**5. Childhood exposure to antibiotics**

Comparisons between breast-fed and formula-fed infants show that breast-fed infants tend to contain a more uniform population of gut microbes dominated by *Bifidobacteria* and *Lactobacillus* [67], whereas formula-fed infants exhibit higher proportions of *Bacteroides,* 

Although infant formulas have evolved greatly during last years, a formula providing exactly the same benefits than human milk has not yet been developed. Among others, human milk contains substantial quantities of complex nondigestible oligosaccharides (known as human milk oligosaccharides, HMOs). HMOs are considered a type of prebiotics as they promote the growth and proliferation of beneficial commensals and, consequently, prevent pathogen colonization of the infant gut and exert positive health effects [70]. Thus, the chemical composition of breast milk does influence the gut microbiome through supplying oligosaccharides that are

Another way to modify the gut microbiome is by the administration of probiotics. Probiotics are defined as "live microorganisms which when administered in adequate amounts, confer a health benefit to the host" [71]. *Lactobacillus* and *Bifidobacterium* species isolated from human milk are the most commonly used probiotic strains. They exert beneficial properties in the gut by suppressing the proliferation of pathogenic microbes, has been extensively studied [72]. For this reason, another area of research regarding formula enrichment is in HMOs and

Certain gut-associated bacterial populations such as *Bifidobacterium spp*. possess gene clusters dedicated to the metabolism of HMOs [73, 74]. Degradation of these compounds produces lactate and short-chain fatty acids (SCFA), which in turn generates an acidic environment that prevents pathogen invasion [75]. Besides *Bifidobacteria*, HMOs may be consumed by other species such as *Bacteroides spp*. (e.g., *Bacteroides* fragilis and *Bacteroides vulgatus*) that consumes a broad range of HMO glycans [76]. Thus, HMOs play an important role in the gut colonization of the infants.

Among the most common prebiotics are fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), inulin, and lactulose. The prebiotic mixture of 90% GOS plus 10% FOS has been assessed to be safe when added to infant formula [77]. Several randomized controlled trials have been made to evaluate the efficacy and safety of prebiotic supplementation in infant formulas [78, 79]. After compiling data of these trials into a meta-analysis, weight gain [weighted mean difference 1.07 g/day] was significantly higher among formula-fed infants supplemented with prebiotics compared to the placebo group [80]. In addition, a large number of clinical trials in term of infants have shown controversial results related to the increase in *Bifidobacteria* in feces due to supplementation of infant formula with GOS and FOS. A systematic review published by Rao et al. [78] reported that some of the randomized controlled trials (RCTs) showed a trend of increasing *Bifidobacteria* counts in formula supplemented fed infants, and another systematic review published by Mugambi et al. [81] failed to show the increase in *Bifidobacteria* or *Lactobacillus* or the decrease of pathogens in infants fed with pre-

Nonetheless, there are promising results from studies which have assessed the effect of prebiotic supplemented formulas on the gut microbiota of infants. Prebiotics are able to change gut

*Clostridium, Streptococcus, Enterobacteria*, and *Veillonella spp*. [66–69].

selectively utilized by specific bacteria in the gut [60].

272 Adiposity - Omics and Molecular Understanding

probiotics and their effects on the infant gut microbiota.

biotic supplemented formula.

Exposure to antibiotics during infancy and childhood use to begin very early. Two different studies showed that >30% of women with a delivery had done systemic antibiotic treatments during pregnancy [88, 89]. Although the effects of antibiotic exposure during pregnancy on acquisition of infants' microbiota have not been established, maternal antibiotic exposure is relevant since infants' microbiota is taken at least in part from their mothers. In addition, prenatal antibiotic exposure has been shown to have effects on the birth weight of neonates and is associated with increased risk of obesity and related metabolic sequelae later in life [90, 91].

After birth, a number of neonates, particularly premature infants, receive antibiotics to prevent or treat bacterial infections. Fjalstad et al. showed that 2.3% of all live-born term infants received intravenous antibiotics in the population, they analyzed from 2009 to 2011 [92]. Higher prescription rates were shown in preterm or term infants with relevant clinical problems. In a study involving neonates admitted to the neonatal intensive care unit in U.S. from 2005 to 2010, more than 88% of extremely low birth weight infants were administrated antibiotics [93].

Over the last decade, several national and international health institutions have made an enormous effort to decrease antibiotic use in the pediatric population by educating parents about the futility of treating viral infections with antibiotics and about concerns of antibiotic resistance [94, 95]. But, despite a recent reduction, widespread antibiotic use in infants and children remains a relevant health problem in the entire industrialized world, mainly because most prescriptions were frequently inappropriate [96].

However, even in countries in which the prescribing pattern usually adheres to national guidelines with respect to the choice of antibiotics, antibiotics are still largely prescribed to children, particularly to very young children [97–100].

In addition to antibiotic exposure for infection prevention and therapy, children could potentially be substantially exposed to antibiotics through the food supply chain or, more rarely, drinking water [101].
