Early-Life Antibiotics and Childhood Obesity: Yeast Probiotics as a Strategy to Modulate Gut Microbiota

This study aimed to review the existing literature to investigate the potential link between early-life antibiotic use and being overweight or obese in children. PubMed, Web of Science, Embase, Google Scholar, and Cochrane Library were searched to identify studies published until August 2021 that assessed the relationship between early-childhood antibiotic use and measures of body mass index. The studies included children aged 0-18 years. Only cohort studies were taken into consideration. Studies published in languages other than English were excluded. Antibiotic usage in early life may increase the risk of obesity in children and the addition of yeast probiotics, such as Saccharomyces boulardii CNCM I 745, to antibiotic prescription can serve as a potential option to mitigate this risk.


Introduction And Background
Obesity is a complicated disease involving the interplay between biological, developmental, environmental, behavioral, and genetic variables, leading to an energy imbalance and the accumulation of extra adipose tissue [1,2]. The worldwide prevalence of obesity more than doubled between 1990 and 2015, and its rates have risen dramatically in recent years owing to a global shift toward an obesogenic environment [3][4][5].
In many countries, obesity in children is rising faster than in adults [3]. Approximately 10% of school-going children worldwide aged 5-17 are either obese or overweight, with a prevalence ranging from 30% in the United States to less than 2% in Sub-Saharan Africa. According to 2016 estimates, obesity has grown 10-fold, from 11 million to 124 million, among school-going children and adolescents in only three decades [4,5]. Childhood obesity can elevate the risk of morbidity later in life, regardless of whether it continues into adulthood. Hypertension, type 2 diabetes, dyslipidemia, left ventricular hypertrophy, non-alcoholic steatohepatitis, obstructive sleep apnea, and orthopedic and psychological issues are all associated with pediatric obesity [1,5].
In India, stunting and underweight exist alongside overweight and obesity in children, creating a dietary conundrum. The prevalence of stunting, wasting, and being underweight in children aged five years was found to be 38%, 21%, and 36%, respectively, in the National Family Health Survey-4 (2015-2016). According to the study, 2% of Indian children under the age of five years were overweight [5]. The prevalence of overweight/obesity among adolescent Indian children increased from 9.8% to 11.7% between 2006 and 2009 [6]. Lobstein and Jackson-Leach predicted India will have 17 million obese children by 2025; this tendency has been documented in both urban and rural regions [5].
In addition to genetic and environmental variables, gut microbiota plays an essential role in the development of obesity. Gut microbiota dysbiosis, an imbalanced or disordered gut microbial ecology, impacts obesity etiology by affecting energy harvest, nutrition metabolism, inflammatory pathways, and the gut-brain axis [7][8][9][10].
Antibiotics significantly contribute to altering the gut microbiota. They are regularly administered to infants and children, and up to 40% of infants are exposed to them either directly or indirectly through maternal intrapartum antibiotic prophylaxis [11]. In the United States, usually, children complete three courses of antibiotics by the age of 2 and 10 courses by the age of 10, with many of these courses prescribed for viral illnesses and, therefore, providing no therapeutic benefit [11,12]. From 2000 to 2015, India's antibiotic consumption increased by 103%, making it the highest among low-and middle-income economies [13]. Antibiotics decrease the total diversity of the intestinal microbiota, including the loss of certain key taxa, resulting in metabolic changes, increased vulnerability of the gut to colonization, and the development of these phyla associated with severe infections. Bacteroides spp. may offer some protection against invasive pathogens; however, Bacteroides have also been linked to bloodstream infections and the development of abscesses [17,18].
Bifidobacteria protects against obesity and its metabolic consequences, partially by improving gut barrier function, which decreases metabolic endotoxemia, the abundance of bacterially generated lipopolysaccharides (LPS) in the blood. Once the ratio of Bifidobacteria to Bacteroides gets perturbed, the abundance of barrier function-improving microbes drops and the number of LPS-producing organisms increases [19,20]. LPS in the bloodstream causes inflammation, insulin resistance, and weight gain, and is thought to play a role in the development of obesity and associated diseases, as shown in Figure 2 [21]. Bifidobacteria can enhance metabolic health by reducing LPS leakage from the gut, probably by upregulating tight junction proteins [19][20][21]. The synthesis of SCFA via colonic fermentation, which involves the anaerobic degradation of food fiber, protein, and peptides, helps the gut bacteria contribute to energy metabolism. SCFAs are bacterial waste products generated to maintain a healthy redox balance in the gut. Acetate, propionate, and butyrate are the most common SCFA species. The Bacteroidetes phylum produces acetate and propionate, whereas the Firmicutes phylum produces butyrate. Body weight, glucose homeostasis, and insulin sensitivity have all been found to benefit from them [17,[19][20][21].

