All these demands are completed by non-digestible oligosaccharides that consist of three to ten sugar molecules, and are naturally present in fruits, vegetables, cereals, milk, etc., or can be industrially produced [1,3,4]. They represent an excellent meal for the resident society of saccharolytic bacteria in our gut. Main end-products of their fermentation are short-chain fatty acids (SCFAs). Different bacteria prefer one energy source over the other [5]. Consequently, diet becomes a powerful tool in directing gut microbial population [6,7]. That is in fact the foundation of prebiotic concept as we have the influence to supply favourite ‘fuel’ to specific microorganisms recognized as promoters of good health.

At the moment, animal and human studies favor the use of galacto-oligosaccharides (GOS), inulin, and fructo-oligosaccharides (FOS). In addition, to imitate the human milk oligosaccharides (HMO) a mixture of short-chain GOS and long-chain FOS was developed. According to the Commission Directive on infant formulae and follow-on formulae in European Union, fructo-oligosaccharides and galacto-oligosaccharides may be added to infant formulae, nonetheless their proportion must not exceed 0.8 g/100 mL in a combination of 90% oligogalactosyl-lactose and 10% high molecular weight oligofructosyl-saccharose [8].

Nutritional and health benefits of prebiotics are gripping attention among consumers, food and pharmaceutical industry, and health professionals [9,10]. Some experts even established them to be superior to probiotics as they are cheaper to produce, more affordable for mass consumers, trust worthier compared to consuming live bacteria, and less susceptible to environmental stresses; nevertheless, probiotics cannot function in the absence of prebiotics [11].

Special attention should therefore be focused on interpreting studies and conclusions as financial drive is enormous, whereas clinical evidence is often sparse.

Indirect effects of prebiotics arise through stimulation of health-promoting microbial taxa, such as Bifidobacterium and Bacteroides [12-14], which block intestinal pathogens, improve intestinal barrier function and orchestrate immune pathways. There is even some evidence of gut microbiota influencing brain function over microbiota-gut-brain axis [15].

Direct effects are due to the action of SCFAs. They are largely produced in colon where they act locally; however, some of them reach high concentration in the bloodstream carrying them across the body and allowing them to interact in extra-intestinal reactions [16]. The main SCFAs formed are acetate, propionate and butyrate. Their primary task is the energy supply for intestinal epithelial cells, though they also play a role in gene expression, gut motility and barrier function, metabolite absorption, lipid metabolism, appetite control, insulin resistance, gut-liver axis regulation, and regulation of the immune system, resulting in prevention of infection, diarrhea, constipation and allergies [17].

In a randomized non-blinded trial, published almost ten years ago, 96 formula-fed infants under 4 months of age with colic received a partially hydrolyzed whey protein formula containing FOS and GOS. They experienced a greater reduction of crying episodes after 7 and 14 days compared with those assigned to a standard formula and simethicone [18]. However, whether the effect is due to partially hydrolysed protein, the prebiotics, or both, is not clear. Pärtty, et al [19]. studied preterm infants randomized to receive a mixture of GOS and polydextrose (1:1), probiotics or placebo during first 2 months of life, and followed-up for 1 year. In both pre- and probiotic groups, significantly less frequent crying was observed compared with the placebo group (19% vs. 19% vs. 47%, respectively; P = 0.02) . On the other hand, a systematic review and meta-analysis including 12 prebiotic studies found no impact of prebiotics on the incidence of colic, regurgitation, crying, restlessness or vomiting [20]. Nonetheless, adding prebiotics to infant formula for full-term infants was reviewed. Although, further confirmatory studies are needed, no adverse effects of prebiotics were found during this review.

Majority of clinical studies concerning the effects of supplementation of infant formulas with prebiotics confirmed increase in frequency of defecation and/or softer consistency of stools, similar to that of breast-fed infants [21-31]. Current analysis of stool characteristics of infants receiving short-chain GOS (scGOS) and long-chain FOS (lcFOS) in ratio 9:1 showed that effects on stool consistency were more often found to be significant than effects on stool frequency [32]. Bongers, et al. [33] published the only therapeutic randomized controlled trial (RCT) using prebiotic formula for functional constipation in 2007. The consumption of a high concentration sn-2 palmitic acid, scGOS/lcFOS 8g/l and partially hydrolyzed whey protein formula resulted in a strong tendency of softer stools in constipated infants, but not in a difference in defecation frequency. In a randomized, double-blind, prospective study [25], it was shown that prebiotics can soften stools and increase stool frequency even in toddlers [25].

