HUMAN MILK OLIGOSACCHARIDES (HMOS): FROM OBSERVATION TO CLINICAL INTERVENTION

Sprenger N.
Nestec S.A., Vevey, Switzerland

Introduction:
“Nothing in biology makes sense, except in the light of evolution” (Dobzhansky, 1973) is of particular bearing for milk, the sole and presumably adapted nutrition of newborn mammals. Besides nutrients, human milk contains a plethora of components without nutritive function and amongst them HMOs, the third largest solid constituent of breast milk by mass. HMOs are extensions of lactose by galactose, N-acetylglucosamine, sialic acid and fucose leading to great number and diversity of distinct structures with over 130 described and about 20 covering the majority. As for blood group glyco-types, HMOs depend on the mother’s genotype leading to distinct HMOs phenotypes like those dependent on fucosyltransferase-2 (FUT2, secretor gene) and -3 (FUT3, Lewis gene).
What drives this HMO diversity and what is the role of HMOs for the suckling newborn are questions fascinating scientists and pediatricians for over a century. We hypothesize that HMOs may provide health benefits to newborn infants likely and largely through effects on the newly establishing gut microbiota.

Methods:
Possible relations between HMOs and clinical measures in infants are increasingly explored in clinical observational studies. FUT2-dependent HMOs are especially suited for such association studies, because a significant number of mothers lack FUT2-HMOs in their milk. Observational studies generate hypothesis towards functions that are further substantiated in preclinical or clinical intervention trials. With the advent of HMOs becoming available such hypothesis can now be tested in randomized, placebo-controlled, blinded intervention trials.

Results:
In clinical observational studies, FUT2-dependent HMOs in breast milk were related with the establishment of a bifidobacteria dominated gut microbiota (Lewis, 2015, Microbiome3:13), with reduced gastrointestinal infections (Newburg, 2004, Glycobiology 14:253-263), and morbidity and mortality (Kuhn, 2015, JON 145:66-72) in infants. In C-section born infants FUT2-HMOs are possibly related with a delayed onset of atopic eczema (Sprenger, 2016, EJON). Likely, most such observations are due to a microbiota modulating effects of specific HMOs, yet some direct HMO effects on pathogens and gut epithelia might explain part of the observations.
In a randomized placebo-controlled clinical intervention trial infants fed infant formula with 2’fucosyllactose and lacto-N-neotetraose, shown to be safe and well tolerated, were less likely to experience reported medication (e.g. antibiotic) use and morbidity, especially lower respiratory tract infections (Puccio, 2016, Nutrition & Growth conference). At 3 months the microbiota profile of the HMOs-supplemented group was shifted away from that of infants fed infant formula without HMOs and towards that of breastfed infants (Berger, 2016, Experimental Biology conference).

Discussion:
Clinical observational studies are an interesting option to help decipher the biology of HMOs. Yet, the infant genotype for glycosyltransferases such as FUT2 needs to be considered as it might bias clinical findings. Further, in breast milk HMOs are in a different matrix compared to HMOs as supplement or in an infant formula, which might impact their effect. Still such association studies provide hypotheses for prospective intervention trials for which synthetic HMOs are now becoming available. A first intervention trial showed that such synthetic HMOs are safe, well tolerated and it advances our understanding of HMO biology.

Keywords: Oligosaccharides, Infant, Microbiota, Milk, Infections, Probiotics

Citation:
Sprenger N. (2016). Human milk oligosaccharides (HMOS): From observation to clinical intervention. Conference Proceedings of IPC2016. Paper presented at the International Scientific Conference on Probiotics and Prebiotics, Budapest (p. 71.). IPC2016

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