Is There Any Evidence That Antibiotics Have the Potential to Cause Obesity or Weight Gain?
We found 20 observational studies encompassing a total of 1,412,275 participants that allowed us to assess the association between antibiotic exposure before the age of four years and later measurements of body mass or the risk of obesity/overweight in childhood ( Table 1). Both prospective and retrospective cohort studies were included in the review. Most studies were conducted in the United States and Europe. The overall exposure window in the studies was 0-48 months of age.   Of the 20 studies, 17 had overall measures of association. Among the remaining three studies that involved a total of 299,949 participants, one study had the most participants (260,556 children) and showed that association with infection, but not with antibiotic usage, was linked to an increased risk of childhood obesity.

Study
The 17 studies comprising a total of 1,112,326 participants clearly highlighted that the use of antibiotics was linked to obesity. Antibiotic exposure in early infancy was related to a higher body mass index (BMI) and a higher prevalence of obesity in healthy children, according to these cohort studies.
Aversa et al. demonstrated that antibiotic exposure during childhood was associated with an increased risk of childhood obesity, asthma, allergic rhinitis, atopic dermatitis, celiac disease, and attention-deficit hyperactivity disorder. The hazard ratios were 1.20-2.89, with a p-value <0.05 for all conditions. This study was conducted and published by the Mayo Clinic [39].
Uzan-Yulzari et al. showed that antibiotic exposure during the neonatal phase was linked to a long-term disruption of the gut microbiota, which may cause stunted development in boys during the first six years of their life, whereas antibiotic usage later in childhood was linked to an increase in BMI. In most studies, antibiotic exposure occurred during the first two years of life and was significantly associated with weight gain/obesity [40].
Another recent study by Aris et al. on 0-48-month-old children documented that antibiotic exposure was associated with statistically significant BMI trajectory milestones during infancy and early childhood. These associations were the strongest for children with at least four episodes of antibiotic exposure [41].

Is There Any Treatment Option Available to Prevent the Consequences Associated With Dysbiosis?
Probiotics seem to be a promising option to treat dysbiosis and are well-tolerated upon long-term usage. The World Health Organization defines probiotics as "live microorganisms which when administered in adequate amounts confer a health benefit on the host." Probiotics are continually used to preserve human intestinal health by improving the equilibrium of internal microbiota. As a result, the number of harmful bacteria that cannot live in acidic environments decreases, whereas helpful bacteria that thrive in such environments multiply, thereby balancing the gut microbiota [42].
Probiotics are available in various forms, the most common being bacterial and yeast probiotics. Only a few of the many available probiotics have scientific merit and global recommendations. Lactobacillus rhamnosus GG is a bacterial probiotic, whereas Saccharomyces boulardii CNCM I 745 is a yeast probiotic. Both have been extensively studied and are recommended as adjunct therapy while managing acute gastroenteritis and antibiotic-associated diarrhea (AAD) in children [43,44].
AAD is characterized by the passage of loose, watery stools three or more times a day following the intake of antibiotics used to treat bacterial illnesses. It affects 5%-30% of patients, either early in the course of antibiotic medication or up to two months after the treatment is completed [44,45]. Although AAD is not evident in every patient, antibiotic intake is still a cause of gut dysbiosis. AAD is the first visual symptom of dysbiosis and both S. boulardii CNCM I 745 and L. rhamnosus GG can be used along with antibiotics for preventing it [46,47].
Probiotics should be administered along with antibiotics and should be continued for a few days after stopping antibiotics to obtain the desired results. However, the concurrent administration of L. rhamnosus GG and antibiotics faces the challenge that the antibiotic may potentially kill the bacterial probiotics. Hence, the two must be administered at least two to four hours apart. On the contrary, a time gap is not required while using S. boulardii CNCM I 745. Further, yeast probiotics are 10 times larger in size than bacteria and can adhere firmly to the epithelial layer of the intestine, precluding the adhesion of any pathogenic bacteria [44,46,47]. S. boulardii CNCM I 745 neither shows resistance to antibiotics nor plays any role in genetic transfer [48].
S. boulardii CNCM I 745 has several established mechanisms of action [46,47]. It shows antitoxic effects against Clostridium difficile toxins A and B, cholera toxin, and Escherichia coli. It can interfere with gut infections either directly or indirectly. For example, it can directly suppress the growth of Salmonella typhimurium, Yersinia enterocolitica, and Aeromonas hemolysin. It can enhance the production of SCFAs, which are depleted during illness, suggesting altered intestinal fermentation. It can decrease mucositis, repair fluid transport routes, promote protein and energy synthesis, or serve as a trophic agent by producing spermine and spermidine, as well as other brush border enzymes that help enterocytes mature. Finally, it can modulate immune responses by acting as a stimulant or by decreasing pro-inflammatory responses.
Intestinal secretory immunoglobulin A (IgA) levels may rise because of S. boulardii infection. It is also linked to elevated levels of blood IgG against C. difficile toxins A and B. It may disrupt nuclear factor-κB-mediated signaling pathways, which promote the generation of pro-inflammatory cytokines.
Some clinical studies that used S. boulardii CNCM I 745 along with antibiotics have shown that it helps prevent and manage dysbiosis. Additional details are presented in Table 2.

