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DEVELOPMENT OF THE PEDIATRIC GUT MICROBIOME: IMPACT ON HEALTH AND DISEASE
Abstract
The intestinal microbiota are important in proper human growth and development before and after birth, during infancy and childhood. Microbial composition may yield insights into the temporal development of microbial communities and vulnerabilities to disorders of microbial ecology such as recurrent Clostridium difficile infection. Discoveries of key microbiome features of carbohydrate and amino acid metabolism are lending new insights into possible new therapies or preventative strategies for inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). In this review, we summarize the current understanding of the development of the pediatric gastrointestinal microbiome, the influence of the microbiome on the developing brain through the gut-brain axis, and the impact of dysbiosis on the development of disease. Microbial dysbiosis will be explored in the context of pediatric allergy and asthma, recurrent C. difficile infection, IBD, IBS, and metabolic disorders. The central premise is that the human intestinal microbiome plays a vital role throughout human life beginning in the prenatal period and extending throughout childhood in health and disease.
INTRODUCTION
The human intestine harbors trillions of microbial cells which form a symbiotic relationship with the host and play a vital role in both health and disease. While the specific microbial composition varies among healthy individuals, the functional repertoire of the microbiome is conserved1. These microbes play important roles in mammalian homeostasis, including providing essential nutrients2, 3, metabolizing dietary fiber into short chain fatty acids4, and ensuring proper development of the immune system5. Therefore, the gut microbiota is considered a crucial factor for proper early life development and lifelong health. However, when the balance of the intestinal microbiota becomes disrupted, alterations can lead to immunologic dysregulation and the development of diseases including Clostridium difficile infection6, inflammatory bowel disease7, 8, irritable bowel syndrome9, 10, asthma11, obesity12, and neurodevelopmental disorders such as autism13. In this review, we describe the development of the pediatric microbiome, starting in utero and progressing through infancy, childhood and adolescence. We then discuss the impact of the microbiome on the developing brain and neural function through the gut-brain axis. We conclude with a discussion on the impact of dysbiosis on disease development.
ESTABLISHMENT OF EARLY LIFE INTESTINAL MICROBIOME
Microbial Colonization of the Neonatal Gut
For many years it was believed that the fetus’ in utero environment was sterile, with infant gut colonization beginning at the time of delivery. However, recent work demonstrating the presence of a microbial community in the meconium14, 15 has challenged this notion. While still controversial16, it is now clear that microbial colonization of the infant gut may begin prior to birth as additional evidence suggests microbial colonization of the placenta17, 18, amniotic fluid19, 20, and the umbilical cord21. Aagaard et al17 collected 320 placental specimens under sterile conditions and found a unique placental microbiome niche, which most closely resembled the human oral microbiome17. Furthermore, a randomized, double blind, placebo-controlled trial demonstrated that maternal probiotic supplementation could affect the expression of Toll-like receptor (TLR)-related genes in both the placenta and the fetal intestine.19 This finding suggested that the fetal intestinal immune gene expression profile could be affected by microbial contact in utero. Similarities between the unique microbiota composition of the placenta and amniotic fluid to that of the infant meconium further suggests a prenatal microbial transfer from mother to fetus.22 Importantly, variations in the placental microbiome have been shown to associate with preterm birth17 as well as low birth weight in full term infants.18
In addition to potential in utero environmental influences, many factors have been found to contribute to early intestinal colonization, such as gestational age at birth. Studies have shown that the intestinal microbiota of preterm infants differs from that of healthy term infants23, with preterm infant microbiomes being dominated by Enterobacter, Staphylococcus, and Enterococcus24, 25. Prematurity is associated with a high risk for neonatal complications and can lead to significant morbidity and mortality26. These premature neonates are often exposed to prolonged hospitalizations, antibiotics, and formula feeding which may all disrupt the maturation of health-associated microbial communities27. Importantly, alterations in the microbiome of preterm infants have been correlated with increased risk for complications such a necrotizing enterocolitis28, 29 and late-onset sepsis30, 31.
