The World Health Organisation (WHO) refers to human milk as the nutritional gold standard for term infants.[1] Infants who are breastfed are at an immunological advantage when compared with formula-fed infants, evidenced by decreased incidence of infections and reduced propensity for chronic conditions including wheeze and/or asthma.[3] Human milk contains many immunomodulatory compounds, listed in Table 1.
Table 1. Immunomodulatory compounds found in breastmilk[1,2]
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Additionally, the carbohydrates present are beneficial not only as an energy source; certain oligosaccharides (e.g. galacto-oligosaccharides) act as prebiotics, showing a clear bifidogenic effect, and contribute partially to the distinct bifidobacteria-dominant microbiota of a breastfed infant compared to a formula-fed infant.[1,4]
Prebiotics improve stool characteristics of formula fed infants[4]
In a study investigating the impact of adding the prebiotic galacto-oligosaccharides (GOS) and fructo-oligosacchardides (oligofructose/FOS) to infant formula, researchers looked at how certain characteristics of stool from breastfed (BF) infants differed from that of infants fed conventional formula (FF) and those given formula fortified with the GOS/FOS blend (PRE). The prebiotic given was administered at a dose of 4g/L of formula, and comprised of GOS and FOS in a ratio of 9:1.
Results revealed the number and proportion of bifidobacteria in the PRE group to be significantly higher than that of the FF group, whereas it did not differ from the BF infants. The PRE group also showed lower Clostridium difficile numbers when compared to the FF group.
These results provided evidence that the addition of a prebiotic to infant formula can assist in establishing a more desirable bifidogenic microbial profile in infants, which closely resembles that of a breastfed infant.
Prebiotic oligosaccharides may reduce the incidence of atopic dermatitis[5]
The prevalence of atopic diseases (AD) has steadily increased during the last decade in developed countries. AD is usually the first manifestation of allergy during infancy, and is believed to be associated with delayed maturation of the Th1 immune responses during early infancy with raised total IgE and specific IgE to dietary antigens in the serum.
There is strong evidence that the intestinal flora influences the postnatal development of the immune system and stimulation of the entire intestinal flora by prebiotics might be a more effective method of altering immune development than by adding a single bacterial species to the intestinal ecosystem.
In a prospective, double-blind, randomised placebo-controlled trial, 259 infants at a high risk for AD were divided into two groups and administered either a prebiotic or placebo for the first 6 months of life. The intervention contained a 9:1 mixture of GOS and FOS administered at 0.8g/100mL of hydrolysed protein formula.
Only 10 infants in the intervention, compared to 24 in the control group, developed AD. Prebiotic supplements were also associated with a significantly higher number of faecal bifidobacteria compared with controls. These results showed for the first time a beneficial effect of prebiotics on the development of AD in a high risk population of infants.\
Prebiotics may prevent intestinal and extra-intestinal infections[6]
Infectious diseases are generally less frequent in breastfed infants than in formula-fed infants and this may be due in part to the peculiar pattern of microbial colonisation typical of a mother’s milk.
As prebiotic addition to formula is shown to increase the load of lactobacilli and bifidobacteria, and to make the intestinal microbiota of formula-fed infants similar to that observed in breast-fed infants, it could be hypothesised that this would translate into benefits in the prevention of intestinal and/or respiratory tract infections.
In a prospective, randomised, placebo-controlled, open trial, 342 healthy infants were enrolled and randomised to a formula with an added mixture of prebiotic (GOS and FOS) or control formula. The incidence of intestinal and upper respiratory tract infections (URTI) and certain anthropometric measures were monitored for 12 months.
Results included a lower incidence of gastroenteritis in the supplemented group compared with controls. The number of episodes of URTI was lower in the GOS/FOS group, however the difference did not reach statistical significance. Among the children with at least one episode of URTI, the number of children with recurrent URTI (defined as more than 3 episodes in the 12 months) was lower in children fed with the GOS/FOS formula, and the difference was close to significance. Furthermore, the number of children with multiple antibiotic courses/year was lower in children receiving prebiotics compared to controls during the first 6 months of follow-up.
Researchers concluded that prebiotic administration reduces intestinal and, possibly, respiratory infections in healthy infants during the first year of age. In addition to the increased concentrations of lactobacilli and bifidobacteria, the addition of GOS and FOS to formula is shown to increase faecal concentrations of secretory IgA (sIgA), suggesting that the positive effect on mucosal immunity may occur, in part, via this mechanism.[7]
GOS and FOS reduces the incidence of NEC in breastfed preterm infants[8]
Necrotising enterocolitis (NEC) is one of the most destructive diseases associated with conditions of neonatal prematurity, with mortality and morbidity rates high.
