Tolerance and safety evaluation in a large cohort of healthy infants fed an innovative prebiotic formula: a randomized controlled trial.

BACKGROUND: the addition of oligosaccharides to infant formula has been shown to mimic some of the beneficial effects of human milk. The aim of the study was to assess the tolerance and safety of a formula containing an innovative mixture of oligosaccharides in early infancy. METHODOLOGY/PRINCIPAL FINDINGS: this study was performed as a multi-center, randomized, double-blind, placebo-controlled trial including healthy term infants. Infants were recruited before the age of 8 weeks, either having started with formula feeding or being fully breast-fed (breastfeeding group). Formula-fed infants were randomized to feeding with a regular formula containing a mixture of neutral oligosaccharides and pectin-derived acidic oligosaccharides (prebiotic formula group) or regular formula without oligosaccharides (control formula group). Growth, tolerance and adverse events were assessed at 8, 16, 24 and 52 weeks of age. The prebiotic and control groups showed similar mean weight, length and head circumference, skin fold thicknesses, arm circumference gains and stool frequency at each study point. As far as the anthropometric parameters are concerned, the prebiotic group and the control group did not attain the values shown by the breastfeeding group at any study point. The skin fold thicknesses assessed in the breastfeeding group at 8 weeks were strikingly larger than those in formula fed infants, whereas at 52 weeks were strikingly smaller. The stool consistency in the prebiotic group was softer than in the control group at 8, 16 and 24 weeks (p<0.001) and closer to that of the breastfeeding group. There was no difference in the incidence of adverse events between the two formula groups. CONCLUSIONS: our findings demonstrate the tolerability and the long term safety of a formula containing an innovative mixture of oligosaccharides in a large cohort of healthy infants. TRIAL REGISTRATION: drks-neu.uniklinik-freiburg.de DRKS 00000201.

A specific prebiotic mixture added to starting infant formula has long-lasting bifidogenic effects.

There is some evidence that early colonization of the intestine affects the composition of the intestinal microbiota after weaning. In the present study, the effect of prebiotics administered from the first day of life on fecal counts of bifidobacteria and lactobacilli were studied during and after the administration of the prebiotics. In this double-blind, randomized, placebo-controlled, explorative study, 20 newborns of hepatitis C virus-infected mothers who decided not to breast feed due to their concerns regarding their plasma viral load were randomly assigned to either a formula with 8 g/L of a specific prebiotic mixture (short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides, ratio 9:1) or a formula containing the same amount of maltodextrin (placebo). Clinical examination including anthropometric measurements, microbiological analysis of fecal samples, and blood leukocyte population analysis were performed at birth and 3, 6, and 12 mo age. At the age of 12 mo, hepatitis B vaccine-specific IgG serum titers (Hepatitis B virus surface antibodies) were also measured. Prebiotic supplementation resulted in more fecal bifidobacteria (P < 0.0001) and lactobacilli (P = 0.0044) compared with the placebo group. These differences between the groups were maintained during the second half of the first year without any prebiotic supplementation. There was no influence of the different diets on anthropometric data or the measured immunological variables. The data from this small explorative study indicate that early colonization of the intestine might have long-lasting effects on the composition of the intestinal microbiota.

Variation of human milk oligosaccharides in relation to milk groups and lactational periods.

