Study Highlights Benefits of Breast Milk for Premature Babies’ Gut Health

Researchers from Yale School of Medicine examined the effects of human milk versus formula on intestinal health using organoids. Their study, published in Gastro Hep Advances, revealed that parental milk promotes epithelial growth and differentiation.

Nutrition’s role in intestinal development

Necrotizing enterocolitis (NEC) is a serious inflammatory complication that typically affects premature infants. The gastrointestinal condition is caused by inflammation of the intestine, resulting in bacterial invasion of the intestinal wall, cell death and intestinal tissue necrosis. Associated with numerous long-term complications, NEC has a mortality rate of up to 50%. Gastrointestinal tract immaturity is believed to play a role in its pathogenesis.

Previous research has identified formula feeding as the largest risk factor for NEC in infants, excluding prematurity. The study found a 6-10 fold lower incidence of NEC among parental milk-fed infants compared to formula. However, it is still unknown how human milk provides its protective benefits.

Considering parental milk is often in low supply in parents of premature infants, understanding how human milk aids intestinal development and thereby offers protection to NEC, could aid the future development of improved supplemented formula.

Human milk supplementation improved organoid growth

Intestinal organoids, derived from fetal intestinal samples that modeled an extremely preterm infant, were cultured for five days in growth media. The organoids were then grown for an additional five days in media supplemented with either parental milk, donor human milk, standard formula, extensively hydrolyzed formula (formula that contains cow’s milk proteins that have already been partially broken down) or a control. The organoids were imaged daily and were preserved for RNA-Seq and immunofluorescence staining. Cytokine and growth factor analysis was performed on the media.

After 5 days, researchers observed that the organoids that were supplemented with human milk, either parental or donor milk, grew much larger than both formula conditions and the control. There was no difference in organoid size found between either human milk condition.

Immunofluorescence staining also revealed that organoids in the human milk groups had the highest proliferation and differentiation rates. In particular, these groups had higher enteroendocrine cell differentiation, which supports proper digestion and peristalsis.

Human milk supplementation also upregulated genes involved in the Wnt signaling pathway and fatty acid metabolism pathways compared to organoids supplemented with formula, which had a downregulation of cell-cycle-promoting genes.

“We found that fetal intestinal tissue fed with formula had a more inflammatory immune profile, while those that were fed with human milk had improved growth, earlier differentiation into mature cell types and a more homeostatic immunophenotype. We think these effects may explain why we see differences in rates of gastrointestinal complications of prematurity, such as necrotizing enterocolitis, between formula-fed and milk-fed preterm infants,” said Dr. Lauren Smith, lead author and hospital resident in the Department of Pediatrics at Yale School of Medicine.

Improving formula milk

“We’re still unclear about whether there are simply good factors in breast milk, detrimental factors in formula or if it’s some combination of both. But some takeaways from this paper are that formula can be detrimental to epithelial growth directly, and that both types of human milk were shown to induce epithelial growth,” said Dr. Liza Konnikova, corresponding author and associate professor of Immunobiology and Neonatal-Perinatal Medicine at Yale School of Medicine.

The team aims to identify the protective factors in human milk, with the goal of supplementing formula milk.

“What we found is that nutritional exposures have a profound impact on the development of the fetal intestinal epithelium. Further research to clarify the mechanism behind this could lead to the ability to supplement the critical factors driving this effect in preterm infants at risk for gastrointestinal complications, reducing morbidity and mortality,” said Smith.

Reference: Smith L, Santiago EG, Eke C, et al. Human milk supports robust intestinal organoid growth, differentiation, and homeostatic cytokine production. Gastro Hep Advances. 2024:S277257232400102X. doi: 10.1016/j.gastha.2024.07.007

This article is a rework of a press release issued by Yale School of Medicine. Material has been edited for length and content.