A more recent study, [34] indicated a significant rush of motilin following prebiotic supplementation. Motilin being a peptide, produced by endocrine M cells, largely presents especially in duodenum and jejunum. Its essential role is to clean undigested food from the gut by controlling inter-digestive migrating contractions [34]. All together suggesting an association with improved gastric emptying, better tolerance to food and improved digestion in general [35].

Changes in defecation patterns in pediatric population due to prebiotic supplementation mostly result in improvement of abdominal comfort and reduction of prevalence of functional constipation. Since constipation affects one third of children usually before the age of five [36-38] but often persists beyond puberty, these observations are relevant for preventive or curative treatment of this very common functional disorder [39]. Yet, to establish specific doses in avoiding diarrhea, more studies are awaited.

Acidic environment in colon increases solubility of certain minerals [40]. Bioavailability of calcium when consuming prebiotic ingredients has been well-studied. Animal studies verified the positive correlation; efficiency in humans is nevertheless not consistent. Abrams, et al. [41] found significantly enhanced calcium absorption and bone mineralization in adolescents after receiving inulin-type fructans daily for a year. On the contrary, no significant effect of prebiotics was observed on calcium absorption or other markers of bone mineralisation in infants [42]. Recent observations show that prebiotic oligosaccharides enhance iron absorption in deficient rats [43]. Clearly, further human trials are needed, but this seems to be encouraging information, given the prevalence of iron-deficiency in children.

At the Summer Meeting of the Nutrition Society in 2010, it was announced that an overview of studies investigating effects of oral SCFA on appetite regulation did not reveal a positive connection. The experts concluded that sensory characteristics are those influencing our choice of which food we eat and the quantity of it rather than a physiological effect of SCFA [44]. In children, especially in the first months of life when milk is the basic nutrition, there are some encouraging results. For instance, Mugambi, et al. [20] conducted a meta-analysis that summarized positive context of prebiotics in infant formulas and increased weight gain; there was no impact on length or head circumference gain. Whether this is the result of intensified energy harvests by intestinal bacteria and/or increased absorption by enterocytes is not yet clear. It is very likely that the outcome is dose-dependent [14]. Interestingly, these results are to some extent antagonistic with the inverse correlation between fibre intake and obesity known in adults as well as in adolescents [22,45,46]. In fact, dietary fibre reduces the risk of childhood obesity by up to 21% [47]. Furthermore, Dasopoulou, et al. [35] found that supplementation of infant formula with scGOS/lcFOS resulted in significantly lower mean cholesterol values compared with preterm neonates fed with standard formula.

An open-label RCT published six years ago [48], included more than 300 healthy infants, age 1-2 months. The group receiving a GOS/FOS mix had a significantly lower number of gastrointestinal infections and antibiotic use per year [48]. Still, when Duggan, et al. [49] studied a group of 282 infants 6-12 months of age, there was no difference in diarrheal prevalence or the mean duration of diarrhea between those receiving an infant cereal enriched with oligofructose with and without prebiotics [49].

Destruction of microbial population in GIT has the power to start the so called antibiotic-associated diarrhea. Preventive intervention by giving prebiotics after or along with antibiotic treatment has so far not been properly evaluated. A RCT published in 2006 by Brunser, et al. [50] showed no significant difference in the frequency of antibiotic-induced diarrhea between two groups, aged 1-2 years. The first group received inulin and oligofructose (total of 4.5 g/L) containing milk formula for 3 weeks after they had ended amoxicillin therapy for respiratory infection. The second group received prebiotic-free milk formula [50]. Another trial was organized by the ESPGHAN Working Group on Pro- and Pre-biotics. In this multi-centre trial, children with oral and/or intravenous antibiotic therapy covering common infections were treated with inulin and FOS in age-dependent doses (max 5g/day) for as long as they were taking antimicrobial drugs. These children were below 11 years old and tolerated the mixture well; nonetheless, it had no effect regarding antibiotic-associated diarrhea. The study was stopped before time because of slow recruitment and the working group concluded that overall prevalence of diarrhea was not high and caution must be taken when judging the results. However, there is a need for further research with different prebiotics [51].