Another major influence on the infant gut microbiome is infant diet. Breast-fed infants have microbiota enriched in Lactobacillus, Staphylococcus, and Bifidobacterium, as compared to formula-fed infants with microbiomes dominated by Roseburia, Clostridium, and Anaerostipes32. Formula-fed infants have greater quantities of microbes associated with inflammation, with a more rapid maturation of their microbiome toward that of an adult-type composition27, 32–34. Conversely, studies have shown that human milk isolates contain symbiotic and potentially probiotic microbes32, 33. Human milk oligosaccharides, the 3rd largest component in human milk, are considered prebiotic, with antimicrobial and antiadhesive properties thought to be protective to the infant35–38. Interestingly, breast-fed infants have reduced microbial diversity than their formula-fed counterparts39. However, this reduced diversity is associated with an increase in genes relevant for degradation of human milk oligosaccharides (HMOs)39. HMOs, in turn, are able to amplify the presence of specific bacterial populations in the infant gut35.
Development of the infant intestinal microbiota
During the first year of an infant’s life, the relatively simple neonatal microbiome matures and develops into a more complex microbiome, with a composition more representative of an adult gastrointestinal tract enriched in Bacteroides and Firmicutes32, 40. During the first year of life, the infant’s microbiome also gains functionality similar to their mother’s gut metagenome, with decreasing inter-individual variation over time32, 40. An increased number of bacterial genes relevant for plant polysaccharide metabolism primes the infant microbiome for the adult diet even before the introduction of solid foods41. Once solid foods are introduced, there is a sustained shift in the microbial composition with an increase in Bacteroidetes. Additional modifications include increased short chain fatty acids in the stool, and expression of genes relevant for carbohydrate metabolism, vitamin biosynthesis, and xenobiotic degredation41.
During the early infant development period many exposures can influence the progression of the intestinal microbiota. For example, antibiotic treatment during this period of early life development can dramatically alter the intestinal microbiota structure40–42. Similarly, exposure to less sanitary environments, including contact with household pets and siblings, have significant effects on the developing microbiome42, 43. In fact, the number of older siblings positively correlates with bacterial diversity and richness at 18 months of age, with increasing relative abundances of Firmicutes and Bacteroidetes in infants with more siblings44.
Conversely, the microbiome also affects the general health status of the infant or child. A longitudinal comparative study of Malawian twins discordant for kwashiorkor found that the malnourished twin displayed abnormal microbiome signatures compared to the healthy twin45. As proof of concept that the microbiome was a causal factor in the development of kwashiorkor phenotype, frozen fecal communities from the discordant twin pairs were transplanted into gnotobiotic mice. The mice receiving kwashiorkor microbiome exhibited marked weight loss with accompanied perturbations in amino acid, carbohydrate and intermediary metabolism45.
Development of pediatric and adolescent intestinal microbiota
While some investigators have suggested that the pediatric microbiome reaches a relatively stable, adult-like configuration within the first 3 years of life32, 46, other studies have demonstrated continued development through childhood into the teenage years47–49. In a study comparing the intestinal microbiota of 1–4 year old children to heathy adults, the adult microbiome had significantly greater diversity (abundance and richness) than young children48. At the phylum-like level, the predominant bacterial groups were similar, including Firmicutes, Bacteroidetes and Actinobacteria48. However, at the genus level, multiple phylogenetic groups were significantly different between the children and adult populations48.
A study comparing the fecal microbiota of adolescents (11–18 years of age) to healthy adults found that the number of detected species were similar between groups, but the relative abundances of genera differentiated adolescents from adults, suggesting that the microbiomes differed, even into adolescence49. Hollister et al47 compared 7–12 year old children to adults, and found that similar to adults, the pediatric gut microbiome was largely composed of Bacteroidetes and Firmicutes (Figure 1). However, the relative abundances of these bacteria differed from adults, with relatively lesser abundances of Bacteroidetes and greater abundances of Firmicutes and Actinobacteria47. They also found that while many taxa were shared between pediatric and adult samples, the distribution was significantly different, with children having greater abundances of bacteria belonging to the genera Faecalibacterium, Dialister, Roseburia, Ruminococcus, and Bifidobacterium47.
