The latest insights on the role of pre- and synbiotics in the dietary management of Cow's Milk Allergy and infection outcomes.

The development of the immune system in the first 1000 days of life

The immune system develops quickly during the first 1000 days of life; it is well known that both the establishment and maintenance of an optimal microbial community is important for the development of the immune system and essential to maintain health, especially in infants and children.¹

Environmental factors such as mode of delivery, diet and use of antibiotics influence the infant gut and immune system. These factors can cause an imbalance of the gut microbiota known as dysbiosis, which impairs the development of the immune system, resulting in a state of inflammation and potentially giving rise to allergic diseases.²

The role of gut microbiota in the development of the immune system and the defense against infections

Infants are particularly susceptible to infections in early life as their immune system is not yet fully functional^1,2.

The establishment of a balanced gut microbiota in early life is important as it has been suggested to be one of the main factors driving the development and appropriate functioning of the immune system and may help to protect infants against infections^1,3 (Figure 1)⁴.

Human milk contains natural prebiotic oligosaccharides and probiotic bacteria that influence the microbiota

Human milk provides the infant with the best possible nutrition and is known to protect the infant against infections⁵. It contains a wide range of health protective components^6,7, for example human milk prebiotic oligosaccharides and beneficial bacteria (probiotics), stimulating the growth of specific bacteria including bifidobacteria, and influence gut microbiota development^1,3,7. 

The gut microbiota of healthy breastfed infants is typically dominated by bifidobacteria, compared to formula fed infants⁸. The increased abundance of bifidobacteria has been linked to appropriate development and functioning of the immune system, as well as providing resistance to infections by preventing colonization by pathogens or pathogen overgrowth⁹ (Figure 1). 

Research shows that infants with CMA have an aberrant gut microbiota composition (dysbiosis)

Infants with CMA show an aberrant gut microbiota composition (dysbiosis), with typically lower levels of beneficial bacteria i.e. bifidobacteria and increased levels of adult-like clostridia group Eubacterium rectale/Clostridium coccoides (ER/CC)^10–13. 

Given the important role of naturally occurring prebiotics and bacteria in human milk in the establishment of a healthy microbiota and the developing immune system, and recognizing that breastfeeding is not always feasible in allergic infants, there is a compelling rationale to combine pre- and probiotic ingredients to hypoallergenic formula for the dietary management of cows’ milk allergy to restore the gut microbiota dysbiosis and modulate the immune system. 

The combination of pre- and probiotics is known as synbiotics¹⁴. In addition to these ingredients reflecting the natural functionality of human milk, the objective of combining pre- and probiotics is to achieve stronger positive effects than with either component alone (synergy) in which the prebiotic stimulates the growth and activity of the probiotic and other health promoting bacteria already present in the gut¹⁵.

Clinical findings show that pre-pro and synbiotics can rebalance gut microbiota composition

Clinical studies in healthy and preterm infants have shown that specific prebiotic oligosaccharides (scGOS/lcFOS) are able to positively impact gut microbiota composition, by stimulating the growth of bifidobacteria¹⁶ and reducing the presence of clinically relevant pathogens in the infants’ gut¹⁷ (Figure 2). 

More recent studies in infants with CMA have shown that an amino acid-based formula (AAF) including a specific synbiotic mixture (scFOS/lcFOS/pAOS/B. breve M-16V) effectively resolved allergic symptoms^18,19, and beneficially modulated the gut microbiota composition¹⁹. 

CMA infants that received the AAF with specific synbiotics (scFOS/lcFOS/B. breve M-16V), showed a gut microbiota composition closer to the profile seen in healthy breastfed infants compared to infants receiving an AAF without synbiotics at 8 weeks, with increased percentages of bifidobacteria and reduced percentages of adult-like clostridia group ER/CC 13 at 8 weeks and 26 weeks²⁰ (Figure 3).

The potential role of pre-, and synbiotics on infection outcomes

In addition to the effects of synbiotics on rebalancing gut microbiota, some clinical studies have also shown a potential role of pre- and synbiotics for the improvement of infection outcomes. 

A clinical trial with infants at risk of atopy demonstrated that 6 months intervention with a hydrolysed infant formula containing specific prebiotic oligosaccharides (scGOS/lcFOS) resulted in a reduction of the total number of infections, cumulative incidence of infections, and recurring infections²¹. The 2-year follow-up data of this study showed a significant reduction of the total number of infections, upper respiratory tract infections, fever episodes, and antibiotic prescriptions²² (Figure 4). 

The effects seen after two years may suggest an imprinting effect of the specific microbiota modulation early in life^21,22. 

In a study of infants with CMA (total n=71) difference have been reported between the two study groups (AAF with and without specific synbiotics (scFOS/lcFOS/B.breve M-16V) with respect to the adverse events and concomitant medication. Although not primary end points of the study, a significant reduction was observed in the subjects receiving the synbiotic-containing AAF regarding the medication subcategory systemic anti-infectives during the 8 weeks intervention (test 8.6% vs. control 34.4%, P = 0.018)¹³, and incidence of ear infection during 26 weeks study period (test 0% vs. control 20%, P = 0.011), which may suggest a beneficial effect on the immune system²⁰. 

Interestingly, comparable results were reported in an earlier study with an AAF with a specific synbiotic mixture (total n=54) showing that significantly fewer subjects in the test group (AAF with scFOS/lcFOS/pAOS/B. breve M-16V) were reported to have infection as adverse events (Test group2%, control 10%, P = 0.008), and lower use of medications categorized asantibacterials for systemic use (test 17%, control 34%; P = 0.049)¹⁹.

Key messages

• Infants with CMA show an aberrant gut microbiota composition (dysbiosis) characterized by typically lower levels of beneficial bacteria, i.e. bifidobacteria and increased levels of adult-like clostridia group ER/CC. Recent studies in CMA infants have shown that hypoallergenic formulas with specific synbiotics are able to bring the gut microbiota composition close to that of healthy breastfed infants, reflected by an increase in bifidobacteria and reduction in adult-like clostridia group ER/CC.
• A potential role of prebiotics on the improvement of infection outcomes have been shown previously. Interestingly, studies with hypoallergenic formula including synbiotics have also showed lower infectious events reported as adverse events in the synbiotic group versus the control group. These findings deserve further study in infants with CMA.

Dr Adam Fox: Effective ways to positively influence the gut microbiota

Professor Nikos Papadopoulos: The long term implications of gut dysbiosis

Learn more about the role of Synbiotics in the management of Cow's Milke Allergy with this short animation

Professor Jan Knol: Gut microbiota and the development of the immune system