Breast milk is a complex biological fluid that is rich in nutrients and bioactive agents that support the healthy growth and development of the newborns. Human milk oligosaccharides (HMOs) are unconjugated glycans that constitute an important component of the protection conferred by breast milk on the neonate. HMOs may act locally on the neonatal intestine by acting as signalling molecules and directly interacting with the host cells. Although fucosylated and sialylated HMOs have little nutritional value, they exert important prebiotic as well as immunomodulatory effects on the infant gut. However, there is heterogeneity in the quantity and quality of HMOs in breast milk produced by mothers under influence of the genetic and environmental factors. This review encompasses the salient aspects of HMOs such as composition, function, structural diversity, and functional impact on the growth and survival of newborns. In this review, the current knowledge on HMOs is contextualised to discuss the gaps in scientific understanding and the avenues for future research.
Human milk is considered as the “gold standard” of infant nutrition during the first few months of human life. The composition of human milk is unique and it is adapted for the infant’s immature digestive and immune systems. Human milk protects infants from infection and inflammation, promotes development of immunity, and facilitates organ maturation [
Although HMOs are of various types and carry out diverse functions, they have a basic structural blueprint (Figure
Structural blueprint of HMOs. The glucose, galactose,
Although the synthetic oligosaccharides such as galactooligosaccharides (GOS) and fructooligosaccharides (FOS) and pectin-derived acidic oligosaccharide (pAOS) have been introduced into the infant formula, they are structurally different from the HMOs. Fructose or its polymers as well as galacturonic acid and its homo- or heteropolymers are not found in human milk. Fucosylated and sialylated oligosaccharides are important HMOs that are yet to be synthesized [
HMOs are classified into three types [ Neutral or fucosylated HMOs: these HMOs contain fucose at the terminal position. Examples: 2’-fucosyllactose (2’-FL) and lactodifucopentose. Neutral N-containing or nonfucosylated HMOs: these HMOs contain N-acetylglucosamine at the terminal end. Example: lacto-N-tetraose. Acidic or sialylated HMOs: these HMOs contain sialic acid at the terminal end. Example: 2’-sialyllactose.
The total HMO concentration decreases within the first 3 months, but the level of some HMOs may increase [
Significant biological variation is evident in specific HMO structures such as 2′-FL and lacto-N-fucopentaose I and II (LNFP I and LNFP II) in mature term breast milk. The variation in
The HMOs vary in structure and composition over the course of lactation. A cross-sectional study of Chinese mothers reported that they produced unique types of HMOs during the different stages of lactation, independent of the mode of delivery and geographical location [
The total HMO concentration in milk of women who deliver preterm is greater than of those who deliver at term [
HMO concentrations were significantly lower in women with a body mass index (BMI) of 14 to 18 than in women with a BMI of 24 to 28 [
The multifarious functions of HMOs are as follows: (i) they act as prebiotics and stimulate the colonization of beneficial microbes, (ii) they exert direct defence mechanisms against pathogens and protect infants from infections, (iii) they act as signalling molecules and interact directly with the host cells, (iv) they act as anti-inflammatory and immune-modulators, and (v) they act as nutrients for neurological development of infants (Figure
Potential benefits for breast-fed neonates. HMOs may serve as prebiotics, immune-modulators, and signalling molecules to enhance the gut immunity of newborns.
The complex oligosaccharide mixture within HMOs attracts both mutualistic mucus adapted species and HMO-adapted bifidobacteria to the infant intestine [
Type of gut microbiota in (a) absence of HMOs and (b) presence of HMOs. The growth of beneficial bifidobacteria is favoured by HMOs over that of pathogens in the gut.
The genomic study of
HMOs are the major constituent of an innate immune system whereby the human milk protects the infant from enteric and other pathogens [
Adhesion of pathogens to gut wall in (a) absence of HMOs and (b) presence of HMOs. The adhesion of the pathogens to the gut wall is prevented by HMOs that serve as decoy.
The sialylated fraction of HMOs showed a strong inhibitory capacity for hemagglutination mediated by enterotoxigenic
The interaction of HMOs with pathogenic microbes prevents their attachment to the intestinal epithelial cells [
Gut epithelial cells in (a) absence of HMOs and (b) presence of HMOs. The interaction with HMOs leads to altered gene expression and growth of the intestinal epithelial cells.
HMOs, especially disialyllacto-N-tetraose, contribute to protection from necrotising enterocolitis [
HMOs exert anti-inflammatory effect by reducing the platelet-neutrophil complex formation that contributes to a reduction in the neutrophil beta-2 integrin expression [
T-cell response in (a) absence of HMOs and (b) presence of HMOs. The modulation of the immune system by the HMOs leads to a more balanced T-cell response.
Acidic HMOs may modulate postnatal allergen-specific immune responses by suppression of Th-2 type responses in atopy-prone individuals [
A randomized controlled study of healthy term infants reported that the formulas supplemented with 2’-FL were well tolerated, and 2’-FL absorption profiles were similar to those of breast-fed infants. There were no significant differences in weight, length, and head circumference between infants fed human milk or 64.3 kcal/dL formulas from birth to 4 months of age [
HMOs represent the next frontier in neonatal nutrition as they constitute a major component of the immune-protection conferred by breast milk upon vulnerable infants. Progress in clinical research has deemed supplementary provision of HMOs an attractive alternative for newborns who cannot be breast-fed. Although there have been significant breakthroughs in our knowledge about the HMOs, there are many key questions that need to be answered. Basic science should dictate the specific choice of HMOs and clinical data should justify the need for supplementing the infant formulas with them. Clinical research could be directed towards addressing pertinent queries such as which are the specific HMOs, in what quantity and for how long should they be administered. Basic research has hitherto laid a firm groundwork for clinical research on HMOs, which in turn has engendered new questions about their clinical implications.
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Human milk oligosaccharides
Galactooligosaccharides
Fructooligosaccharides
Pectin-derived acidic oligosaccharide
European Food Safety Authority
United States Food and Drug Administration
2′-fucosyllactose
Lacto-N-neotetraose
Lacto-N-fucopentaose
Fucosyltransferase
Secretor
Lewis
3-fucosyllactose
Lacto-N-tetraose
Galacto-N-biose
Lacto-N-biose
Enterotoxigenic
Uropathogenic
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
The authors declare that they have no conflicts of interest regarding the publication of this paper.
The authors contributed towards the drafting and revising of the review article. They provided their approval for the final version of the article to be published.
We acknowledge the support of Fahmina Anwar, Nestle South Asia region, in literature search to understand the current researches on HMOs.