The normal intestinal flora is composed of nearly 100 trillion microorganisms, consisting of 500 to 3,000 different species, and over 5 million distinct genes.1 The intestinal microbiome (or gut microbiome) is a complex ecosystem of microorganisms that colonize the gut and is inclusive of their associated genes, proteins, and metabolites.2 The gut microbiome plays an essential role in nutrition, metabolism, and immune signaling through proinflammatory and anti-inflammatory cytokines, as well as endocrine and neural pathways via the gut-brain axis.2
A person's microbiota is dynamic throughout the various stages of life, influenced by several factors largely related to diet and geography. This naturally evolving process can be disrupted by various external factors, particularly antibiotic administration. Changes in microbiota homeostasis, or dysbiosis (imbalance), may lead to negative long-term metabolic effects including obesity, diabetes mellitus (DM), and other metabolic diseases.3
Obesity is a particularly devastating worldwide epidemic that may lead to significant increases in morbidity and mortality rates. Based on the National Health and Nutrition Examination Survey, approximately 33% of adults and 17% of children in the US are obese, and these rates have not significantly decreased over the last 15 years.4 Although many factors contribute to the pathogenesis of obesity in adulthood, including diet and host genetics, there is increasing evidence to suggest that childhood exposure of antibiotics to the gut microbiota may be among the earliest influences that increase the risk of developing obesity later in life.
This article highlights the role of the gut microbiome in normal human development and explores the metabolic consequences of microbial perturbations from antibiotic use in young children. Additionally, we aim to provide insight into an evolving epidemic of inappropriate antimicrobial use and the role of antimicrobial stewardship in mitigating the described negative effects.
Evolution of the Intestinal Microbiome in Humans
Contrary to long held beliefs, colonization of the gastrointestinal tract (GIT) actually begins before birth.3 Prenatally, the fetus is exposed to microbes through amniotic fluid, which is affected by maternal diet and translocation of bacteria from the mother's GIT. Perinatal exposure comes primarily from direct transfer of microbes from the mother's vaginal tract during a vaginal delivery, which could be influenced by maternal infection and peripartum antibiotic therapy.5
The Intestinal Microbiome In Infancy
The most rapid stage of microbial colonization occurs during the postnatal period via breast-feeding, bathing, and skin-to-skin contact.5 A fecal density of 108 to 1,010 bacteria/gram stool is established within a few days of birth.6 The dominant bacterial phyla in healthy, full-term infants are Firmicutes, Actinobacteria, and Proteobacteria.5
External influences to gut microbial composition include factors such as delivery mode (vaginal versus cesarean delivery), diet, rearing environment, and antibiotic use. Host factors include genetics, gut epigenetics, gut immunity, and the structure of the gut.6,7 After birth, a full-term breast-fed infant's intestinal microbiome evolves over four time periods: (1) during the first 2 weeks of life there is rapid colonization with “pioneer bacteria” or aerotolerant microbes; (2) after 2 weeks of life and throughout breast-feeding there is continued development of these aerotolerant microbes; (3) during weaning, the stepwise appearance of strict anaerobes occurs; and (4) by ages 2 to 3 years, the intestinal microbiota resembles that of an adult.7 In preterm infants, these phases of microbiome growth are disrupted by external factors such as cesarean delivery, maternal and neonatal exposure to antibiotics, low birth weight, and decreased skin-to-skin time with the mother.7
Compared to full-term infants, preterm infants are particularly susceptible to developing an abnormal microbiome profile, and therefore are at increased risk for the associated metabolic sequelae. Preterm infants have relatively lower proportions of bacteria considered beneficial, such as Bifidobacterium and Lactobacillus; and higher proportions of potentially pathogenic bacteria including Enterobacteriaceae, Enterococcaceae, and Staphylococcus. The bacterial diversity, or richness, of the microbial ecosystem is also observed to be lower in preterm infants, likely increasing the risk for invasion by pathogenic microbes.7 These observations may be secondary to the multiple exposures to antibiotic therapy that very low birth weight (<1,500 g) infants often experience due to the risk of and treatment of acquired infections. Additionally, inherent differences in immune function exist between preterm and full-term infants, which impact the GIT immune system and microbial interactions. Both innate and adaptive immunity are less robust and more inefficient in the preterm infant. Lastly, the full-term infant's exposure to the multiple beneficial immune components in breast milk starts earlier, and is in larger quantities as compared to preterm infants.
