Human Milk Oligosaccharides: Their Effects on the Host and Their Potential as Therapeutic Agents

Abstract

Breastmilk is known to be very important for infants because it provides nutrients and immunological compounds. Among these compounds, human milk oligosaccharides (HMOs) represent the third most important component of breastmilk after lipids and lactose. Several experiments demonstrated the beneficial effects of these components on the microbiota, the immune system and epithelial barriers, which are three major biological systems. Indeed, HMOs induce bacterial colonization in the intestinal tract, which is beneficial for health. The gut bacteria can act directly and indirectly on the immune system by stimulating innate immunity and controlling inflammatory reactions and by inducing an adaptive immune response and a tolerogenic environment. In parallel, HMOs directly strengthen the intestinal epithelial barrier, protecting the host against pathogens. Here, we review the molecular mechanisms of HMOs in these different compartments and highlight their potential use as new therapeutic agents, especially in allergy prevention.

Keywords: allergy; epithelial barrier; human milk oligosaccharides (HMO); immune system; microbiota.

Figure 1

Graphical abstract: beneficial effects of HMOs on human health.

Figure 2

The structure of human milk oligosaccharides. HMOs can be classified into neutral fucosylated HMOs (2’-FL, 3FL, and LNFPI-II), neutral HMOs (LNnT) and sialylated HMOs (3’SL and 6’SL). Only the most prevalent HMOs are presented here (4).

Figure 3

HMOs strengthen and protect the gut epithelial barrier. HMOs are able to modify the extracellular glycocalyx of epithelial cells, limiting the adhesion of bacteria and viruses to epithelial cells. HMOs can protect the intestine due to their capacity to amplify the secretion of muc2 (main protein constituting the mucus protecting epithelial cells) and their capacity to strengthen tight junctions. A small portion of HMOs can be absorbed and thus can modulate gene expression inside epithelial cells, limiting their proliferation and inducing their differentiation into villus enterocyte-type cells. Absorbed HMOs also limit the expression of proinflammatory cytokines.

Figure 4

HMOs promote the proliferation of specific intestinal bacterial strains beneficial for health and promote the secretion of short-chain fatty acids. HMOs modulate the intestinal and colon microbiota, inducing the proliferation of Bifidobacterium, Firmicutes, and Actinobacteria in the intestine and Bifidobacterium, Bacteroides, and Lachnospiraceae in the colon. In parallel, HMOs decrease populations of bacteria harmful to health, such as Enterococcus, Proteobacteria, Streptococcus, and Lactobacillus in the intestine and Rothia, Enterococcus, and Clostridia in the colon.

Figure 5

HMO receptors on immune cells (lectin receptors). HMOs can directly interact with the immune system by binding to several receptors present on immune cells. Thus, HMOs can prevent allergic asthma, limit inflammatory cytokine release, and inhibit the rolling of leucocytes inside blood vessels by competing with substrates for these receptors.

Figure 6

HMOs activate a controlled inflammatory innate immune response. HMOs participate in the inflammatory immune response, stimulating cellular (macrophages, mast cells, natural killer cells, and platelets) and molecular (cytokines and chemokines) actors of the innate response to fight against infection (left figure). In parallel, HMOs limit this inflammatory reaction in a cellular and molecular feedback loop (right figure).

Figure 7

HMOs activate the adaptive immune response towards the Th1 response and establish a tolerogenic environment. HMOs can also act on cellular actors in the adaptative immune (Th1, TH17, TCD4+, Treg, Breg, memory B cells) response in order to fight against infectious diseases with a downregulation of Th2 immune response in the intestine and in the spleen. Furthermore, HMOs are able to introduce a tolerogenic environment with stimulation of Treg and Breg cells.