**4. Prebiotics**

Prebiotics are defined as oligosaccharides refractory to the human digestive process with ability to stimulate and promote the growth and/or metabolism of bifidobacteria and lactobacilli in human gut [56]. More than 200 oligosaccharide complexes (neutral and cyclical oligosaccharides) have been identified in human breast milk [57]. Neutral oligosaccharides account for 70% of the total count and include the isomers lacto-N-tetraose, lacto-N-neotetraose, lacto-N-hexaose, monofucosyl-lacto-N-hexaose, and difucosyl-lacto-N-hexaose. Low levels of acidic oligosaccharides containing sialic acid or sulfate groups are present in HBM, and they primarily contain 5-N-acetyl-neuraminic acid [58].

Colostrum is composed of higher oligosaccharide concentrations (15–23 g/L), whereas mature HBM contents range from 1 to 10 g/L [59]. Oligosaccharides account for 8% of the total nutrient contents of HBM and are the third prevalent component following lactose and lipids.

Most of these oligosaccharides are non-absorbable and reach the colon, where they have different functions. Thus, they compete for membrane receptors with pathogenic bacteria and viruses in intestinal epithelium; they contribute to acidification via fermentation by colon bacteria; inhibit the growth of bacteroides, clostridia, and coliforms; promote lactobacilli and bifidobacteria growth; and stimulate the development of infant's immune system. A direct relationship has been documented between oligosaccharides and selectins, integrins, and other receptors, and they mediate leukocyte-endothelial cell interactions [59]. Fermentation of prebiotics by gut bacteria produces short-chain fatty acids, which exert a direct anti-inflammatory effect and promote intestinal barrier integrity by stimulating the proliferation and differentiation of gut mucosal cells.

Cow milk oligosaccharide content is substantially lower than that of HBM, and infant formula supplementation with prebiotics with the purpose of obtaining their health benefits is well founded. At present, GOS and FOS combinations are used, and other HBM oligosaccharides have been recently incorporated to infant formulae.

### **4.1 Infant formulae supplemented with prebiotics**

The European Scientific Committee on Food approved prebiotic supplementation in infant and follow-on formulate up to a maximum of 0.8 g/100 ml to a GOS:FOS ratio of 9:1. By contrast, a systematic review on the safety and health effects of prebiotic-supplemented infant formulae conducted by ESPGHAN Committee on Nutrition [19] did not provide conclusive evidence due to variability in the type and dose of the prebiotic used and period of intervention.

2′-flucosyllactose, a HBM oligosaccharide, was recently synthesized and has been incorporated to some infant formula [60].

### *4.1.1 Safety*

Formulae fortified with prebiotics do not raise safety concerns with regard to growth and adverse effects. [19]. Infant formulae containing HBM oligosaccharides have proven to be safe and well tolerated, and synthetic oligosaccharides have demonstrated to have similar effects to those of HBM oligosaccharides [60].

#### *4.1.2 Prevention and treatment of infant disorders*

There is solid evidence that infant formula containing some prebiotics is associated with less-consistent feces and a higher frequency of defecation [61]. However, inconsistent evidence has been obtained on the association between prebiotics and the frequency of defecations [32, 62].

The use of prebiotic-fortified formulae has been associated with a lower risk for intestinal and respiratory infections [63, 64] and an increase in fecal secretory IgA levels [65]. By contrast, they have not been proven to exert any effects on humoral and cellular immunity [66]. In general terms, there is no conclusive evidence supporting that supplementation of infant formulae with prebiotics exerts any protective effects against infections, colic, crying/irritability, regurgitation, or vomiting [19, 32]. Fortification with 2′-flucosyllactose does seem to improve infant immunity, as it has been reported to be related to a lower incidence of infections, especially respiratory infections [60].

GOS:FOS mixtures favor the growth of bifidobacteria and lactobacilli in the feces of infants receiving fortified formulae. However, they have a limited effect on the reduction of pathogenic bacteria [19]. Yet, some studies suggest that prebiotics reduce pathogenic micro-organism concentrations, while the infant is receiving a formula supplemented with oligosaccharides [67]. A number of studies [25, 32, 62] have failed to demonstrate that bifidobacteria, lactobacilli, or pathogen count decreases with prebiotics.

Other studies have shown similarities between the bifidogenic effect of prebiotic-fortified formulae and HBM, as compared to non-fortified formulae [59, 68, 69]. Indeed, prebiotics have been reported to have special effects on some bifidobacteria species such as *Bifidobacterium breve*. Thus, fecal *Bifidobacterium breve* concentrations in infants fed with a fortified formula have been documented to be similar to those found in breastfed infants.

Although prebiotic-supplemented formulae are thought to prevent eczema in infants at high risk of developing allergies [43, 63, 70], there is no sufficient evidence on the role that prebiotics play in the prevention of eczema, atopic dermatitis, or food hypersensitivity [71, 72]. A partially hydrolyzed formula containing specific prebiotics has been reported to generate a gut microbiota similar to that of breastfed infants. A potential link between microbial activity and eczema onset was identified, which could suggest a suboptimal implementation of gut microbiota in specific developmental stages of infants at high risk of developing allergy [73].

#### *4.1.3 Conclusion*

ESPGHAN Committee on Nutrition does not recommend routine use of infant formulae supplemented with prebiotic. In agreement with the American Academy of Pediatrics, they recommend that further studies are conducted to assess the safety and efficacy of prebiotic supplementation.

**9**

**Author details**

José Maldonado

Unit of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Virgen de las Nieves University Hospital, University of Granada, Spain

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Symbiotics are mixtures of probiotics and prebiotics that beneficially affect the host by improving the survival and implantation of the probiotic bacteria and stimulate the activity of the host's endogenous bacteria [56]. Symbiotics are believed to act synergistically to increase the overall gut health by offering more benefits than the use of either a probiotic or prebiotic agent alone. Considering a huge number of possible combinations, the application of symbiotics for the modulation of intestinal microbiota in humans seems promising [74]. A disadvantage to using symbiotics is that it is difficult to predict the selectivity and specificity of each

of the components and what the resulting mechanisms of action will be.

recommend routine use of infant formula fortified with symbiotics.

composition of gut microbiota or on immune response.

Limited data have been provided on concomitant prebiotic and probiotic supplementation of infant formulae. The few studies carried out with symbiotics [19, 32, 75] revealed that symbiotics: (a) do not exert effects on growth; (b) do not reduce the incidence of digestive disorders (colic, regurgitation, crying, vomiting, to name a few) or infections; (c) increase the frequency of daily defecations but do not influence fecal consistency; and (d) no data are available on their effects on the

There is no conclusive evidence on the effects of supplementation of infant formula with symbiotics. Therefore, ESPGHAN Committee on Nutrition does not

\*Address all correspondence to: jmaldon@ugr.es

provided the original work is properly cited.

*Probiotics and Prebiotics in Infant Formulae DOI: http://dx.doi.org/10.5772/intechopen.88609*

**5. Symbiotics**
