A future perspective of HMOs role in Allergy Prevention

Key messages:

• Preclinical data have shown that 2’FL, 3’SL, 6’SL and LNT can modulate allergic response.

• Observation study associating breast milk HMO composition with allergic sensitisation or disease in infants did not reach a consensus.

• HMO-induced cross feeding of bifidobacteria and production of SCFA and metabolites is a first step in the understanding of the mechanism of action.

Human Milk Oligosaccharides (HMOs) are the third most abundant component in breast milk after fat and lactose. More than 200 lactose-based complex and diverse glycans compose this HMO family. HMOs have been shown to improve immune function, strengthen the gut barrier, and promote the growth of beneficial colonic bacteria in infants. Interestingly, the above are also underlying mechanisms involved in allergic sensitisation.

Allergic development is confounded by many genetic and environmental parameters and observational studies looking at the link between allergy and HMO consumption have thus yielded divergent results.

Human observational studies

In 2007, Sjogren et al. 1 observed in a small group of children (n=20) that an allergic infant had consumed higher levels of neutral HMOs from colostrum. However, no direct association between HMO and allergy was found. In C-section born infants at risk for allergy, Sprenger et al.2  observed a beneficial association between IgE-mediated eczema and lower level of 2’FL. In this study, the specific fucosylated HMOs were suggested to delay the IgE-associated onset of eczema due to an early modulation of the infant microbiota.

Others did not find any significant association in larger cohorts such as Seppo et al., 3 who, in a cohort of 80 infants, did not observe a direct association with cow’s milk allergy (CMA). Adjusting for many confounders, CMA was found to be associated with lower breastmilk levels for 6’SL, LNFP I, LNFP III and DSLNT. Finally, these authors also noted that levels of LSTc, DSLNT and 6’SL were lower in the milk of mothers with an infant with atopic dermatitis (AD) compared to infants without AD.

Miliku et al. 4 observed in a larger cohort study of 421 infant/mother pairs, that specific profiles of 10 HMOs in breast milk were significantly different between sensitized and non-sensitized food allergic infants. Other clusters of HMO levels have now been associated with allergy susceptibility in different larger cohorts.5,6 

Interestingly, in a randomized clinical study testing the safety of 2’FL, supplementation with 2’FL did not result in any case of reported eczema compared to the placebo group, with 5 reported adverse eczema events. While this study was not powered for allergy, this is an encouraging direction.7

Preclinical observations and mechanistic understanding

The body of evidence linking the efficacy of HMOs with the early microbiota establishment comes from preclinical studies or indirect evidence. Many studies have shown that HMO, more particularly 2’FL, 3’SL and 6’SL can prevent allergic sensitisation or allergic manifestations in animal models 8-10 of food allergy 9 or house dust mite-induced AD.10

Specifically, oral administration of 3’SL to mice reduced allergen sensitisation and AD development. Mechanistically, pre-clinical in vivo studies hint to a possible direct effect of HMO on immune cells combined with an indirect effect through bacterial growth, HMO fermentation and metabolites production.

One common observation is the induction of regulatory T cells and an increase in in feces.10 One mode of action for a reduction of allergic sensitisation also discussed in the literature is the production of SCFA due to the HMO fermentation. The role of the early life microbiota composition or activity and its influence in allergy risk reduction is not fully understood and is subject of current investigations in observational cohorts.

Interestingly, an intervention study has shown that HMOs modulate the microbiota in a direction closer to breast-fed infants increasing the abundance of beneficial bacteria such as bifidobacteria, that directly or through their metabolites, may educate the infant immune system through induction of tolerance.11  Inversely, lower presence of bifidobacteria in infant feces is associated with increased risk of developing allergy. As such, HMO is a promising path to be investigated in the context of allergy prevention.

References

1. Sjogren YM, et al. Neutral oligosaccharides in colostrum in relation to maternal allergy and allergy development in children up to 18 months of age. Pediatr Allergy Immunol. 2007.

2. Sprenger N, et al. FUT2-dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk. Eur J Nutr. 2017.

3. Seppo AE, et al. Human milk oligosaccharides and development of cow’s milk allergy in infants. J Allergy Clin Immunol. 2017.

4. Miliku K, et al. Human milk oligosaccharide profiles and food sensitisation among infants in the CHILD Study. Allergy. 2018.

5. Lodge CJ, et al. Human milk oligosaccharide profiles and allergic disease up to 18 years. J Allergy Clin Immunol. 2021.

6. Jiang S, et al. Comprehensive Human Milk Patterns Are Related to Infant Growth and Allergy in the CHMP Study. Mol Nutr Food Res. 2021.

7. Marriage BJ, et al. Infants Fed a Lower Calorie Formula With 2’FL Show Growth and 2’FL Uptake Like Breast-Fed Infants. J Pediatr Gastroenterol Nutr. 2015.

8. Li A, et al. The human milk oligosaccharide 2’-fucosyllactose attenuates beta-lactoglobulininduced food allergy through the miR-146amediated toll-like receptor 4/nuclear factor-kappaB signaling pathway. J Dairy Sci. 2021.

9. Castillo-Courtade L, et al. Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model. Allergy. 2015.

10. Kang LJ, et al. 3’-Sialyllactose prebiotics prevents skin inflammation via regulatory T cell differentiation in atopic dermatitis mouse models. Sci Rep. 2020.

11. Berger B, et al. Linking Human Milk Oligosaccharides, Infant Fecal Community Types, and Later Risk To Require Antibiotics. mBio. 2020.