Administration of prebiotic compounds via oral rehydration solution (ORS) is under investigation. A decade ago, Hoekstra, et al. [52] also completed a multi-centre European double-blind randomized placebo controlled study on behalf of the ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology, and Nutrition) Working Group on intestinal infection. The subject was ORS containing a mixture of prebiotics (soy polysaccharides 25%, alpha-cellulose 9%, gum arabic 19%, FOS 18.5%, inulin 21.5%, resistant starch 7%) in the acute diarrhea treatment. Children aged 1 month to 3 years with acute diarrhea resulting in mild-to-moderate dehydration were given either supplemented or non-supplemented ORS [52]. There was no significant difference between participants of the two groups in mean 48-h stool quantity, duration of symptoms and hospitalization [52]. No significant influence on clinical course of acute gastroenteritis was also reported by Israeli analysts. A mixture of 80% lcFOS/scGOS and 20% AOS in a three 2-g sachets per day significantly increased stool consistency (P=0.048) but not total of daily stools number (P=0.66) in 9- to 24-month-old children [53]. A recent randomized controlled trial in Italian children showed significant efficiency when FOS and xylo-oligosaccharides – both 0.35 g/L were consumed along with hypotonic ORS. Children aged 3 months to 3 years in prebiotic group drunk more ORS in the first 24 hours (P<0.001), diarrhea was over after 72 hours in a greater percentage (P=0.01) and their parents missed fewer working days compared to placebo "team" of parents (P<0.001) [54]. An older double- blind, placebo controlled RCT including boys from Bangladesh enrolled a group of 150 male children, aged 4 to 18 months that looked for medical help because of watery non-cholera diarrhea of less than 48 hours of duration. Adding partially hydrolyzed guar gum to oral rehydration solution resulted in important reduction of total extent of acute gastroenteritis [55].

To summarize, evidence to date is often contradictory but in general does not uphold the role of prebiotics in prevention or treatment of infectious diseases. However, supplementation of prebiotic compounds in infant formulas, as early as preterm period of life, and in ORS seems to be the most useful.

Grüber and his team performed an international double-blind placebo-controlled trial in 832 low atopy-risk infants [58]. They were assigned either to the formula containing 6.8 g/L GOS/FOS (9:1) plus AOS 1.2 g/L, or standard formula. Results were compared to 300 breast-fed infants. At one year follow-up, the prebiotic group had almost comparable incidence of eczema to breast-fed babies (5.7 vs 7.3%, vs controls 9.7%). However, a similarly designed but more recent study found no difference in prevalence of atopic eczema and bronchial hyper-reactivity when GOS/FOS plus acidic oligosaccharides (4:1) mixture was added to milk formula in a lower dose (1.5 g/kg/day) in 92 preterm, low birth weight infants [57]. On the other hand, Ziegler, et al. [31] found that unselected term infants fed with chosen blends of prebiotics (polydextrose and GOS: 4 g/L vs polydextrose and GOS and lactulose: 8 g/L vs control) have a statistically important elevated risk for developing eczema (18% vs 4% vs 7%) .

There are still many questions about not only the etiology, immunology and genetics, but also about the role of prebiotic substances in prevention and/or treatment of allergic diseases. Evidence is still very sketchy; however, it seems that early supplementation, at least in predisposed population, might be of benefit.

Regarding the mechanisms of action, prebiotics seem to be very appealing in prevention and treatment of many clinical conditions as in contrast to probiotics they may have more extensive influence on overall bacterial community in the gut, both regarding its composition and functioning. However, in contrast to probiotics the number of published methodologically adequate clinical trials on the efficacy of prebiotics, especially RCTs, supported with exact type and dose information, is rather sparse, especially beyond the age of infancy. The strongest evidence on beneficial effects of prebiotics in children exists in relation to the fight against constipation, poor weight-gain in preterm infants and eczema in atopic children. The reasonableness of using prebiotics in some other diseases, including infantile colic, absorption of minerals and infectious diseases is still under investigation. It must be highlighted; however, that the safety profile of prebiotic use is excellent as no adverse effects were found in this review.

In conclusion, due to their strong potential to influence gut microbiota composition and function, as well as the extremely low risk of their use for serious adverse effects, prebiotics seem to be more than a promising tool for supporting health, prevention and treatment of many pathologic conditions in the intestine and beyond it. However, further large clinical studies are required using commercially available products to help health care providers and users in making an appropriate decision concerning the correct use of prebiotics in these conditions.

Contributors: Both authors contributed to review of literature, interpretation of data and manuscript writing.

Funding: None; Competing interest: None stated.

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