In search of the best milk recipe for the intestinal bacteria of premature babies

PMature newborns, also called preterms, face additional challenges during their first months of life due to the lack of protection and nourishment they would otherwise get in the womb. Many of these babies, for example, have higher nutritional requirements, for which human or bovine milk fortifiers (a more concentrated version of the formula given to full-term infants) are added to their main source of milk, whether it is their mother’s milk or that of a donor. If they feed primarily on formula, they also get a more concentrated recipe designed for their condition.

See “Why so early?”

Two independent studies, including one published on August 19 in Cell host and microbe and the other to appear this week in Medicine Reports Unit—assessed the role of these different food components in the development of the intestinal microbiome of premature infants. Their results suggest that there is no strong evidence that human-derived milk fortifiers are more beneficial than those from cows in this regard. They conclude, on the other hand, that receiving their mother’s own milk, as opposed to that of a donor, is likely more beneficial for their developing microbiomes.

No obvious benefit from human-derived milk fortifiers

The microbial community that inhabits the intestines of preterm infants bears little resemblance to that of healthy full-term babies, likely due to antibiotic use, separation between mother and baby and breastfeeding delays, according to a nutrition scientist from the University of Toronto Deborah O’Connorco-author on Cell host and microbe study that in the late 1990s sold patents for powdered milk fortifiers for a dollar each.

During this period, milk fortifiers derived from cow’s milk became available as additives. Over the past decade, however, human-derived milk fortifiers have become commercially available – a expensive option it can cost around $10,000 during a baby’s stay in the neonatal intensive care unit. Whereas positive clinical results have been observed as a result of their use – which may make it cost effective for extremely premature infants – there are still debate on the extent of their benefits over those derived from cows, as the quality of the current evidence is judged down by some specialists.

University of Manitoba Breastmilk Scientist Meghan Azadwho co-wrote the second, Medicine Reports Unit study, and his colleagues were interested in comparing the effects of the two types of fortifiers on the microbiota of premature infants, which is currently poorly understood. Given the big differences that had previously been observed between the use of formula and breast milk on the gut bacterial composition of babies, Azad says she expected similar differences when comparing fortifiers of human or bovine origin, for which she and his collaborators have designed a clinical test with a small sample of 30 very low birth weight infants. (Azad has previously been paid to speak at symposia sponsored by Prolacta Biosciences, a company that markets human-derived milk fortifiers and partially funded her research.)

See “Breast milk and obesity”

Their results, which will be published this week, show that infants given human or cow-derived fortifiers for 11 to 39 days (depending on their gestational age at birth) had broadly similar diversity of microbiota in their stools. Azad says she was surprised by these findings, and maybe more babies need to be studied to find differences. But she adds that it also suggests that “if there is a difference, it is much smaller than . . . expected.”

The second independent study, led by O’Connor and published last week, found significant differences between the gut microbiomes of children who received different types of fortifiers. The results derive from a clinical test which involved 119 very low birth weight babies who received human- or bovine-based milk fortifiers for a median of 48 and 51 days, respectively. One of their key findings was that the use of human-derived fortifiers led to a decrease in microbial diversity, as well as changes in the presence and proportions of certain bacterial groups.

However, it is difficult to know whether these differences reflect a positive effect on the health of the youngest. “Sometimes lower diversity is associated with breastfeeding” in full-term babies, and therefore with “better health outcomes,” says O’Connor, but that’s because these healthy infants are full of bifidobacteria, which they receive from their mothers, which help them digest the complex sugars present in breast milk and also foster the development of their immune system. However, for “preemies, it’s the opposite,” she adds, and there’s more bacterial diversity. associated with faster growth, long-term neurodevelopment and better metabolic outcomes.

Overall, O’Connor, who is currently collaborating with Azad on a different project, says the results of the two studies do not suggest that human-derived milk fortifiers significantly improve the microbial composition of preterm infants. “If there’s a benefit to these fortifiers, it’s not clear that it comes through the microbiome,” she concludes.

Mama’s milk may matter more

O’Connor adds that it’s unclear whether the differences they observed between the two types of fortifiers could be explained by the amount of milk in the final product. While the bovine-derived fortifiers used in each study were powdered, the human-derived ones were liquid, creating an end product that reduced the total volume of the mother’s or donor’s milk. In fact, in an analysis where they assessed the impact of the volume of fortifiers and milk — sourced from the mother or a donor, and sometimes given in mixed batches — on the microbiota, O’Connor’s team found that a higher volume of mother’s milk was associated with increased microbial diversity. The team also found an increased abundance of Veillonelleassociated with protection against asthma, in the stools of infants who ingested a larger volume of breast milk.

See “Infant Gut Microbiome and Probiotics That Work”

The importance of milk supply was further emphasized in the work of Azad and his colleagues. Compared to donated human milk, which has been pasteurized and frozen, a mother’s fresh milk was strongly associated with weight gain in infants and appeared to be the primary determinant of their gut bacterial composition. For example, premature infants consuming more breast milk had a higher proportion of bifidobacteria and Veillonelle in their microbiomes and lower levels of fecal calprotectin, a biomarker of gut inflammation, all generally associated with better health outcomes.

These studies reinforce the idea that breastmilk is almost a form of “personalized medicine,” which changes via a “feedback mechanism” based on the infant’s needs, says Steven Townsend, an organic chemist studying human breast milk at Vanderbilt University who was not involved in any of the studies. For example, studies have show that the milk of mothers who give birth to premature infants contains higher concentrations of certain molecules, such as growth factors, than that of mothers of full-term infants. Both papers show “that breast milk modulates the health of the baby, and part of that modulates the microbiome.”

Considering how expensive human-made fortifiers are and that, at least from a microbial point of view, their positive effect seems to be minimal, Azad wonders if it would not be better to invest the time and effort research elsewhere, namely to improve children’s access to milk by developing research and infrastructure to study lactation. Helping mothers express and store their own breastmilk or achieve equivalent benefits for those who can’t “is probably something that needs a lot more attention,” she says.

See “How breastfeeding protects mothers”