June 17, 2019

A new study involving March of Dimes grantee Misty Good, MD, MS, and a team led by Timothy W. Hand, PhD, Michael J. Morowitz, MD, and colleagues, finds that antibodies found in breastmilk are necessary to prevent necrotizing enterocolitis (NEC), a serious and often deadly bacterial disease of the intestines in sick or preterm babies.

Dr. Good, a neonatologist physician-scientist and assistant professor of Pediatrics in the Division of Newborn Medicine at Washington University School of Medicine in St. Louis, is a former March of Dimes Basil O’Connor Research Scholar who worked on the study that appears today in Nature Medicine. Dr. Hand is with UPMC Children’s Hospital of Pittsburgh and Dr. Morowitz with University of Pittsburgh; Dr. Morowitz is also a former Basil O’Connor Research Scholar.

Immunoglobulin A (IgA) is an antibody that binds to bacteria in the gut and plays an important role in fighting off disease.  According to today’s study, the more bacteria that are tied up with IgA, the less likely babies are to develop NEC. Since preterm babies usually get IgA only from mothers’ milk in their first weeks of life, the authors emphasize the importance of breastmilk for these babies.

“All of us are born with bacteria in our gut, including some that are harmless, but preterm babies are extremely vulnerable to developing infections caused by bacteria known as Enterobacteriaceae,” says Kelle H. Moley, MD, March of Dimes Chief Scientific Officer. “We’re still not sure exactly why this happens. This team has discovered that it’s not how much of this harmful bacteria is present in a baby’s gut that matters, but whether it’s bound to IgA. This offers us a new opportunity to provide treatment for fragile newborns and prevent them from developing NEC, which can destroy their intestines.”
The researchers looked at fecal samples from 30 preterm infants with NEC and 39 age-matched controls. Overall, breastmilk-fed babies had more IgA-bound gut bacteria than their formula-fed peers, and those who developed NEC were more likely to have been formula-fed. Tracking these babies’ gut microbiomes over time, the team found that for the healthy babies, Enterobacteriaceae was largely tied up by IgA, allowing diverse bacterial flora to flourish. But for the NEC infants in the days leading up to diagnosis, IgA-unbound Enterobacteriaceae was free to take over.

To demonstrate causation between IgA and NEC, the research team used a mouse model. “Mice, when they’re born, are equivalent in their intestinal development to a human baby born at 24 weeks,” says lead author Kathyayini Gopalakrishna, MD, a PhD student in the Pitt Graduate School of Public Health's Department of Human Genetics, “so they’re a perfect model to study NEC in preterm infants.”

The researchers bred mice that couldn’t produce IgA in their breastmilk. Pups reared on IgA-free milk were just as susceptible to NEC as their formula-fed littermates. So the authors concluded that breastfeeding in and of itself is not sufficient for NEC prevention. The milk must contain IgA to confer this specific benefit.

However, the solution for NEC may not be as simple as putting IgA into formula, the authors say. Because breastmilk has other benefits beyond IgA, donor milk is still the best option to fill the gap when breastfeeding or providing pumped maternal milk is not an option. The researchers suggest that the antibody content of donor milk could be tested and then the most protective milk could be targeted to the most at-risk infants.

“Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants” appeared online today on Nature Medicine's website.  Other authors on the study were Benjamin R. Macadangdang, Matthew B. Rogers, Justin T. Tometich, Brian A. Firek, Robyn Baker, Junyi Ji, Ansen H. P. Burr, and Congrong Ma. Funding for the work was provided by March of Dimes, the National Institutes of Health and the R.K. Mellon Foundation Institute for Pediatric Research.