professor of pediatrics in the division of neonatology at the Perelman School of Medicine at the University of Pennsylvania, emphasized that researchers do not know definitively how closely newborn mice resemble preterm human babies from an immunological perspective, so this study cannot be applied directly to humans. But the results point to a fascinating pathway for investigation that could offer new interventions.

The CHOP researchers found that regulation of postnatal granulocytosis likely lies within the gut microbiome. By adulthood, a community of a hundred trillion microbes form along a person’s gastrointestinal tract, but at birth, the gut is sterile. Microbial colonization of the gut starts upon an infant’s arrival into the world, initiating an immune response.

“When you interrupt this pattern of colonization, either by giving antibiotics or some other mechanism, you make the babies more susceptible to infection,” Dr. Deshmukh suggested.

A prevailing thought is that antibiotics act on the bone marrow and decrease its ability to produce white blood cells, but Dr. Deshmukh and his team showed that this is not the case. They demonstrated 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.

“While some antibiotics may affect the bone marrow directly, we believe these effects are due to the influence of antibiotics on bacteria in the gut,” Dr. Deshmukh said. “If you were to replace some of those microbes, you might restore the resistance of the newborn to the infection.”

His research team proved this by taking normal intestinal microbiota from mice that were not exposed to antibiotics and transferring them to mice that had received antibiotics. In adult humans, this procedure is called a fecal transplant, which is highly effective at eradicating C. difficile infection.

“Fecal transplant could be one of the ways in which you could make sure that babies have more resistance or more power to fight infection,” Dr. Worthen said.

But he cautioned that substantial research and safety testing must be done to determine which groups of microbes potentially are beneficial for preterm infants. Once researchers pinpoint the good and bad bugs, they could isolate, purify, and manipulate certain bacterial components that could trigger postnatal granulocytosis.

“One of the things you could do with this mixture is to use it to rapidly reconstitute an infant after they’ve finished a course of antibiotics,” Dr. Worthen said. “We still have to give antibiotics, but what happens after you stop? The infants get colonized with the germs that are in the NICU. That’s a horrible combination of events.”

Dr. Deshmukh and his team will focus their future research on identifying bacterial components that could generate a new microbial community for preterm infants’ who needed antibiotics and subsequently preserve or restore their resistance to infection.