Human and Nonhuman Milk Products Have Similar Effect on Preemies' Gut Microbiota

Diana Swift

March 02, 2023

No significant differences emerged in gut microbial diversity in preterm infants who exclusively received human milk products, compared with those receiving bovine milk formula or fortifiers, a randomized controlled trial found. Nor were any differences noted in the secondary endpoint of clinical outcomes in the U.K. study, published online in JAMA Network Open.

The finding was unanticipated, according to lead author Nicholas D. Embleton, MBBS, MD, a professor of neonatal medicine at Newcastle University in England. "Over the last 10 years we've focused particularly on the role of the microbiome to better understand causal mechanisms of necrotizing enterocolitis, or NEC," he said in an interview. "We anticipated that an exclusive human milk diet would have measurable impacts on microbiome diversity as a potential mechanism [in] disease modulation as part of the mechanism by which exclusive human milk diets benefit preterm infants."

Shortfalls in a mother's own milk supply often necessitate the use of bovine formula or pasteurized human milk from donor milk banks or commercial suppliers.

The effect of an exclusive human milk diet versus one containing bovine products on vulnerable preterm infants is unclear, but some studies have shown lower rates of key neonatal morbidities, possibly mediated by the gut microbiome. In two randomized controlled trials, for example, one showed a lower rate of NEC with donated human milk while the other showed no difference.

Neither, however, was powered to detect a clinically important difference in surgical NEC.

Milk and the microbiome

The current study's primary endpoint was the effect of an exclusive human milk diet on gut bacterial richness and diversity, as well as the proportions of specific microbial taxa in preterm infants from enrollment to 34 weeks' postmenstrual age.

Conducted at four neonatal intensive care units in the United Kingdom from 2017 to 2020, the study recruited 126 infants born at less than 30 weeks' gestation and fed exclusively with their own mother's milk before 72 hours of age. With a median gestational age of 27 weeks and a median birth weight of just over 900 grams, the babies were randomized 1:1 either to their own mother's milk plus a pasteurized ready-to-feed human milk product or to their mother's milk plus a standard preterm formula (controls). Stool samples were collected to analyze intestinal microbiota.

In terms of clinical outcomes, four infants died in the standard-care control group and eight in the intervention group at a median postnatal age of 25 days and 15 days, respectively, but none died primarily of NEC. Formula and ready-to-feed human milk both represented less than 1% of all fluid intake, respectively.

Although there were no effects on overall measures of gut bacterial diversity, there were some insignificant effects on specific bacterial taxa previously associated with human milk feeding. "These findings suggest that the clinical impact of human milk-derived products is not modulated via microbiomic mechanisms," the authors wrote.

Human milk could benefit, however, via components such as specific oligosaccharides, which act largely by modulating the growth of friendly Bifidobacteria and other species, Dr. Embleton said. "However, it's possible these oligosaccharides might also directly interact via the gut epithelium as a signaling molecule. And, of course, there are many other components that might also act directly on the gut without changing the microbiome."

Commenting on the study but not involved in it, Brenda L. Poindexter, MD, MS, chief of the division of neonatology at Children's Healthcare of Atlanta and Emory University, called it "incredibly important," especially in the context of the claims of superiority made by the manufacturers of human-milk-based fortifiers. "These findings convincingly debunk the notion that the use of bovine-derived fortifiers increases risk of morbidities such as NEC through the mechanism of alterations in the microbiome," Dr. Poindexter said.

"They refute that claim as there was no difference in NEC between the groups and, interestingly, no impact on the microbiome. One of the hypothesized mechanisms for those who purport that bovine fortifiers are 'bad' is that they alter the microbiome, which increases risk of NEC," she said. “The only limitation is that the study was not powered to detect a difference in NEC, but it is incredibly important nonetheless."

The current findings differ somewhat from those of a similar trial from 2022 showing lower microbial diversity and higher relative abundances of Enterobacteriaceae and lower abundances of Clostridium sensu stricto in preterm infants receiving an exclusive human milk diet. "These results highlight how nutrient fortifiers impact the microbiota of very-low-birth-weight infants during a critical developmental window," the authors wrote.

Dr. Embleton conceded that his group's study set the bar deliberately high to avoid finding too many differences purely due to chance, and it therefore might have missed bacterial changes present in low proportions. "Also, the technique we used, 16s rRNA, doesn't explore the microbiome at the strain level, so there may have been changes we didn't detect."

He added that the study populations also had a relatively high usage of mother's own milk and findings may differ in other populations and settings where the use of mother's own milk is much lower. Furthermore, the differences reported by individual hospitals in the babies' gut microbiomes were more significant than most feeding interventions.

So can mothers needing to use nonhuman supplements be reassured by the results? "It is difficult to know how parents may interpret our findings. We need more studies powered to detect differences in functional outcomes before we can draw conclusions and share those findings in a way parents can understand," Dr. Embleton said. "At present, there is perhaps a too simplistic message that cow milk formula is ‘harmful.' "

Most babies exposed to cow's milk fortifier or formula do not develop NEC, and many with NEC have only ever received their own mother's milk or donor milk, he added. "It could be that with advances in pasteurization or other similar techniques the quality and therefore the functional benefits of human milk can be better preserved."

More research is needed on the mechanisms of preterm feeding interventions, including donor human milk, fortifiers, and probiotics, Dr. Embleton said. "The gut microbiome in preterm infants is complex and very different from that in term infants."

The study was sponsored by Newcastle Hospitals NHS Foundation Trust and funded by Prolacta Biosciences, which provided human milk formula and fortifier. Dr. Embleton reported financial ties to Danone Early Life Nutrition, Nestlé Nutrition Institute Lecture, Astarte Lecture, and NeoKare outside of the submitted work. Several coauthors reported similar ties to multiple private companies and various research funding bodies.

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