Probiotics and prebiotics are beginning to show promise in reducing the incidence of the condition. Oligosaccharides contained in breast-milk sit on the position of microbial receptors and prevent pathogens from binding with epithelial cell walls of infant's gastrointestine (GI). They have also been found to protect the growth of lactobacilli and bifidobacteria in the GI of breast-fed infants and, therefore, supplementation with enteral oligosaccharides have been found to stimulate bifidogenic intestinal microflora and decrease pathogens.
A study aimed at investigating the efficacy and safety of enteral supplementation of a prebiotic mixture GOS and FOS versus no intervention on the incidence of NEC in preterm infants was conducted.
In this trial, 75 preterm infants on 30mL/kg/day volume of breast-milk were randomly allocated to have enteral supplementation with a prebiotic mixture (GOS:FOS 9:1) or to not receive any prebiotic.
The prebiotic mixture was well tolerated by very low birth weight (VLBW) infants and results showed that its administration significantly reduced the incidence of NEC in this prebiotic group who were also fed exclusively breast-milk. The time taken to reach a total milk intake was also decreased in the prebiotic groups, as was duration of hospitalisation. Authors suggested that the prebiotic mixture was synergistic to the benefits of human oligosaccharides in breastmilk.
Maternal microbiota and vitamin D status play a role in infant immune modulation
Supporting maternal microbial imbalance appears to be important in supporting healthy foetal immune development. Emerging evidence has revealed the presence of microbes and their DNA signatures within the maternal uterine environment, whilst maternal supplementation with probiotics is associated with changes in foetal intestinal innate immune gene expression profile (e.g. TLR expression), while probiotics are shown to assist in modulating maternal and placental immune physiology.[9]
This supports the importance of a healthy maternal microbiota during pregnancy for optimal immune function in the offspring. Furthermore, antibiotic use during pregnancy (which disrupts the maternal microbial balance) sees a dose-related increase in allergy (asthma) risk in the offspring.[10]
It is important to note that the facilitation of microbial diversity, although significant, should be recognised as just one component of optimising infant immune development. Healthy vitamin D status is fundamental to sound immune modulation, with its deficiency being linked to compromised innate and adaptive immune function, resulting in an altered cytokine profiles and increased risk of allergic conditions.[11]
In conclusion, FOS and GOS appear to be very beneficial, together with probiotics, to assist formula-fed infants in achieving a microbial balance which is closer to the seemingly more beneficial balance identified in breast fed infants. This appears to assist in significantly reducing the risk of local and extra-intestinal infections and modulating immune function to reduce allergy risk.
Related content: Early Infant Nutrition: The Role of Prebiotics
References
- Jeurink PV, van Bergenhenegouwen J, Jiménez E, et al. Human milk: a source of more life than we imagine. Benef Microbes 2013;4(1):17-30. [Abstract]
- Jeurink PV, van Esch BC, Rijnierse A, et al. Mechanisms underlying immune effects of dietary oligosaccharides. Am J Clin Nutr 2013;98(2):572S-577S. [Full text]
- Dixon D. The role of human milk immunomodulators in protecting against viral bronchiolitis and development of chronic wheezing illness. Children 2015;2(3):289-304. [Full text]
- Holscher HD, Faust KL, Czerkies LA, et al. Effects of prebiotic-containing infant formula on gastrointestinal tolerance and fecal microbiota in a randomized controlled trial. JPEN J Parenter Enteral Nutr 2012;36(1 Suppl):95S-105S. [Abstract]
- Moro G, Arslanoglu S, Stahl B, et al. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 2006;91(10):814-819. [Full text]
- Bruzzese E, Volpicelli M, Squeglia V, et al. A formula containing galacto- and fructooligosaccharides prevents intestinal and extra-intestinal infections: an observational study. Clin Nutr 2009;28(2):156-161. [Abstract]
- Scholtens PA, Alliet P, Raes M, et al. Fecal secretory immunoglobulin A is increased in healthy infants who receive a formula with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides. J Nutr 2008;138(6):1141-1147. [Full text]
- Armanian AM, Sadeghnia A, Hoseinzadeh M, et al. The effect of neutral oligosaccharides on reducing the incidence of necrotizing enterocolitis in preterm infants: a randomized clinical trial. Int J Prev Med 2014;5(11):1387-1395. [Full text]
- Rautava S, Collado MC, Salminen S, et al. Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebocontrolled trial. Neonatol 2012;102(3):178-184. [Abstract]
- McKeever TM, Lewis SA, Smith C, et al. The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands general practice database. Am J Respir Crit Care Med 2002;166(6):827-832. [Abstract]
- Jones AP, D'Vaz N, Meldrum S, et al. 25-hydroxyvitamin D3 status is associated with developing adaptive and innate immune responses in the first 6 months of life. Clin Exp Allergy 2015;45(1):220-231. [Abstract]
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