**5.2. Epidemiologic evidence**

There is epidemiologic evidence that exposure to antibiotics in early life is associated with increased risk of excess adiposity. Recently, epidemiological studies have shown that this phenomenon can also occur in humans starting in the fetal stage of life. In that sense, Mueller et al. observed in a U.S. cohort that the administration of antibiotics to women in the last two trimesters of pregnancy increased 84% the risk of obesity in children at 7 years old compared to children born to mothers without antibiotics administration at the same period [110]. Also, Mor et al. observed similar results in a study performed in Denmark where they showed that prenatal exposure to systemic antibacterials was associated with an increased risk of overweight and obesity at school age, and this association varies by birth weight [111].

After birth, the exposure to antibiotics has been associated to obesity due to the analysis of different human cohorts in various countries. In a Danish mother-child pairs cohort, Ajslev et al. showed antibiotic exposure in children during the first 6 months was associated with an increased risk of being overweight at 7 years of age; the effect was stronger in boys than in girls. In a U.K. cohort, Trasande et al. showed that antibiotic use in the first 6 months of life was associated with increased BMI at 10, 20, and 38 months of age [19]. Both studies also determined that maternal BMI was a contributing factor for the development of obesity following exposure to antibiotics in early life, with increased effects seen in children with mothers of normal weight compared with children from mothers who were overweight. Also, Azad et al. in a study of Canadian infants showed that antibiotics administered in the first year of life increased the likelihood of a child being overweight at 9 years and 12 years of age being almost seen in boys [112], which was consistent with the previous results from Ajslev et al. In a U.S. cohort, Bailey at al. observed that repeated exposure to broad-spectrum antibiotics at ages 0–23 months was associated with early childhood obesity. Importantly, this observation was associated with the use of broad-spectrum antibiotics, but not with the use of narrow-spectrum antibiotics.

Finally, in a multicenter, multicountry, cross-sectional study (The International Study of Asthma and Allergies in Childhood Phase III) Murphy et al. observed a significant interaction between sex and early-life antibiotic exposure. Exposure to antibiotics during the first 12 months of life was associated with a small increase in BMI in boys aged 5–8 years but not in girls in this large international cross-sectional survey.

Colonization of neonate's gut microbiota relies on vertical transmission from the mother at the time of delivery; thus, during pregnancy or early-life exposure to antibiotics could have effects on weight later in life by disturbing the proper establishment of the gut microbiota.

#### **5.3. Antibiotic exposure and dysbiosis in children**

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 anti-

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

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

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,

In last 50 years, farmers have been using low doses of antibiotics to promote growth and feed efficiency of pigs, cows, sheep, and poultry [102]. Different antibiotics have been demonstrated to have these effects independently of its class, chemical structure, and mode of action and spectrum of activity. Moreover, the effects on growth are greater when animals receive

Also, studies in mice using multiple types of antibiotics have further confirmed this association, as well as identifying early life as the key period for microbe-mediated programing of

Experiments with germ-free animal models have provided direct evidence of the key role of the microbiota in the association between low doses of antibiotics exposure and growth promotion. In 1963, Coates et al. showed that in germ-free chicken antibiotics alone have no growth promoting effects [108]. Recently, Cox et al. showed that germ-free mice who received the microbiota from mice treated with low dose penicillin gained more weight and fat mass

Then, there are two main findings from these experiments. First, early life is a critical time for metabolic development of the host, and second, the microbiome has a key role in this process and its disturbance duty to antibiotic exposure at this time affects the course of growth and

There is epidemiologic evidence that exposure to antibiotics in early life is associated with increased risk of excess adiposity. Recently, epidemiological studies have shown that

antibiotics early in life than if the exposure occurs later in life [103–105].

than mice colonized with microbiota from control animals [107].

most prescriptions were frequently inappropriate [96].

children, particularly to very young children [97–100].

biotics [93].

274 Adiposity - Omics and Molecular Understanding

drinking water [101].

**5.1. Evidence from animals**

host metabolism [106, 107].

development [109].

**5.2. Epidemiologic evidence**

Prospective studies have showed that changes in gut microbiota in early life may precede the development of overweight and obesity [113, 114].

In particular, some bacterial taxa has been associated with the risk of obesity development, regarding to this, a high abundance of intestinal *Bifidobacteria* in early life appears to be associated with lower risk of overweight [114, 115], whereas high amounts of *Bacteroides fragilis* increase the risk of obesity development [113]. Thus, likely factors that exert an impact on gut microbiota composition and functionality in early life may also modulate the risk of obesity development.

Therefore, antibiotic exposure during childhood can reduce the phylogenetic diversity and microbial load of the gut microbiota [116].

Regarding preterm infants it has been shown that treatment with amoxicillin and gentamicin during the first week of life reduced the bacterial diversity and raised the relative abundance of *Enterobacter* in the second and third weeks of life compared to preterm infants not exposed to antibiotics [117].

Moreover, administration of penicillin, ampicillin, cephalexin, gentamicin, amikacin, erythromycin, vancomycin, clindamycin, and teichomycin to preterm infants has been associated with a decrease in the relative abundance of *Bifidobacteriaceae, bacilli*, and *Lactobacillales spp*., commonly linked with a healthy status and an increase in the presence of potentially pathogenic *Enterobacteriaceae* [117–119]. Besides short-term-effects, the dysbiosis produced by antibiotics administration in infants may produce long-term effects like the persistence of the risk of obesity development. It has been observed that 3 months after of antibiotics persists the microbiota disruption [120]. However, antibiotic administration to neonates has been linked to several critical clinical conditions in which modification of the microbiota composition is thought to play a relevant role, in diseases such as necrotizing enterocolitis and sepsis [121, 122].

Antibiotic treatments in early life can lead to long-term alterations in microbiota composition that result in changes to host metabolic functions, particularly during development, increasing the risk of obesity [109].
