An increase in Enterobacteriaceae not bound to IgA drives the reduced intestinal bacterial diversity that precedes necrotizing enterocolitis in preterm infants

Preterm infants exhibit higher rates of necrotizing enterocolitis (NEC), which is a major cause of both mortality and neurodevelopmental morbidity. Although an altered gut microbiota composition and metabolome has been found in preterm infants, the few studies exploring the microbiome in NEC and preterm infants have reported inconsistent results.

Within the mechanisms by which the development of NEC occurs, a bloom of Proteobacteria prior to NEC onset has been observed in some preterm infants. This feature has prompted scientists to explore the role of commensal bacteria in mitigating intestinal dysbiosis in preterm infants.

For instance, preterm infants who receive human milk instead of formula are less likely to develop NEC. However, even though human milk oligosaccharides (HMOs) are among the factors in human milk involved in protecting infants against NEC, an understanding of the mechanism is lacking.

A new case-control study, led by Dr. Timothy W. Hand from UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine, reveals an increase in Enterobacteriaceae not bound to IgA in infants who develop NEC compared with healthy controls.

The authors started exploring the indirect role of IgA—an antibody that synergizes with the gut microbiota to maintain gut health homeostasis—in preterm infant mucosa. The percentage of IgA-associated fecal bacteria in 11 out of 19 exclusively formula-fed preterm infants became detectable at 10 days of life and remained at less than 1% during the first 40 days after delivery.

An analysis of samples from a single formula-fed preterm infant confirmed these findings by showing the absence of bacteria bound to IgA prior to 4 weeks of age, which is the period B cells need to populate the intestine. IgA in the premature infant gut during the first 40 days of life is likely to come from human milk and authors limited their analysis to this period of time.

In a post-diagnosis preterm cohort and a prospective longitudinal preterm cohort, it was found that IgA binding to fecal bacteria of preterm infants was positively correlated with maternal milk feeding and negatively correlated with the development of NEC.

The separation of bacteria bound to maternal IgA from those bacteria that were not bound along with their subsequent characterization revealed that infants with NEC or who went on to develop NEC showed a higher proportion of Enterobacteriaceae not bound to IgA, which drove a depleted IgA-bound bacterial fraction.

In contrast, healthy infants showed a drop in Enterobacteriaceae not bound to IgA.

Therefore, IgA from breastmilk was able to bind to Enterobacteriaceae in the gut of preterm infants while there is a fraction of Enterobacteriaceae not bound to IgA that increases in infants who develop NEC. Gopalakrishna and colleagues hypothesize that preterm infants who develop NEC might not have the effective concentration of secretory IgA in their guts needed to associate with pathobionts such as Enterobacteriaceae.

The crucial role of IgA in preventing NEC was subsequently confirmed in a mouse model. NEC-induced pups fed milk from mothers deficient in IgA or all immunoglobulins had survival rates more similar to formula-fed controls than pups fed milk from wild-type mothers.

Altogether, these findings add new evidence to the protective role of breast milk against NEC. Beyond the previously described protective effects of HMOs, it now seems clear that other non-nutritive milk components such as IgA are also needed.

In the light of these findings, it is also important to consider to what extent milk fortification and donor milk processing may affect the ability of IgA from breastmilk to bind to Enterobacteriaceae and its subsequent impact on NEC development, as Dunne-Castagna and Taft state in this accompanying preview of the study. Similarly, the breastfeeding method used has recently been shown to affect milk microbiota composition.

References:

Gopalakrishna KP, Macadangdang BR, Rogers MB, et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat Med. 2019; 25(7):1110-5. doi: 10.1038/s41591-019-0480-9.

Dunne-Castagna VP, Taft DH. Mother’s touch: milk IgA and protection from necrotizing enterocolitis. Cell Host Microbe. 2019; 26(2):147-8. doi: 10.1016/j.chom.2019.07.013.