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. 2014 Dec 23;5(6):681–687. doi: 10.4161/19490976.2014.972237

Prebiotics in infant formula

Yvan Vandenplas 1,*, Elisabeth De Greef 1, Gigi Veereman 1
PMCID: PMC4615227  PMID: 25535999

Abstract

The gastrointestinal microbiota of breast-fed babies differ from classic standard formula fed infants. While mother's milk is rich in prebiotic oligosaccharides and contains small amounts of probiotics, standard infant formula doesn’t. Different prebiotic oligosaccharides are added to infant formula: galacto-oligosaccharides, fructo-oligosaccharide, polydextrose, and mixtures of these. There is evidence that addition of prebiotics in infant formula alters the gastrointestinal (GI) microbiota resembling that of breastfed infants. They are added to infant formula because of their presence in breast milk. Infants on these supplemented formula have a lower stool pH, a better stool consistency and frequency and a higher concentration of bifidobacteria in their intestine compared to infants on a non-supplemented standard formula. Since most studies suggest a trend for beneficial clinical effects, and since these ingredients are very safe, prebiotics bring infant formula one step closer to breastmilk, the golden standard. However, despite the fact that adverse events are rare, the evidence on prebiotics of a significant health benefit throughout the alteration of the gut microbiota is limited.

Keywords: fructo-oligosaccharide, galacto-oligosaccharide, infant feeding, infant formula, oligosaccharide, polydextrose, prebiotic

Introduction

Prebiotic oligosaccharides (OS) are the third most prevalent component in mother's milk, and they are virtually absent in cow's milk.1 Human milk OS constitute a complex mixture of glycan compounds. Prebiotics are non-digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system in ways claimed to be beneficial to health. It is well known that the gastrointestinal (GI) microbiota develop in a different way in breastfed and standard formula fed infants.2 There are many aspects in the composition of mother's milk and cow's milk that contribute to these differences, such as the carbohydrate, protein, iron and phosphor content. The GI microbiota can be considered as an organ within an organ contributing to host nutrition, developmental regulation of intestinal angiogenesis, protection from pathogens and development of the immune response.3

The concept of dietary modulation of the human colonic microbiota with prebiotics was developed some 20 y ago.4 In infant formula, mainly galacto-OS (GOS) and/or fructo-OS (FOS) and/or polydextrose (PDX) are used. GOS, which are quite similar to the human milk OS, have emerged with strong clinical support for both digestive and immune health.5 This was also shown for inulin-type fructans.6 The prebiotic effect is defined as “the selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.7

Method

We performed a search in June 2014 of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials using the search terms oligosaccharide, galacto-oligosaccharide, fructo-oligosaccharide, polydextrose, prebiotic, infant formula,

Both authors summarized the content of each paragraph in a short conclusion statement on which there was consent.

Prebiotics, gut metabolic activity and bifidogenic effect

The addition of prebiotics results in a bifidogenic effect on the GI microbiota of the host. This effect is per definition global. Protein, both its'source (whey, α-lactalbumin) and amount, lactose, low phosphor, iron and lipids (β-palmitate) are also bifidogenic.8

Prebiotics and composition of GI microbiota

Short-chain (sc) prebiotics are mainly fermented in the cecum and colon ascendens. Long chain (lc) OS are fermented along the entire colon. Formulas containing PDX, GOS and FOS blends are more likely to influence gut microbes when administered during early infancy.9 Sixty-8 bacterial strains, representing 29 human-derived lactobacilli (lacto) and 39 bifidobacteria (bifido), both human- and animal-derived, were tested for their ability to metabolize 10 different carbohydrates.10 The transcriptional effect of a semi-synthetic medium containing GOS - which, like human milk, contains a large amount of lactose and galactose- on the Bifido longum transcriptome revealed substantial similarity with carbohydrate-utilization genes in human milk.11 GOS and lactulose support the most favorable growth characteristics, whereas relatively poor growth of lacto and bifido was observed on inulin, maltodextrin and PDX.10 These results suggest a beneficial interaction when combining lacto and/or bifido with prebiotics, such as GOS, as synbiotics.10 Prebiotics potentially reduce harmful effects of antibiotics on gut microbiota.12 An in vitro study in a fermentation screening platform compared the impact of GOS on adult gut microbiota (composition and activity) while treated with 4 antibiotics at 2 different doses.12 The changes in bacterial concentration during antibiotic treatment and the bifido and lacto proliferation upon GOS addition revealed to be antibiotic and dose dependent.12

