It is well known that the incidence of necrotizing enterocolitis (NEC), a devastating disease that affects neonatal premature infants, is lower in infants that are fed breastmilk. However, the reasons for breastmilk’s protective effect are poorly understood. New research suggests that the presence of the IgA antibody in breastmilk is necessary to prevent NEC, acting to shape the host-microbiota relationship in the infants.

The work is published in a Nature Medicine paper titled, “Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants.

The team from the University of Pittsburgh and UPMC Children’s Hospital of Pittsburgh knew that NEC is associated with decreased diversity and increased numbers of Enterobacteriaceae in the intestine. They hypothesized that differential binding of the preterm microbiota by maternal IgA plays a role in this process and is, indeed, a central feature of NEC pathogenesis.

“It’s been well known for a decade that babies who get NEC have particular bacteria—Enterobacteriaceae—in their guts, but what we found is that it’s not how much Enterobacteriaceae there is, but whether it’s bound to IgA that matters. And that’s potentially actionable,” said Timothy Hand, PhD, assistant professor of pediatric infectious diseases at the R.K. Mellon Institute for Pediatric Research and Pitt’s School of Medicine and senior author on the study.

Since preterm infants get IgA only from breastmilk in their first weeks of life, the authors emphasize the importance of breastmilk for these babies. But, breastmilk alone is not enough to confer the protective benefits against NEC. By breeding mice that couldn’t produce IgA in their breastmilk, the team discovered that pups reared on IgA-free milk were just as susceptible to NEC as their formula-fed littermates. Therefore, the authors concluded that breastmilk must contain IgA to confer this specific benefit.

“Mice, when they’re born, are equivalent in their intestinal development to a human baby born at 24 weeks,” said 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.”

Mice reared by IgA-deficient mothers were just as susceptible to NEC as formula-fed mice. [Kathyayini Gopalakrishna, MD]

According to the study, IgA binds to the intestinal bacteria of preterm infants. And, the more bacteria that’s tied up with IgA, the less likely babies are to develop NEC. The researchers uncovered this by analyzing fecal samples from 30 preterm infants with NEC and 39 age-matched controls. They found that 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 infants’ 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. 

This finding extends previous studies that have shown an association between the abundance of Enterobacteriaceae and NEC. They have deepened the understanding by showing that “IgA-unbound Enterobacteriaceae are more closely linked to NEC development than total Enterobacteriaceae abundance.”

Kathyayini Gopalakrishna, MD and Timothy Hand, PhD. [Dr. Timothy Hand]

But the solution for NEC may not be as simple as putting IgA into formula, Hand said. 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 isn’t an option.

“What we showed is that IgA is necessary but may not be sufficient to prevent NEC,” Hand said. “What we’re arguing is that you might want to test the antibody content of donor milk and then target the most protective milk to the most at-risk infants.”

The authors write that “previous attempts to prevent NEC with intravenous immunoglobulins have largely failed to show efficacy.” However, they noted that bacterial specificity was not accounted for and that future strategies may use precision microbiome-informed efforts including “rationally selected protective antibodies.”

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