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Premature newborns, otherwise known as preemies, face additional challenges in their first months of life as a result of missing out on the protection and nourishment they would otherwise get inside the womb. Many of these babies, for example, have higher nutritional requirements, for which human- or bovine-derived milk fortifiers (a more concentrated version of the formula given to term infants) are added to their primary source of milk, whether it is their mother’s or a donor’s. If they are mainly feeding on formula, they also get a more concentrated recipe designed for their condition.

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Two independent studies—one published August 19 in Cell Host & Microbe and the other published August 26 in Cell Reports Medicine—assessed the role of these different dietary components in the development of the preemie gut microbiome. Their results suggest that there is no strong evidence that human-derived milk fortifiers are more advantageous than cows’ in this respect. 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 evident advantage of human-derived milk fortifiers

The microbial community inhabiting the intestines of preemies bears little resemblance to that of full-term healthy babies, likely due to antibiotic use, separation between mother and baby, and delays in breastfeeding, says University of Toronto nutritional scientist Deborah O’Connor, a coauthor on the Cell Host and Microbe study who in the late 1990s sold patents for powdered milk fortifiers for one dollar each.

During that period, milk fortifiers derived from cow’s milk became available as an additive. In the past decade, however, human-derived milk fortifiers have become commercially available—an expensive option that can cost around $10,000 over the course of a baby’s stay in the neonatal intensive care unit. While positive clinical outcomes have been observed as a result of their use—which could make it cost-effective for extremely premature infants—there is still debate on the extent of their benefits over those derived from cows, as the quality of the current evidence is judged low by some specialists.

University of Manitoba breast milk scientist Meghan Azad, who coauthored the second, Cell Reports Medicine study, and her colleagues were interested in comparing the effects of both types of fortifiers on the microbiota of premature infants, something that to date is poorly understood. Given the large differences that had been previously observed between the use of formula and breast milk on the gut bacterial composition of babies, Azad says she expected similarly large differences when comparing human- or bovine-derived fortifiers, for which she and her collaborators designed a clinical trial with a small sample of 30 very-low-weight infants. (Azad has previously been paid for speaking at symposia sponsored by Prolacta Biosciences, a company that markets human-based milk fortifiers and partially funded her research.)

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Their results, published August 26, show that infants receiving human- or cow-derived fortifiers for between 11 to 39 days (depending on their gestational age at birth) had largely similar microbiota diversity in their stool. Azad says she was surprised by these findings, and that maybe more babies need to be studied to find differences. But she adds that this also suggests that “if there is a difference, it’s much smaller than . . . expected.” 

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

Whether these differences reflect a positive effect on the health of the little ones, however, is difficult to know. “Sometimes, lower diversity is associated with breastfeeding” in full-term babies, and thus, with “better health outcomes,” says O’Connor, but this is because these healthy infants are full of bifidobacteria, that they get from their mother, which help them digest the complex sugars found in breast milk and also foster the development of their immune system. However, for “preterm infants, it’s the opposite,” she adds, and more bacterial diversity is 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 that the two studies’ results don’t suggest that human-derived milk fortifiers significantly improve the microbial composition of preemies. “If there’s an advantage to these fortifiers, it’s not obvious that it’s going to be mediated by the microbiome,” she concludes.

Mom’s milk may matter more

O’Connor adds that it is 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 a final product that reduced the total volume of the mother’s or the donor’s milk. In fact, in an analysis where they assessed the impact of the volume of the fortifiers and the milk—sourced from either the mother or a donor, and sometimes given in mixed batches—on the microbiota, O’Connor’s team found that a higher volume of the mother’s own milk was associated with increased microbial diversity. The team also found an increased abundance of Veillonella, associated with protection from asthma, in the stools of infants who ingested a greater volume of their mother’s milk.

See “The Infant Gut Microbiome and Probiotics that Work

The importance of the milk’s sourcing was further highlighted in the work by Azad and her colleagues. When compared to donated human milk, which has been pasteurized and frozen, a mother’s fresh milk was strongly associated with weight gain in the infants and appeared to be the major determinant of their gut bacterial composition. For example, preemies with a higher intake of their mother’s milk had a higher proportion of bifidobacteria and Veillonella in their microbiomes and lower levels of fecal calprotectin, a biomarker of gut inflammation—all which are commonly associated with better health outcomes.

These studies add to the idea that a mother’s milk is almost a form of “personalized medicine,” that changes via a “feedback mechanism” based on an infant’s needs, says Steven Townsend, an organic chemist studying human breast milk at Vanderbilt University who did not participate in either of the studies. For instance, studies have shown that the milk of mothers who give birth to premature infants has higher concentrations of certain molecules, such as growth factors, than that of mothers of full-term infants. Both papers showcase “that mother’s milk modulates baby’s health, and part of that is modulating the microbiome.”

Considering how expensive human-derived fortifiers are and that, at least from a microbial perspective, their positive effect seems to be minimal, Azad wonders whether it would be better to invest research time and effort elsewhere—namely, in improving children’s access to their mother’s milk by developing research and infrastructure to study lactation. Supporting mothers in pumping and storing their own breastmilk or getting equivalent benefits to those who can’t “is probably something that needs a lot more attention,” she says.

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