In preterm infants, FOS supplemented preterm formula has beneficial effects on gut microbiota development.13 Healthy preterm bottle-fed infants were randomized within the first 14 d after birth to either standard preterm formula or the same formula supplemented with FOS (0.4g/100ml): the proportion of infants colonized and the number of fecal bifido were significantly higher in the study group (P = 0.032 and P = 0.03, respectively). FOS enriched formula resulted in a significant reduction of E. coli and Enterococci (P = 0.029 and P = 0.025, respectively).13 A recent meta-analysis including data from 7 trials concluded that prebiotics in preterm infants did not shorten the time to full enteral feeds, but resulted in significantly higher concentrations of beneficial microbes.14

Similar results were reported for standard infant formula compared to GOS/FOS formula, evaluating acceptability, the proportion of bifido versus clostridia and growth parameters.15 The proportion of bifido at the age of 6 weeks was non-significantly higher in the prebiotic group (P = 0.262).15 The percentage of fecal clostridia at the end of the study was significantly lower in the prebiotic group (P = 0.042).15 When comparing Orafti Synergy1 (50 oligofructose/50 FOS) 0.4 g/dL or 0.8 g/dL, GOS/FOS (90:10) 0.8 g/dL, or a standard formula, bacterial composition of infants taking SYN1 0.8 g/dL or GOS/FOS-supplemented formula were closer to the breast-fed pattern.16 Several other studies evaluated the effect of prebiotics on the intestinal microbiota in infants. Different levels of GOS (0.24 or 0.44 (starter formula) - 0.50 (follow-on formula) g/100 mL) in infant formula were studied and seem to stimulate intestinal bifido and lacto similarly to those fed human milk.17-19 Administration of prebiotic-supplemented partially hydrolyzed infant formula or breastfeeding showed similar gut microbiota.20 The addition of the prebiotic GOS/FOS mixture to an infant formula was proven to have a stimulating effect on the growth of bifido 21 and feces from infants fed a GOS/GOS mixture had a higher absolute number (P = 0.0083) and proportion (P = 0.0219) of bifido, very similar to breastfed infants.22 An intervention of 26 weeks with 6 g/L scGOS and lcFOS (ratio 9:1) resulted in increased percentages of bifido in the supplemented group (60.4%) compared to the control group (52.6%, P = 0.04). The percentages of Clostridium spp. were 0.0 and 3.27%, respectively (P = 0.006).23 The bifidogenic effect of GOS was also shown in 4–6 month old formula-fed infants. In this multicenter, double-blind study infants were randomized to an experimental follow-on formula supplemented with 5 g/L GOS (77 infants), or to a standard follow-on formula (control, 82 infants).24 The addition of GOS to a follow-on formula increased the number of bifido in infants during the supplementation period.24 Using qPCR, counts in PDX/GOS were closer to the breast-fed group. They tended to be higher than controls for total bifido (P = 0.069) and Bifido longum (P = 0.057) at 30 days, and were significantly higher for total bifido and Bifido longum at 60 d and Bifido infantis at 30 d (P = 0.002).25 No significant differences were detected between PDX/GOS and controls from baseline to 30 or 60 d for total bifido (by fluorescent in situ hybridization or qPCR); however, Bifido infantis changed significantly between PDX/GOS and control at 30 d and Bifido longum at 60 d (P ≤ 0.035).25 No local or systemic side effects were recorded in this study.24 There is also a report on GOS supplementation and its effect on bifido numbers in vivo and in vitro in women and men over 50 y old.26

In conclusion: prebiotic oligosaccharides stimulate the development of bifidobacteria.

Prebiotics and fecal pH

Intestinal pH modulates the intestinal environment inhibiting or favoring the growth of different bacterial populations; a low intestinal pH results in a decrease of pathogenic microorganisms.27 Fecal pH was lower (P = 0.01) in breastfed and prebiotic-formula fed infants than with standard infant formula.22 A low level of GOS (0.24 g/100 mL) in infant formula brings the fecal pH to the same level as with human milk.17 In a recent, large trial including 365 infants receiving GOS up to the age of 1 year, fecal pH was decreased.19

Prebiotics and metabolic activity

Metabolic gut activity in infants on GOS/FOS formula compares to that of breastfed infants.28,29 Acetic acid, whose formation is consistent with bifido metabolism, is the major SCFA synthesized.30 Increased butyrate production indicates a beneficial modulation of the gut microbiota.26 Changes in short chain fatty acids (SCFAs) and lactate (and pH) were studied in a prebiotic group and represented a fermentation profile similar to the breastfed group compared to the control formula group.29 As SCFAs represent metabolic activity of intestinal microbiota,31 these findings suggest that gut microbiota between breastfed and supplemented formula fed infants develop in a similar way. Interestingly, a recent large study in which GOS was administered during one year resulted in a decrease of butyric acid, despite the increase in bifido.19

Probiotics do not induce a similar metabolic activity. In a bifido Bb-12 group, composition and metabolic activity of the microbiota resembled those of the standard group.28

In conclusion: prebiotic oligosaccharides decrease fecal pH.