The Intestinal Microbiome and Nutrition
Concurrent with developmental advances in feeding skills, dietary influences on microbial composition occur sequentially as forms of nutrition change throughout infancy and early childhood.8 Breast-fed and formula-fed infants reveal different ecologies, with exclusively breast-fed infants showing predominantly Bifidobacteria and relatively fewer counts in some species of Escherichia and Clostridia among others, as compared to exclusively formula-fed infants.9 Ongoing changes occur with the introduction of solid foods when the predominant bacterial species seen in infancy, including Bifidobacterium, Streptococcus, Lactococcus, Lactobacillus, and Enterobacteriaceae, give way to a more diverse group of organisms largely from the phylum Bacteroidetes.10 Additional influences include the introduction of foodstuffs such as animal protein and fat, which increase the proportion of the phyla Firmicutes and Proteobacteria.11,12
Although diet is an important influence, geographic habitat must also be considered. These two factors are likely inter-related by the simple explanation that marked differences in dietary habits exist in different areas of the world.11 Diet-related shifts in microbes must also be considered in context of other environmental exposures including lifestyle changes such as exercise, sleep, and screen time.
The Effects of Antibiotics on the Intestinal Microbiome
Multiple studies have shown that antibiotic exposures resulting in altered intestinal microbiota have long-lasting effects on host metabolism, especially when experienced early in life. One potential mechanism may be the resultant lower proportion of specific populations of protective bacteria, such as Lactobacillis, Allobaculum, and Candidatus, leading to increased production of microbiota-derived calories and altered hepatic metabolism.3,13 Changes in the microbiota may also result in a dampened immune system, and thus inappropriate regulation of immunomodulatory factors, leading to abnormal metabolic responses in the host.3,13
Even when directed toward a specific pathogen, antibiotics cause an overall reduction in microbial diversity. This reduced diversity has been detected even weeks after antibiotic administration has ceased, with remnant microbial content often not recovering to its previous state.14 The consequences of this are illustrated in a metagenomic study by Le Chatelier et al.,15 who reported that people with low bacterial diversity gained more weight, had higher inflammatory tone, increased insulin resistance, and more dyslipidemia compared to those with higher bacterial diversity.
Early-Life Antibiotic Exposure May Lead to Obesity
Early exposure and repeated administration of antibiotics to the neonate can change the gut microbiome by decreasing the number of obligate anaerobes (Bifidobacteria and Bacteroides), bacteria known to be antiobesogenic.16
In a Danish population, Ajslev et al.17 conducted a prospective cohort study of just over 28,000 mother-child dyads evaluating the association of early antibiotic exposure (younger than age 6 months) and risk of obesity at age 7 years. Early exposure to antibiotics was associated with an increased risk of obesity in children when adjusted for maternal prepregnancy body mass index (BMI) (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09–2.17). In the United Kingdom, Trasande et al.18 performed a longitudinal cohort study examining the association of early antibiotic exposure (age 0–2 years) and BMI in pediatric patients up to age 7 years.18 In this longitudinal birth cohort study of 11,532 children, exposure to antibiotics was evaluated at three different time frames: (1) younger than age 6 months, (2) age 6 to 14 months, and (3) age 15 to 23 months. Antibiotic exposure during the earliest time frame was consistently associated with increased BMI after controlling for social and behavioral obesity risk factors. Bailey et al.19 conducted an observational cohort study in US children (n = 64,580) to evaluate the impact of antibiotics prescribed in infancy (age 0–23 months) on obesity in early childhood (age 24–59 months).19 They observed that 79% of children were exposed to antibiotics before age 24 months with an average of 2.3 episodes per child. Cumulative exposure to antibiotics was associated with later obesity for ≥4 exposures (relative risk [RR] 1.11, 95% CI 1.02–1.21). The association was slightly greater in those infants prescribed broad-spectrum antibiotics (RR 1.16, 95% CI 1.06–1.29).19 Finally, Murphy et al.20 conducted a multicenter (31 centers), multinational (18 countries), cross-sectional study (n = 74,946) measuring the association of antibiotic exposure in the first year of life with childhood BMI.20 After adjustment for multiple covariates, they found that early-life antibiotic exposure was associated with increased childhood BMI in boys age 5 to 8 years, but not in girls.
Perturbations of the gut microbiome by antibiotics could lead to obesity later in life, as evidenced by these large cohort, multicenter studies. Although several risk factors for childhood obesity have been identified, future obesity research should continue to account for the significant relationship between early-life antibiotic exposure, gut microbial alterations, and the risk of obesity.
