Immunomodulation by Human Milk Oligosaccharides: The Potential Role in Prevention of Allergic Diseases

Abstract

The prevalence and incidence of allergic diseases is rising and these diseases have become the most common chronic diseases during childhood in Westernized countries. Early life forms a critical window predisposing for health or disease. Therefore, this can also be a window of opportunity for allergy prevention. Postnatally the gut needs to mature, and the microbiome is built which further drives the training of infant's immune system. Immunomodulatory components in breastmilk protect the infant in this crucial period by; providing nutrients that contain substrates for the microbiome, supporting intestinal barrier function, protecting against pathogenic infections, enhancing immune development and facilitating immune tolerance. The presence of a diverse human milk oligosaccharide (HMOS) mixture, containing several types of functional groups, points to engagement in several mechanisms related to immune and microbiome maturation in the infant's gastrointestinal tract. In recent years, several pathways impacted by HMOS have been elucidated, including their capacity to; fortify the microbiome composition, enhance production of short chain fatty acids, bind directly to pathogens and interact directly with the intestinal epithelium and immune cells. The exact mechanisms underlying the immune protective effects have not been fully elucidated yet. We hypothesize that HMOS may be involved in and can be utilized to provide protection from developing allergic diseases at a young age. In this review, we highlight several pathways involved in the immunomodulatory effects of HMOS and the potential role in prevention of allergic diseases. Recent studies have proposed possible mechanisms through which HMOS may contribute, either directly or indirectly, via microbiome modification, to induce oral tolerance. Future research should focus on the identification of specific pathways by which individual HMOS structures exert protective actions and thereby contribute to the capacity of the authentic HMOS mixture in early life allergy prevention.

Keywords: allergic diseases; early life nutrition; fucosyllactose; human milk oligosaccharides; mucosal immunity; non-digestible oligosaccharides; sialyllactose.

Figure 1

General composition of human milk oligosaccharides and synthetic analogs. (A) All HMOS consist of only 5 different monosaccharides. The chemical structures of these monosaccharides are presented in a D- configuration. (B) The composition of HMOS follows a distinct structure. Elongation of the core structure and decoration with fucose and/or sialic acid residues leads to the large number of different structures discovered to date. (C) As examples, six simple oligosaccharide structures are displayed.

Figure 2

Overview of the possible functions of HMOS related to the prevention of allergic diseases. The diversity in structures suggests engagement in several mechanisms related to maturation of the infant's gastrointestinal tract. (1) HMOS have shown to function as prebiotics and therefore stimulate growth of commensal bacteria. In addition, HMOS have shown to bind pathogens, thereby preventing binding of these pathogens to the intestinal epithelium itself and possible consequent infections. SCFAs produced during HMOS fermentation can enhance epithelial barrier integrity and locally and systemically modify immune responses. (2) HMOS can promote mucus production and epithelial tight junction integrity, thereby supporting the physical barrier between the intestinal epithelium and the gut content. (3) Several mechanisms by which HMOS directly affect the immune function have been described. Modulation of the response of DCs is one of those described mechanisms which may be relevant for the instruction of protective mucosal immune development. (4) Transportation of a small fraction of HMOS over the intestinal epithelium, results in systemic availability of these structures. This suggests an immunomodulatory role for HMOS, also beyond the gastrointestinal tract. All these HMOS related mechanisms can potentially enhance tolerance induction and therefore possibly prevent allergic diseases. Adjusted from Ayechu-Muruzabal et al. (48).