Do HMOs Play a Role in the Allergic Response and Management of Cow’s Milk Protein Allergy?

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Multiple studies provide evidence that human milk oligosaccharides (HMOs) have significant functions in shaping the infant gut microbiota, maturation of the immune system, and maintaining the integrity of epithelial barriers.1,2 Because of these, new clinical studies have explored the potential of HMOs in the management of cow’s milk protein allergy (CMPA), a common condition that affects 5-15% of infants.3 

Leading experts in pediatric immunology and allergy presented the latest findings on the role of HMOs in the infant gut microbiota and immune system, and its relevance in the management of CMPA during the last European Academy of Allergy and Clinical Immunology (EEACI) FAAM-EUROBAT Digital Conference held last December 1, 2022.4 

HMOs regulate the immune response through 3 mechanisms

Liam O’Mahony discussed the 3 main mechanisms by which HMOs influence the infant immune system. First, studies suggest that Bifidobacteria and other protective microbes in the gut utilize HMOs for their proliferation. The cell surface of Bifidobacteria have immunomodulatory structures, which could induce the activity of T regulatory cells and diminish allergic inflammatory response.4

The second mechanism is through alteration of microbial gut metabolism and production of essential immune regulatory compounds. Infants given HMOs were noted to have elevated levels of sphingolipids, which are important for the development of natural killer T cells. HMOs also modulate intestinal levels of short-chain fatty acids (SCFA), which have been associated with a lower risk of allergic outcomes.4

The third mechanism involves the direct effects of HMOs on the integrity of gut epithelial barrier and immune cells. HMOs bind to pathogens in the gut, thereby preventing adhesion and resulting infection. HMOs also reinforce the epithelial barrier by inducing proliferation and reducing apoptosis. In addition, HMOs directly upregulate IL-22 secretion, which further reinforces the gut epithelium.4

Figure 1. Three mechanisms by which HMOs regulate the immune response 4

 

Specific HMOs that support the gut microbiome in cow’s milk protein allergy (CMPA)

Claire Boulangé presented the new findings of the CINNAMON study*, which explained how HMOs benefit infants with CMPA. This study revealed that adding two HMOs, namely 2’fucosyllactose (2’FL) and lacto-N-neotetraose (LNnT), to a formula feed resulted in normal growth in infants with CMPA and possible protective benefit against ear and respiratory infections during infancy.5

Data analyses showed that HMO feeding resulted in the proliferation of early types of fecal communities, which are composed mainly of Bifidobacteria. Results also suggested that supplementation with HMOs promoted bile acid deconjugation, which can contribute to delayed maturation of the infant gut microbiota. Delayed shifting to an adult-type of gut microbiota promotes proliferation of Bifidobacteria, which aids the proper development of the infant’s immune system. This is particularly beneficial in infants with CMPA, as they are at higher risk of having a dysbiotic microbiota.4

Clinical use of 2’FL and LNnT in the management of cow’s milk protein allergy

Anna Nowak-Węgrzyn presented some key findings from the most recent research studies on the use of 2’FL and LNnT, two types of HMOs that have been incorporated to infant milk formula. A recent study established the hypoallergenicity of w-EHF supplemented with 2’FL and LNnT in infants with CMPA.6 

Subsequently, the CINNAMON study* showed that infants with CMPA, who were given whey-based extensively hydrolysed formula (w-EHF) supplemented with 2’FL and LNnt, had a reduced relevant risk of upper and lower respiratory tract infections, otitis media, and gastrointestinal infections, suggesting that HMO-supplemented formula has immune-enhancing benefits for infants with CMPA.5

Meanwhile, the PLATYPUS study* revealed that giving amino acid-based formula (AAF) containing 2’FL and LNnT resulted in improved growth parameters and dramatic improvement of CMPA symptoms (Fig. 2). It  also confirmed the increase of Bifidobacteria within the first month of feeding. The study further showed a significant decrease of Proteobacteria, a known microbe in gut dysbiosis. A significant increase in fecal SCFA concentrations was also noted. Overall, the results of the PLATYPUS study show that feeding AAF supplemented with 2’FL and LNnt has beneficial intestinal effects for infants with CMPA.7

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Figure 2. Improvement of common symptoms of CMPA after 1 month with HMO-supplemented formula feeding. V1, V2, V3, and V4 corresponded to visits after 1, 2, 3, and 4 months, respectively. The final study visit was during the infants’ 12th month of age.7

Key Takeaways

HMOs positively impact the infant gut microbiota and immune system through various mechanisms. These include upregulation of Bifidobacteria proliferation, modulation of immune responses, and reinforcement of the gut epithelial barrier. As shown in several studies, w-EHF and AAF containing 2’FL and LNnt could, therefore, have an essential role in the clinical management of infants with CMPA.

*Subjects included in the studies were non-breastfed infants diagnosed with CMPA and the mothers were encouraged to continue breastfeeding their infants despite having CMPA.

References:

  1. Seppo A, et al. Human milk oligosaccharides and development of cow's milk allergy in infants. J. Allergy Clin Immunol. 2017;139(2):708-711.
  2. Rousseaux A, et al. Human milk oligosaccharides: Their effects on the host and their potential as therapeutic agents. Frontiers in Immunology. 2021. Available at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.680911.    
  3. Mousan G, Kamat D. Cow’s milk protein allergy. Clinical Pediatrics. 2016;55(11):1054-1063.
  4. EMJ Reviews. Can human milk oligosaccharides modulate the allergic response and improve the management of cow’s milk protein allergy? [Internet]. [Cited 12 April 2023]. Available at: https://emj.emg-health.com/wp-content/uploads/sites/2/2023/01/Can-Human-Milk-Oligosaccharides-Modulate-the-Allergic-Response-and-Improve-the-Management-of-Cows-Milk-Protein-Allergy.pdf.
  5. Vandenplas Y, et al. Effects of an extensively hydrolyzed formula supplemented with two human milk oligosaccharides on growth, tolerability, safety and infection risk in infants with cow’s milk protein allergy: A randomized, multi-center trial. Nutrients. 2022; 14(3):530.
  6. Nowak-Wegrzyn A, et al. Confirmed hypoallergenicity of a novel whey-based extensively hydrolyzed infant formula containing two human milk oligosaccharides. Nutrients. 2019 Jun 26;11(7):1447. 
  7. Gold MS, et al. Effects of an amino acid-based formula supplemented with two human milk oligosaccharides on growth, tolerability, safety, and gut microbiome in infants with cow's milk protein allergy. Nutrients. 2022 May 30;14(11):2297.