Prebiotics and immune parameters

One of the research areas of modern infant formula focuses on the development of the immune system. The addition of LC-PUFAs and nucleotides are outside the topic of this review, but have shown to positively influence the development of the immune system. A larger number of bifido may promote postnatal maturation of the immune system, and therefore protect against infection and allergy. The correlation between bifido and the amount of intestinal secretory IgA is known since many years.32,33 Prebiotic inulin and oligofructose clearly modulate immunological processes at the level of the gut-associated lymphoid tissue, which may be associated with significant health benefits in infants and patients with intestinal inflammatory diseases.34 GOS reduces colitis by modulating the function and trafficking of NK cells in mice.35

However, not all literature is in agreement. The addition of a specific mixture of 0.6 g/100 mL of scGOS and lcFOS in a ratio of 9/1 to infant formula showed that immune parameters at weeks 8 and 26 did not differ between both groups.36 Administration of a prebiotic OS mixture in healthy infants during the first 6 months of life did not change the basal level of immune parameters compared to standard formula fed infants and exclusive breastfed infants.36 No significant differences were detected between PDX/GOS and controls from baseline to 30 or 60 d for sIgA.25 A scGOS/lcFOS supplementation has a bifidogenic effect on maternal gut microbiota that is not transferred to neonates.37 The increased maternal bifidobacteria did not affect fetal immunity as measured by a comprehensive examination of cord blood immunity variables.37

Others observed a prebiotic effect beyond the intervention period suggesting an immune modulating effect through the intestinal microbiota as the principal mechanism of action.38 After a 26 wk intervention with the same mixture, the concentration of sIgA was higher (P < 0.001) in the scGOS/lcFOS group (719 microg/g) than in the control group (263 microg/g).23 Interestingly, a recent large study with GOS for one year, showed the opposite result with lower sIgA levels in the prebiotic group.19 GOS/FOS supplementation was also reported to induce a beneficial antibody profile.39 GOS/FOS would reduce the total Ig response and modulate the immune response toward CMP, leaving the response to vaccination intact.39

In practice, different supplements (prebiotics, lipids, nucleotides,…) in infant formula are often combined, making it hard to decide “which supplement did what.”

In conclusion: prebiotic oligosaccharides are likely to enhance immune response.

Prebiotics and growth

Growth parameters have been part of the evaluation of prebiotic supplemented formulas. Comparing prebiotic enriched to standard infant formula, there were no group differences in growth rate between 14 to 120 d of age.40 Discontinuation rates were not significantly different among study groups.40 Tolerance of a formula enriched with FOS/GOS was excellent and no difference in growth parameters was observed after 6 and 12 weeks.15 A transient increase in body weight was observed in children on prebiotics compared to controls during the first 6 months of follow-up.41 Prebiotics in formula increased weight gain but had no impact on length or head circumference.22,42 However, the quality of this evidence is compromised by imprecision, inconsistency of results, use of different study preparations and publication bias.42

With a GOS/FOS mixture, growth was normal and similar to a standard infant formula.38,43 A multi-center, randomized, double-blind, placebo-controlled trial including 1130 healthy term infants showed a similar mean weight, length and head circumference, skin fold thicknesses and arm circumference evolution in all infants.44 The skin fold thicknesses in the breastfeeding group at 8 weeks were strikingly higher than those in formula fed infants, whereas the opposite is true at 52 weeks.44 According to a systematic review from 2009, 10 publications evaluated the effect of prebiotics on growth during the first year of life.45 None of these trials showed a significant difference in growth parameters; infants fed the supplemented formula had slightly better weight gain (weighted mean difference, 1.07 g; 95% CI, 0.14-1.99; 4 RCT).45

In conclusion: prebiotic oligosaccharides are unlikely to stimulate growth.