Human milk oligosaccharides, representing the third largest fraction of human milk, have been assigned important protective functions for newborns acting as bifidogenic substrates or as inhibitory agents towards pathogens. Using high-pH anion-exchange chromatography and an enzyme test kit, twenty oligosaccharides and lactose were determined in milk samples of German women from days 3 to 90 postpartum. Twenty-two secretor mothers with Lewis blood group Le(a - b+) synthesised all twenty oligosaccharides, and could be assigned to milk group 1. Five non-secretor mothers (Le(a+b - )) produced all oligosaccharides with the exception of α1,2-fucosylated compounds (milk group 2), whereas three secretor mothers with blood type Le(a - b - ) lacked α1,4-fucosyloligosaccharides, corresponding to milk group 3. Secretor women of milk groups 1 and 3 synthesised significantly higher amounts of total neutral oligosaccharides and of several total core structures (e.g. lacto-N-tetraose) than non-secretor women. Generally, these oligosaccharides significantly decrease during the first 3 months postpartum. By comparing fucosyloligosaccharides within and among the three milk groups, insight into their biosynthesis could be gained. Six acidic oligosaccharides without fucose residues were detected in milk samples of all mothers. Regression analysis confirmed that total acidic oligosaccharides declined threefold during the study period. Milk samples corresponding to the three milk groups exhibited significant qualitative and quantitative differences during the first 3 months of lactation. It can be assumed that particularly milk of non-secretor women (milk group 2) exerts a modified biological protection in the babies in comparison with milks of secretors (groups 1 and 3).

Prebiotic carbohydrates in human milk and formulas.

Human milk oligosaccharides play an important role, as prebiotic soluble fibres, in the postnatal development of the intestinal flora. Infant formulas are virtually free of prebiotic oligosaccharides. As a consequence, formula-fed infants develop an intestinal flora significantly different to the flora of breastfed infants. Due to the complexity of human milk oligosaccharides, it is necessary to use alternative sources of prebiotic ingredients as components of infant formulas. The present review summarizes the data of experimental research and clinical studies with a prebiotic mixture containing 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosacchrides are summarized. The data demonstrate that, with this prebiotic mixture, the growth of bifidobacteria and lactobacilli can be stimulated, the faecal pH can be decreased, and the presence of pathogens can be reduced to levels similar to those of breastfed infants. Thus, prebiotic oligosaccharides such as the studied mixture provide beneficial effects for formula-fed infants.

Dietary prebiotic oligosaccharides are detectable in the faeces of formula-fed infants.

UNLABELLED: Human milk oligosaccharides are not digested during intestinal passage and can be detected in stools. In this study it was investigated whether a prebiotic mixture of low-molecular-weight galacto-oligosaccharides (GOS) and high-molecular-weight fructo-oligosaccharides (FOS) can be detected in stool samples of formula-fed infants. The test formula was supplemented with 0.8 g/dl oligosaccharides (GOS+FOS). In the control formula, maltodextrins were used as placebo. Fecal flora was assessed at the beginning (day 1) and at the end of a 28-d feeding period (day 2). At day 2 the content of galacto- and fructo-oligosaccharides in the stool samples were measured. On study day 1, the number of bifidobacteria was not different among the groups (supplemented group: 7.7 (6.2) CFU/g; placebo group: 8.0 (6.0) CFU/g). At the end of the 28-d feeding period, the number of bifidobacteria was significantly higher in the group fed the supplemented formula when compared to placebo (supplemented group: 9.8 (0.7) CFU/g stool; placebo group: 7.1 (4.7) CFU/g stool; p<0.001). In all infants fed the supplemented formula, GOS and FOS could be identified in the stool samples. That was not the case in infants fed the non-supplemented formula. CONCLUSION: The present data confirm the bifidogenicity of oligosaccharides and indicate that dietary galacto-oligosaccharides and long chain fructo-oligosaccharides remain during the whole passage in the lumen of the gastrointestinal tract, similarly to human milk oligosaccharides.

Increase of faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula-fed preterm infants.

UNLABELLED: In a previous study on formula-fed preterm infants, we were able to demonstrate that dietary oligosaccharides (a mixture of 90% galacto-oligosaccharides and 10% fructo-oligosaccharides in a concentration of 1 g/dl) stimulate the growth of faecal bifidobacteria. In the present explorative analysis of this study, we focus on the effect of the dominance of bifidobacteria on the presence of clinically relevant pathogens (Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Proteus, Streptococcus group B, Clostridium difficile, Bacillus subtilis and Acinetobacter). CONCLUSION: The data demonstrate that stimulation of bifidobacteria by prebiotic oligosaccharides reduces the presence of clinically relevant pathogens in the faecal flora, indicating that prebiotic substances might have the capacity to protect against enteral infections.