Study
Year of publication and location

Study title Study design Conclusion
Selig et al. [48] 2020, United  A study of 60 women treated for bacterial vaginosis analyzed the effects of antibiotic therapy alone, concurrently with S. boulardii treatment, or followed by S. boulardii treatment. In the study, 60 women were given metronidazole (3 × 400 mg/day) and ciprofloxacin (2 × 500 mg/day) to treat bacterial vaginosis. Group I received antibiotics for the first and second weeks. Group II received 250 mg S. boulardii tid in addition to antibiotics for weeks one and two. Group III received antibiotics for weeks one and two, followed by 250 mg S. boulardii tid for weeks three and four. Fluorescence in situ hybridization analysis of Carnoy fixated stool cylinders was done from days -90, -60, -30, 7, 14, 28, 42, 56, and 70.
As shown in Figure 3, the main microbial population is drastically reduced (blue line) after two weeks of antibiotic therapy (red area). S. boulardii (red area; red line) provided during antibiotic therapy can mitigate this loss by preserving the microbiome. If S. boulardii is given after antibiotic therapy (green area; green line), it can help the microbial community regenerate more quickly. As a result, a combination of both, with S. boulardii therapy during and after antibiotic treatment, would be ideal. The hypothetical black dotted line drawn from the other lines represents this. The worst-case situation is that no S. boulardii therapy is provided (blue line) (Figure 3). Although stable enterotypes were seen before treatment, the antibiotics led to the suppression of the habitual/essential (most prevalent) bacteria as well as other significant bacterial groups. If given concurrently with an antibiotic, S. boulardii might reduce the suppression of these bacteria caused by the antibiotic. After receiving antibiotic therapy, S. boulardii dramatically accelerated the return of the natural microbiota. S. boulardii also decreased the number of pre-and post-mismatches in the microbial community. Contrary to what would have happened if S. boulardii had been provided, antibiotic therapy greatly increased population differences (compared to before treatment) [46].
As this is an attempt to present a narrative review of the evidence, there are a few limitations to this review. We only considered cohort studies. Moreover, the age groups and study durations were different. Another important limitation is that we did not focus on any specific antibiotic while including studies in this review. Dosage regimens were different in all cohort studies. Finally, per the evidence, yeast probiotics are superior to bacterial probiotics, but head-to-head studies are very limited. Therefore, for establishing a strong correlation between antibiotics and obesity, we need further larger controlled studies.

Conclusions
Antibiotics are very commonly used in the first few years of a child's life, and there are many hypotheses linking early antibiotic exposure to childhood obesity. Antibiotics mainly impact the gut microbiota, and this altered gut microbiota increases BMI or obesity later in life. In this review, 17 studies showed an association between antibiotic usage in early life and obesity in later stages of life. Evidence-based yeast probiotics, S.