Prebiotics and stool consistency

The influence of prebiotics on stool consistency was evaluated. A low level of GOS (0.24 g/100 mL) in infant formula increases stool frequency, as in those fed human milk.17,18 Infants fed a prebiotic GOS/FOS mixture had softer stools than those fed standard infant formula (P = 0.026).15 Five g/L (GOS) decreased stool consistency.24 Two hundred 30 term infants fed either a control formula or the same formula with PDX/GOS (4g/L, 1:1 ratio; PDX/GOS) for 60 d completed a study.25 The infants consuming PDX/GOS had softer stools than controls at all times (P < 0.001).25 No differences in formula intake or infant fussiness or gassiness were observed. During study weeks 1 and 2 and at 60 d of age stool consistency ratings were higher (i.e. softer stools) for infants in the PDX/GOS and GOS groups vs. controls and remained higher at 120 d for the PDX/GOS group (all P < 0.05).40 When comparing Orafti Synergy1 (50 oligofructose: 50 FOS) 0.4 g/dL or 0.8 g/dL, GOS:FOS (90:10) 0.8 g/dL, or a standard formula, stool consistency of infants taking SYN1 0.8 g/dL or GOS/FOS-supplemented formula were closer to the breast-fed pattern.16 In a large study in 1130 infants, the stool consistency in the prebiotic group was softer than in the control group at 8, 16 and 24 weeks (P < 0.001) and more similar to that of the breastfed group.44

Prebiotic supplemented formula was reported not to alter stool patterns22 as well as to soften stools comparable to breastmilk.40 Prebiotics were also reported to increase stool frequency but not to impact on stool consistency (and the incidence of colic, spitting up / regurgitation, crying, restlessness or vomiting).42 The effect of prebiotics on stool frequency and consistency was evaluated in a systematic review.45 Four RCTs demonstrated that stool frequency was similar to the frequency of breastfed infants and significantly higher than in infants with standard formula.45 Similar data were obtained regarding stool consistency: 6 RCTs showed significantly softer stools.45 A recent large trial evaluating GOS supplementation confirmed an increased frequency of defecation.19

In conclusion: in healthy infants, prebiotic oligosaccharides increase bowel frequency and soften the stools.

Prebiotics and general health

Different aspects and on general health and infections were evaluated in literature.

GOS was shown to reduce calcium excretion in feces in normal and gastrectomised rats, therefore preventing osteopenia.46 The addition of a specific mixture of 0.6 g/100 mL of scGOS and lcFOS in a ratio of 9/1 to infant formula did not decrease cholesterol concentrations, although the levels in formula fed infants were significantly lower than in breast-fed infants.47

Early prebiotic supplementation may alleviate symptoms associated with crying and fussing in preterm infants.48 A meta-analysis of 7 trials showed that supplementation with prebiotic OS in preterms was safe but did not result in decreased incidence of necrotizing enterocolitis.14

In a large randomized, double-blind, placebo-controlled trial performed in 830 healthy term infants in 7 centers in 5 West European countries, there was no effect of adding specific prebiotics to standard formula feeding in reducing the number of fever episodes.49 On the contrary, other data state that infants fed a scGOS/lcFOS mixture were reported to have fewer episodes of physician-diagnosed overall and upper respiratory tract infections (P < 0.01), fever episodes (P < 0.00001), and fewer antibiotic prescriptions (P < 0.05) during the period of intervention and up to the age of 2 y.38,50 In an open trial including 342 healthy infants comparing standard infant formula with a GOS/FOS enriched formula given during 6 months, at the age of 12 months the incidence of gastroenteritis was reduced (0.12 + 0.04 vs. 0.29 + 0.05 episodes/child/12 months; p = 0.015), the number of children with more than 3 episodes of gastroenteritis tended to be lower (17/60 vs. 29/65; p = 0.06) and the number of children with multiple antibiotic courses/year was lower (24/60 vs. 43/65; p = 0.004).41 Early dietary intervention with the OS prebiotic mixture showed a protective effect against infections,51 but a GOS supplementation during one year did not result in a reduced incidence of infections.19 Formulas containing Bifido lactis and a GOS/FOS prebiotic mixture did not reduce infection rates beyond those containing only Bifido lactis.52

In conclusion: only limited data suggest that prebiotic oligosaccharides improve general health and reduce infections.

Prebiotics and allergy and atopic dermatitis

The role of prebiotics in allergy and more specifically atopic dermatitis is summarized below. A specific scGOS/lcFOS mixture was shown to reduce the allergic reaction against ovalbumin in mice.53 GOS/FOS in dietary products was shown to possibly provide an opportunity to stimulate the adaptive immune response in a Th1-direction and subsequently inhibit infections and Th2-related immune disorders in humans, such as allergies.51 GOS blocks atopic dermatitis in mice by at least partly inducing production of IL-10 and suppressing the production of cytokines such as IL-17, which are involved in skin inflammation.54 Dietary supplementation with DHA/AA and GOS/Polydextrose both improved symptoms of allergen-induced dermatitis in mice.55 The preventive effects of prebiotic feeding during perinatal and post weaning periods in a mouse model of allergy were analyzed by studying biomarkers related to tolerance (IgG2a, IgA, IFN-γ, TGF-β, and IL-10), to allergy (IgE, IgG1, IL-4, IL-17, symptoms), and to microbiota (propionate and MyD88).56 Regardless of diet, sensitized mice exhibited similar levels of IgE, IgG1, CD-23, IL-4, IL-17, and similar symptoms.56 Prebiotic exposure during perinatal and post weaning periods induced the highest expression of biomarkers related to tolerance without affecting allergy related biomarkers.56

