Human milk oligosaccharides

Human milk oligosaccharides deflect pathogens

Human milk oligosaccharides (HMO) deflect pathogens and reduce the risk of infections. They can bind pathogens themselves or on their receptor docking site, and thereby prevent pathogen attachment to target cells. This mechanism has been shown effective against bacteria, viruses and toxins. Because the mechanism is structurally dependent, single isoforms deflect specific pathogens only.

HMO reduce infection risk

Breastfed infants may receive a clinically relevant infection protection that is mediated by human milk oligosaccharides. High HMO concentrations are associated with a reduced risk of diarrhoea (Morrow et al. 2004⁠; Stepans et al. 2006), an effect that seems to be particularly related to fucosylated HMO (Newburg et al. 2004). In addition, the risk for respiratory and bronchial infections seems to be reduced and may be related to 2'‑fucosyllactose and lacto‑N‑neo‑tetraose (Puccio et al. 2017⁠; Stepans et al. 2006).

How do HMO deflect pathogens?

HMO are capable of binding to pathogens as decoy receptors and thereby blocking the attachment of pathogens to glycans in the intestine (Bode. 2012⁠; Triantis et al. 2018). Interactions between glycan structures and carbohydrate-binding proteins are a common metabolic process. They mediate selective substance uptake and cellular signal recognition (Taylor and Drickamer. 2014). Pathogens make use of this process because various cells in the intestine and respiratory tract have glycan structures on their surface. These represent binding targets to microbial pathogens. HMO show structural similarities to these surface glycans and some isoforms use the same mechanism of inhibiting pathogen infection: HMO either bind to the pathogen itself or they bind competitively to the cell surface, thereby blocking the interaction sites of pathogens or the receptor docking sites, respectively (Plaza-Diaz et al. 2013⁠; Triantis et al. 2018). This way, human milk oligosaccharides protect mechanically from infection.

HMO may deflect bacteria, viruses, and toxins

Representatives of each HMO category bind specifically to bacteria or viruses and bacterial toxins. Acidic or sialylated HMO (Figure 534_01-07) prevent adhesion of E. coli (Angeloni et al. 2005⁠; Facinelli et al. 2019) and fucosylated HMO (Figure 534_01-06) bind to various pathogens, including Campylobacter jejuni (Ruiz-Palacios et al. 2003⁠; Weichert et al. 2013), Helicobacter pylori (Xu et al. 2004), Salmonella enterica, Pseudomonas aeruginosa and enteropathogenic E. coli (EPEC) (Weichert et al. 2013). In addition, fucosylated HMO prevent adhesion of (intestinal) viruses such as Norwalk or Noroviruses by blocking their docking sites (decoy receptor) (Koromyslova et al. 2017⁠; Laucirica et al. 2017⁠; Shang et al. 2013). The efficacy of pathogen inhibition is structurally dependent; e.g. 2'-fucosyllactose has greater inhibition capacity on Campylobacter jejuni than 3'‑fucosyllactose (Weichert et al. 2013).

HMO not only bind pathogens but also their toxins: Fucosylated HMO bind heat-stable enterotoxin of E. coli in vitro (Newburg et al., 1990) and may mitigate the activity of different bacterial exotoxins such as toxin A and B of Clostridium difficile, Shiga toxin type 1, and type 2 holotoxin (El-Hawiet et al. 2015⁠; Nguyen et al. 2016).

Structural HMO diversity is required for broad effectiveness

Many of the protective effects of breast milk may be related to HMO presence, concentrations, and composition of the HMO fraction. However, a direct effect of specific HMO isoforms or the HMO cluster with reduced disease incidence has not been demonstrated yet. Since breast milk is rich in bioactive compounds – many of which are involved in immune protection – not all preventive effects can be dedicated to the HMO cluster or individual isoforms (Ballard and Morrow. 2013). Clinical data are needed to clearly identify the extent and mechanisms behind preventative effects hypothesised for HMO. Nevertheless, HMO deflect various pathogens and are thereby promising prebiotic candidates contributing significantly to microbiota-mediated health benefits (Triantis et al. 2018).