Early-Life Antibiotic Exposure May Lead to Diabetes Mellitus
The risk of DM has been shown to be associated with exposure to antibiotics early in life.21 A Finnish study explored the association between maternal and child antibiotic use and the development of type 1 diabetes mellitus (T1DM) in children (n = 437 with T1DM and n = 1,700 controls).22 Maternal use of penicillin and quinolones prepregnancy was found to be associated with a 1.7 times and 2.4 times increased risk of T1DM (OR 1.7, 95% CI 1.08–2.68 and OR 2.43, 95% CI 1.16–5.10, respectively). Increased risk of T1DM was also found in children for whom macrolide use was documented in both mother (prepregnancy) and child (OR 1.76, 95% CI 1.05–2.94).22 Increased T1DM risk was also found in those children who received ≥7 courses of antibiotics (OR 1.66, 95% CI 1.24–2.24) compared to those who received fewer courses.
The mechanism of action relating an altered composition of the gut microbiome with DM, as suggested by Sanz et al.,21 is that intestinal dysbiosis leads to the growth of pathogenic organisms that interact with intestinal cells and cause inflammatory cytokine production, leading to macrophage activation, adipocyte inflammation, insulin resistance, and hepatic steatosis.
Antibiotic Usage Trends in the United States
Antimicrobial use has come under scrutiny over the last several years. The Institute of Medicine, the Centers for Disease Control and Prevention, and the World Health Organization have reported on antimicrobial overuse, resultant microbe resistance, and other deleterious effects of antimicrobial misuse that can affect a person's health and create a high-cost health care system.23
Although prescribing habits differ widely among providers, several US-based studies report that children age 0 to 4 years receive more than half of all antibiotic prescriptions within the pediatric population.24 Within neonatal intensive care units (NICUs) in California, Schulman et al.25 found a 40-fold variation in practice of antibiotic use, even though all NICUs had similar burdens of proven infection, surgical volume, and mortality, indicating that much of the antibiotic use was unwarranted.
On a national level, it is important to understand the burden of unnecessary or inappropriate antimicrobial use. Multiple large, national surveys conducted in the last 20 years to assess antibiotic use have found that in both pediatric and adult populations, approximately 50% of outpatient antibiotic prescriptions given for common clinical diagnoses such as acute respiratory tract infections were unwarranted. One of these studies, conducted in 1998, found that approximately 55% of antibiotic prescriptions were given to patients unlikely to have a bacterial infection. The estimated cost of this was over $720 million.26
Fortunately, evidence suggests improved appropriateness of antibiotic prescribing habits among physicians in recent years. Antibiotic prescription rates for acute respiratory infection in children younger than age 14 years have changed, with an overall decrease in antibiotic prescriptions by 24% from 1993–1994 to 2007–2008.27 The increasing importance of judicious antimicrobial use coupled with the severity of current antimicrobial resistance prompted an executive order from the White House in September 2014, creating a Task Force dedicated to address the issue of antibiotic resistance and the need for antimicrobial stewardship.28
Antimicrobial stewardship has become an essential component of optimal antimicrobial use in both hospital and outpatient settings, with the goals of achieving clinical cure, limiting toxicity and adverse events, reducing cost of infection-related health care, and limiting the development of resistant organisms.29 Antimicrobial stewardship is defined by the Infectious Diseases Society of America as interventions targeted toward the improvement and monitoring of appropriate antimicrobial use by selecting the most optimal drug regimen, including the type of drug, the dose, duration of therapy, and route of administration.29 Several studies have demonstrated the consequences of a health care system without antimicrobial stewardship, including negative effects on three important areas: quality of patient care, clinical outcomes, and cost. Adverse events related to antimicrobials and their misuse, such as kidney and liver toxicity, diarrheal illness and resistant-bacterial infection, negatively impact all three of these areas.30 Hospitals have used various methods of inpatient stewardship such as prospective audit with feedback to providers, antimicrobial restriction, and authorization requirement.31 These systems are often supported by an Antimicrobial Stewardship Program team, which includes at minimum an infectious diseases physician and clinical pharmacist and, if feasible, a microbiologist, infection preventionist, hospital epidemiologist, and information systems specialist. Hospitals have been able to achieve the goals of stewardship in acute care and inpatient settings with measurable increases in quality of patient care and appropriate antimicrobial use, concurrent with decreases in adverse events, cost of hospitalization, and bacterial resistance.31
The composition of the intestinal microbiome evolves relatively rapidly within the first few years of life. Risk of metabolic disorders including obesity and DM appears to be influenced by certain changes in the composition of the intestinal microbiome. Antibiotics are an important pharmacologic intervention for some of the world's most devastating diseases. With this positive effect comes an emergence of pathogenic microorganisms that can alter the human GIT and immune system leading to long-term medical complications. Although the onset of obesity and DM begins later in childhood or adulthood, mounting evidence suggests that disturbances in the intestinal microbiome's composition due to antibiotic exposure at the earliest ages may contribute a latent susceptibility. Additionally, improving long-term health outcomes and reducing health care–associated costs are valid justifications for the judicious use of antibiotics. Antimicrobial stewardship, beginning in the perinatal and infant time periods, is likely one mechanism by which physicians and health care institutions may mitigate this early established risk for metabolic disorders.