Prebiotics were shown to reduce immunoglobulin free light-chain concentrations in infants at risk for allergy.57 Although a reduction of eczema was reported in infants, this effect was not consistent between studies and caution was advised in view of methodological concerns regarding included studies.58 Short-term enteral supplementation of non-human neutral and acidic OS during the neonatal period in preterm infants dids not decrease the incidence of allergic and infectious diseases during the first year of life.59

A large study in 259 high risk infants, prebiotic supplements to formula feeding reduced the development of atopic dermatitis at the age of 6 months.60 Early dietary intervention with OS prebiotics showed a protective effect against allergic manifestations.38 Nevertheless, systematic reviews failed to proof the efficiency of prebiotics in the prevention of atopic dermatitis.61 OS prebiotics (scGOS/lcFOS), when started early in life had a protective effect against allergic manifestations in high risk infants lasting beyond infancy until 5 y of life, for atopic dermatitis and allergic rhinoconjunctivitis.62 Although the intervention group had a 75% reduction in the prevalence of persistent wheezing (4.8 vs 14%), no significance was shown.62 There is some evidence that a prebiotic supplement added to infant feeds may prevent eczema.63 A Cochrane meta-analysis of 4 studies found a significant reduction in eczema (1218 infants, typical risk ratio 0.68, 95% CI 0.48 to 0.97; typical risk difference -0.04, 95% CI −0.07 to −0.00; number needed to treat to benefit 25, 95% CI 14 to >100; P = 0.03).63 Individual studies reported a significant reduction in asthma and eczema with a mixture of GOS/FOS (9:1 ratio) (8 g/L) in infants at high allergy risk; and in eczema alone for supplementation with GOS/FOS (9:1) (6.8 g/L) and acidic OS (1.2 g/L) in infants not randomized by allergy risk.63,64 On the contrary, a recent study on GOS supplementation during one year reported no difference in allergy.19

In this particular field, several studies have been performed with synbiotics. Recently, in a double-blind, placebo-controlled multi-center trial, 90 infants with atopic dermatitis, age <7 months, were randomized to receive an infant formula with Bifido breve M-16V and a mixture of scGOS/lcFOS, or the same formula without synbiotics during 12 weeks.65 There were no significant differences between the synbiotic and the placebo group.57 The same group showed that synbiotics prevented asthma-like symptoms in infants with atopic dermatitis.66 At the same time, another group reported that a synbiotic combination of Lacto salivarius plus FOS is superior to the prebiotic alone for treating moderate to severe childhood atopic dermatitis.67

It is unclear whether the use of prebiotics should be restricted to infants with a high risk of allergy or may have an effect in low risk populations as well; or which different allergic presentations it may affect.63

Today, reported data are difficult to interpret as studies are often in contradiction. The European Academy of Allergology and Clinical Immunology (EAACI) recently concluded that there is not enough evidence to recommend prebiotics (or probiotics) in the allergy prevention.68

However, a recent meta-analysis came to an opposite conclusion regarding atopic dermatitis: “Based on studies with prebiotics, there was a long-term reduction in the incidence of atopic dermatitis. Supplementation with prebiotics (and probiotics) appear useful for the reduction of the severity of atopic dermatitis”.69

In conclusion: there is only limited evidence to suggest that prebiotic oligosaccharides prevent atopic dermatitis or decrease its severity.

Conclusion

There is not enough evidence to state that supplementation of term infant formula with prebiotics (or synbiotics) results in relevant clinical health benefits.40 An increase in bifido, a decreased stool pH, softer stools and an increase in stool frequency compared to standard infant formula is an almost constant finding. Existing literature is often contradictory, especially regarding clinical benefits. This may be related to the heterogeneity of the clinical trials: different prebiotic oligosaccharides, different dosages and different duration of administration. However, many studies showsome advantages, even though not always statistically significant, but clinical data is often heterogeneous. Since pro- and prebiotics are present in mothers’ milk, and since their addition to infant formula is safe, it seems fair to add them to infant formula. Nevertheless, the evidence for health benefits remains limited and future research has to focus on specificity, safety, dosage, and combinations.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

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