The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, ‘normobiosis’ characterises a composition of the gut ‘ecosystem’ in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to ‘dysbiosis’, in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in ‘prebiotic effects’), 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.’ Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.

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).

Background: Oligosaccharides may alter postnatal immune development by influencing the constitution of gastrointestinal bacterial flora. Aims: To investigate the effect of a prebiotic mixture of galacto-and long chain fructo-oligosaccharides on the incidence of atopic dermatitis (AD) during the first six months of life in formula fed infants at high risk of atopy. Methods: Prospective, double-blind, randomised, placebo controlled trial; 259 infants at risk for atopy were enrolled. A total of 102 infants in the prebiotic group and 104 infants in the placebo group completed the study. If bottle feeding was started, the infant was randomly assigned to one of two hydrolysed protein formula groups (0.8 g/100 ml prebiotics or maltodextrine as placebo). All infants were examined for clinical evidence of atopic dermatitis. In a subgroup of 98 infants, faecal flora was analysed. Results: Ten infants (9.8%; 95 CI 5.4-17.1%) in the intervention group and 24 infants (23.1%; 95 CI 16.0-32.1%) in the control group developed AD. The severity of the dermatitis was not affected by diet. Prebiotic supplements were associated with a significantly higher number of faecal bifidobacteria compared with controls but there was no significant difference in lactobacilli counts. Conclusion: Results show for the first time a beneficial effect of prebiotics on the development of atopic dermatitis in a high risk population of infants. Although the mechanism of this effect requires further investigation, it appears likely that oligosaccharides modulate postnatal immune development by altering bowel flora and have a potential role in primary allergy prevention during infancy.

These data indicate that supplementation of a term infant's formula with a mixture of galacto- and fructooligosaccharides has a dose-dependent stimulating effect on the growth of Bifidobacteria and Lactobacilli in the intestine and results in softer stool with increasing dosage of supplementation.

ContextOligosaccharides are the third largest solid component in human milk. These diverse compounds are thought to have numerous beneficial functions in infants, including protection against infectious diseases. The structures of more than 100 oligosaccharides in human milk have been elucidated so far.ObjectiveThe aim of this review was to identify the main factors that affect the concentrations of oligosaccharides in human milk and to determine whether it is possible to calculate representative and reliable mean concentrations.Data SourcesA comprehensive literature search on oligosaccharide concentrations in human milk was performed in 6 electronic databases: BIOSIS, Current Contents Search, Embase, Lancet Titles, MEDLINE and PubMed.Study SelectionThe initial search resulted in 1363 hits. After the elimination of duplicates, the literature was screened. The application of strict inclusion criteria resulted in 21 articles selected.Data ExtractionOligosaccharide concentrations, both mean values and single values, reported in the literature were sorted by gestational age, secretor status of mothers, and defined lactation periods.ResultsMean concentrations, including confidence limits, of 33 neutral and acidic oligosaccharides reported could be calculated. Concentrations of oligosaccharides in human milk show variations that are dependent on both the secretor type of the mother and the lactation period as examined by analyses of variance. In addition, large interlaboratory variations in the data were observed.ConclusionsWorldwide interlaboratory quantitative analyses of identical milk samples would be required to identify the most reliable methods of determining concentrations of oligosaccharides in human milk. The data presented here contribute to the current knowledge about the composition and quantities of oligosaccharides in human milk and may foster greater understanding of the biological functions of these compounds.

Axons rely on guidance cues to reach remote targets during nervous system development. A well-studied model system for axon guidance is the retinotectal projection. The retina can be divided into halves; the nasal half, next to the nose, and the temporal half. A subset of retinal axons, those from the temporal half, is guided by repulsive cues expressed in a graded fashion in the optic tectum, part of the midbrain. Here we report the cloning and functional characterization of a membrane-associated glycoprotein, which we call RGM (repulsive guidance molecule). This molecule shares no sequence homology with known guidance cues, and its messenger RNA is distributed in a gradient with increasing concentration from the anterior to posterior pole of the embryonic tectum. Recombinant RGM at low nanomolar concentration induces collapse of temporal but not of nasal growth cones and guides temporal retinal axons in vitro, demonstrating its repulsive and axon-specific guiding activity.

Evidence is accumulating that short chain fatty acids (SCFA) play an important role in the maintenance of gut and metabolic health. The SCFA acetate, propionate and butyrate are produced from the microbial fermentation of indigestible carbohydrates and appear to be key mediators of the beneficial effects elicited by the gut microbiome. Microbial SCFA production is essential for gut integrity by regulating the luminal pH, mucus production, providing fuel for epithelial cells and effects on mucosal immune function. SCFA also directly modulate host metabolic health through a range of tissue-specific mechanisms related to appetite regulation, energy expenditure, glucose homeostasis and immunomodulation. Therefore, an increased microbial SCFA production can be considered as a health benefit, but data are mainly based on animal studies, whereas well-controlled human studies are limited. In this review an expert group by ILSI Europe’s Prebiotics Task Force discussed the current scientific knowledge on SCFA to consider the relationship between SCFA and gut and metabolic health with a particular focus on human evidence. Overall, the available mechanistic data and limited human data on the metabolic consequences of elevated gut-derived SCFA production strongly suggest that increasing SCFA production could be a valuable strategy in the preventing gastro-intestinal dysfunction, obesity and type 2 diabetes mellitus. Nevertheless, there is an urgent need for well controlled longer term human SCFA intervention studies, including measurement of SCFA fluxes and kinetics, the heterogeneity in response based on metabolic phenotype, the type of dietary fibre and fermentation site in fibre intervention studies and the control for factors that could shape the microbiome like diet, physical activity and use of medication.

Background: The establishment of a balanced intestinal microflora which may protect against infection is desirable for the preterm infant. Objective: To investigate the effect of a preterm formula milk supplement consisting of oligosaccharides in similar proportions to human milk on the faecal flora and stool characteristics of preterm infants. Study design: To resemble the effect of human milk, an oligosaccharide mixture consisting of 90% galacto-oligosaccharides and 10% fructo-oligosaccharides was used to supplement a standard preterm formula at a concentration of 10 g/l. This supplemented formula was studied in 15 preterm infants, and the results were compared with those found in 15 infants fed a formula supplemented with maltodextrin as placebo. A group fed fortified mother's milk was investigated as a reference group (n = 12). On four days during a 28 day feeding period (1, 7, 14, and 28), the faecal flora was investigated, and stool characteristics, growth, and possible side effects were recorded. Results: During the study period, the number of bifidobacteria in the group fed the oligosaccharide supplemented formula increased to the upper range of bifidobacteria counts in the reference group. The difference between the supplemented and non-supplemented groups was highly significant (p = 0.0008). The stool characteristics were also influenced by the supplement: the stool frequency after 28 days was significantly lower in the control group than in the oligosaccharide supplemented group (p = 0.0079) and the reference group (p < 0.0001). Over the study period, the stool consistency in the control group became harder, but remained fairly stable in the other two groups. There was no effect of the different diets on the incidence of side effects (crying, regurgitation, vomiting) or on weight gain or length gain. Conclusion: Supplementing preterm formula with a mixture of galacto-and fructo-oligosaccharides at a concentration of 10 g/l stimulates the growth of bifidobacteria in the intestine and results in stool characteristics similar to those found in preterm infants fed human milk. Therefore prebiotic mixtures such as the one studied may help to improve intestinal tolerance to enteral feeding in preterm infants.