- Groer MW, Luciano AA, Dishaw LJ, Ashmeade TL, Miller E, Gilbert JA. Development of the preterm infant gut microbiome: a research priority. Microbiome. 2014;2:38. doi:10.1186/2049-2618-2-38 [CrossRef]
- Keunen K, van Elburg RM, van Bel F, Benders MJ. Impact of nutrition on brain development and its neuroprotective implications following preterm birth. Pediatr Res. 2015;77(1–2):148–155. doi:10.1038/pr.2014.171 [CrossRef]
- Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol. 2015;11(3):182–190. doi:10.1038/nrendo.2014.210 [CrossRef]
- Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311(8):806–814. doi:10.1001/jama.2014.732 [CrossRef]
- Cacho N, Neu J. Manipulation of the intestinal microbiome in newborn infants. Adv Nutr. 2014;5(1):114–118. doi:10.3945/an.113.004820 [CrossRef]
- Cilieborg MS, Boye M, Sangild PT. Bacterial colonization and gut development in preterm neonates. Early Hum Dev. 2012;88Suppl 1:S41–49. doi:10.1016/j.earlhumdev.2011.12.027 [CrossRef]
- Unger S, Stintzi A, Shah P, Mack D, O'Connor DL. Gut microbiota of the very-low-birth-weight infant. Pediatr Res. 2015;77(1–2):205–213. doi:10.1038/pr.2014.162 [CrossRef]
- Robinson DT, Caplan MS. Linking fat intake, the intestinal microbiome, and necrotizing enterocolitis in premature infants. Pediatr Res. 2015;77(1–2):121–126. doi:10.1038/pr.2014.155 [CrossRef]
- Penders J, Thijs C, Vink C, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118(2):511–521. doi:10.1542/peds.2005-2824 [CrossRef]
- Koenig JE, Spor A, Scalfone N, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A. 2011;108Suppl 1:4578–4585. doi:10.1073/pnas.1000081107 [CrossRef]
- Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222–227.
- Endo A, Partty A, Kalliomki M, Isolauri E, Salminen S. Long-term monitoring of the human intestinal microbiota from the 2nd week to 13 years of age. Anaerobe. 2014;28:149–156. doi:10.1016/j.anaerobe.2014.06.006 [CrossRef]
- Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–1031. doi:10.1038/nature05414 [CrossRef]
- Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108Suppl 1:4554–4561. doi:10.1073/pnas.1000087107 [CrossRef]
- Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500(7464):541–546. doi:10.1038/nature12506 [CrossRef]
- Reinhardt C, Reigstad CS, Backhed F. Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr. 2009;48(3):249–256. doi:10.1097/MPG.0b013e318183187c [CrossRef]
- Ajslev TA, Andersen CS, Gamborg M, Sorensen TI, Jess T. Childhood overweight after establishment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes (Lond). 2011;35(4):522–529. doi:10.1038/ijo.2011.27 [CrossRef]
- Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and early-life body mass. Int J Obes (Lond). 2013;37(1):16–23. doi:10.1038/ijo.2012.132 [CrossRef]
- Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 2014;168(11):1063–1069. doi:10.1001/jamapediatrics.2014.1539 [CrossRef]
- Murphy R, Stewart AW, Braithwaite I, et al. Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study. Int J Obes (Lond). 2014;38(8):1115–1119. doi:10.1038/ijo.2013.218 [CrossRef]
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- Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal intensive care unit antibiotic use. Pediatrics. 2015;135(5):826–833. doi:10.1542/peds.2014-3409 [CrossRef]
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- The White House. Executive Order--Combating Antibiotic-Resistant Bacteria. https://www.whitehouse.gov/the-press-office/2014/09/18/executive-order-combating-antibiotic-resistant-bacteria. Accessed October 20, 2015.
- Society for Healthcare Epidemiology of AmericaInfectious Diseases Society of AmericaPediatric Infectious Diseases Society. Policy Statement on antimicrobial stewardship by the Society for Healthcare Epidemiology (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol. 2012;33(4):322–327. doi:10.1086/665010 [CrossRef]
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