The effects of Human Milk Oligosaccharides on the Microbiome

Nina Heppner

Key messages:

• Human Milk Oligosaccharides (HMOs) serve as a substrate for bacteria in the gut and thus modulate the developing infant’s microbiota.
• The presence or absence of specific HMOs in breast milk can have a direct impact on
microbial composition and the risk for developing certain diseases.
• Adding even a few HMOs structurally identical to that in human milk to infant formula has been shown to shift the infant microbiota to a composition that is more similar to that of
breastfed babies.

Human breast milk is an evolutionary masterpiece and the recommended way to feed a newborn infant. Despite it being exceptionally dynamic and individualized, the third largest component of maternal milk is always Human Milk Oligosaccharides (HMOs).1

In the last few years, HMOs became a focus point for research in the field of infant nutrition for their potential to act as prebiotic factors, among other benefits. They have been shown in clinical and preclinical studies to have an impact on the infant’s developing gut microbiota, as they serve as a substrate for beneficial bacteria.
There are well-described differences in the gut microbiota of babies that are breastfed compared to those that are bottle-fed. The majority of studies show an increase in the abundance of Bifidobacteria in breastfed babies in combination with an overall less
diverse microbial community.2

The establishment of the infant gut microbiota, especially in the first few months of life, is believed to be heavily influenced by components of maternal milk, such as HMOs. Through their modulation of the microbiota composition, these milk components
can thus have an impact on host health. The establishment of an optimal microbial community immediately after birth and the maintenance of a balanced intestinal
microbiota are important factors in the development of the immune system.
Human Milk Oligosaccharides are structurally very diverse, yet not every mother can produce all types of HMOs3. Genetic disposition of the lactating mother, such as being a “secretor” (and thus having a functional α1-2-fucoslyltransferase FUT2), influences the HMOs composition in the maternal milk. This in turn can then directly influence the bacterial species present in the infant gut.4 Prematurely born infants are especially
at risk for developing diseases like Necrotizing entercolitis (NEC), a severe and often fatal intestinal disorder. Whilst breastmilk has been shown to have a protective effect compared to formulafeeding when it comes to the risk for developing NEC, some premature babies still develop NEC despite being predominantly breastfed.5

A prospective cohort study showed that breast milk of babies that developed NEC differed from that of the healthy babies by having a significantly lower concentration of
a specific Human Milk Oligosaccharide called disialyllacto- N-tetraose (DSLNT).6

This is an example how HMOs can potentially modulate the microbiota and in turn
affect the health status of the infant. Different HMOs are currently being studied in this field. Thanks to recent technological advances, it is now possible to synthesize a small subset of HMOs for use in infant formula. The hope is to transfer some of the observed
benefits of human milk oligosaccharides to children who are bottle-fed. 2-fucosyllactose (2-FL) and lacto-N-neotetraose (LNnT) have been shown in a double-blind, randomized clinical trial to significantly increase the relative abundance of Bifidobacteria and steer the microbial composition more towards the microbiota of
breastfed infants at month 3.7

The formula-fed babies that had acquired a fecal community type similar to that of breastfed babies in the HMOs supplementation group were less likely to require antibiotic treatment up to the age of 12 months, compared to babies with other fecal community types.7 These results paint a positive outlook for the future where infant formula can be further optimized to minimize differences in gut microbiota composition, which could therefore result in potential health benefits.

1. Andreas NJ, Kampmann B, and Le-Doare KM. Human breast milk: A review on its composition and bioactivity. Early human development, 2015. 91(11): p. 629-635.
2. Milani C, et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota.
Microbiology and Molecular Biology Reviews, 2017. 81(4).
3. Bode L. Human milk oligosaccharides: every baby needs a sugar mama. lycobiology, 2012. 22(9): p. 1147-1162.
4. Bazanella M et al. Randomized controlled trial on the impact of early-life intervention with bifidobacteria on the healthy infant fecal microbiota and metabolome. The American journal of clinical nutrition, 2017. 106(5): p. 1274-1286.
5. Bode L. Human milk oligosaccharides in the prevention of necrotizing enterocolitis: a
journey from in vitro and in vivo models to mother-infant cohort studies. Frontiers in
pediatrics, 2018. 6: p. 385.
6. Autran CA et al. Human milk oligosaccharide composition predicts risk of necrotising
enterocolitis in preterm infants. Gut, 2018. 67(6): p. 1064-1070.
7. Berger B et al. Linking Human Milk Oligosaccharides, Infant Fecal Community
Types, and Later Risk To Require Antibiotics. Mbio, 2020. 11(2)