Human Milk Oligosaccharides Influence Neonatal Mucosal and Systemic Immunity

Abstract

The immune system of the infant is functionally immature and naïve. Human milk contains bioactive proteins, lipids, and carbohydrates that protect the newborn and stimulate innate and adaptive immune development. This review will focus on the role human milk oligosaccharides (HMO) play in neonatal gastrointestinal and systemic immune development and function. For the past decade, intense research has been directed at defining the complexity of oligosaccharides in the milk of many species and is beginning to delineate their diverse functions. These studies have shown that human milk contains a higher concentration as well as a greater structural diversity and degree of fucosylation than the milk oligosaccharides in other species, particularly bovine milk from which many infant formulae are produced. The commercial availability of large quantities of certain HMO has furthered our understanding of the functions of specific HMO, which include protecting the infant from pathogenic infections, facilitating the establishment of the gut microbiota, promoting intestinal development, and stimulating immune maturation. Many of these actions are exerted through carbohydrate-carbohydrate interactions with pathogens or host cells. Two HMOs, 2'-fucosyllactose (2'FL) and lacto-N-neotetraose (LNnT), have recently been added to infant formula. Although this is a first step in narrowing the compositional gap between human milk and infant formula, it is unclear whether 1 or 2 HMO will recapitulate the complexity of actions exerted by the complex mixture of HMO ingested by breastfed infants. Thus, as more HMO become commercially available, either isolated from bovine milk or chemically or microbially synthesized, it is anticipated that more oligosaccharides will be added to infant formula either alone or in combination with other prebiotics.

Fig. 1.

Human milk may orchestrate gastrointestinal, immune, and microbiota development. The intestinal ecosystem represents a complex, interactive environment in which human milk influences intestinal development, establishment of gut microbiota, and maturation of the gut mucosal and systemic immune system. In turn, signals from the microbiota stimulate maturation and specificity of the mucosal and systemic immune systems. In addition, the immune system and microbiota promote intestinal development. Human milk contains bioactive nutrients and other components that are modulators of these processes, of which the oligosaccharides are a key component.

Fig. 2.

Potential mechanisms whereby human milk oligosaccharides (HMO) influence host immune function. HMO affects innate immunity through the epithelial barrier: HMO reduce intestinal crypt cell proliferation (1), increase intestinal cell maturation (2), increase barrier function (3), and may influence goblet cell function (4), as has been shown for galacto-oligosaccharides. In addition, HMO affect epithelial immune gene expression both directly (5) and indirectly through the microbiota (6). HMO serve as prebiotics to promote the growth of healthy bacteria, including Bifidobacteria and Bacteroides species (7), and HMO inhibit infections by bacteria and viruses by either binding to the pathogen in the lumen or by inhibiting binding to cell-surface glycan receptors (8). HMO affect immune cell populations and cytokine secretion (9). HMO are also absorbed into the blood (10), where they affect binding of monocytes, lymphocytes, and neutrophils to endothelial cells (11) and formation of platelet-neutrophil complexes (12).