Healthy pediatric and adult gastrointestinal tracts differ in relative abundances of gut bacterial taxa. (a) Phylum level relative abundances via 16S rRNA gene sequencing. Genus level relative abundances by (b) 16S sequencing and (c) shotgun metagenomic sequencing. (Adapted from Hollister et al.47)
Importantly, Hollister et al47 also characterized the metagenomic profiles of pediatric and adult microbiomes. Children demonstrated an enrichment of genes which may support ongoing development, including genes involved in vitamin synthesis, de novo folate synthesis, and amino acid metabolism47. Meanwhile, adults were enriched in pathways previously linked to inflammation, including genes involved in oxidative phosphorylation, lipopolysaccharide biosynthesis, flagellar assembly, and steroid hormone biosynthesis47. While the intestinal communities of children shared 35–46% similarity to each other taxonomically, they had substantially greater overlap at the functional level, with >90% similarity of the ortholog group and pathway levels47. This difference implies that the functional capacity of microbes present in the pediatric gastrointestinal tract is more highly conserved than microbial composition.
THE GUT-BRAIN AXIS
Impact on brain development
The human brain undergoes rapid growth during the perinatal period, corresponding to dramatic changes in the maternal microbiota50. Mothers demonstrate an increase in Proteobacteria and Actinobacteria, and a decreased richness as they progress from the first to the third trimester of pregnancy50. While these changes are often correlated with metabolic syndrome in nonpregnant females, in the setting of pregnancy these changes are beneficial in promoting energy storage and allowing for adequate growth of the fetus50.
Many studies have demonstrated the importance of the microbiota during brain development, including the microbiome’s indirect effect on tryptophan metabolism and serotonin (5-HT) synthesis (Figure 2). 5-HT is known to be crucial to CNS development51. Knock-in mice lacking the tryptophan hydroxylase 2 gene, demonstrated that a lack of brain 5-HT caused improper wiring of the brain that may lead to long-term changes and neurodevelopmental disorders51. When compared to specific pathogen free (SPF) mice, germ-free mice have increased motor activity and decreased anxiety, as well as altered levels of neurotransmitters such as noradrenaline, dopamine and 5-HT52. Importantly, these abnormalities can be prevented by exposing the mice to gut microbiota early in life52. Germ-free mice also have a decreased kynurenine:tryptophan ratio compared to conventionally raised mice, which normalizes upon exposure to gut microbiota immediately after weaning53. Similarly, aberrant anxiety responses were corrected with bacterial colonization of the gut in these animals53. Furthermore, rats treated with Bifidobacterium infantis showed reduced 5-HIAA concentrations in the frontal cortex, and increased plasma concentrations of tryptophan and kynurenic acid compared to controls54. Gut bacteria can also have direct effects on the metabolism and synthesis of tryptophan and 5-HT55. For example, there is in vitro evidence that some bacterial strains can produce 5-HT from tryptophan55. Meanwhile, some bacteria are able to synthesize tryptophan using enzymes such as tryptophan synthase56, 57, while others degrade tryptophan with tryptophanase enzyme57, 58.
The bidirectional gut-brain axis. The gut-brain axis is a complex interplay between the central nervous system, the neuroendocrine and neuroimmune systems, the autonomic nervous system, the enteric nervous system, and the microbiota. 5-HT, 5-hydroxytryptamine. DC, dendritic cell. GABA, γ-aminobutyric acid. (Adapted from Collins et al.136)
Colonic bacteria have an important role of fermenting carbohydrates and proteins to produce metabolites, including short chain fatty acids (SCFA), which are essential for human health4. Erny et al determined that SCFA regulate microglial homeostasis59. Therefore, defective microglia were found in mice with altered microbiota, including germ-free mice, mice with temporal eradication of microbiota, and mice with limited microbial complexity59. Exposure to an indigenous microbiota during early development is also crucial for the development of a normal hypothalamic-pituitary-adrenal (HPA) system60. Germ-free mice display an exaggerated HPA stress response, which was reversible with exposure to specific pathogen-free (SPF) feces during early development60. However, reconstitution with SPF feces at a later developmental stage was ineffective at reducing the aberrant stress response60. This study demonstrates the important role that the microbiota play during early postnatal brain development, while brain plasticity may still be preserved.
Bidirectional gut-brain axis and its impact on brain function
The brain-gut-microbiota axis is a complex interplay between the CNS, the neuroendocrine and neuroimmune systems, the sympathetic and parasympathetic arms of the autonomic nervous system, the enteric nervous system, and the microbiota10. The communication throughout this axis is bidirectional, with brain signals affecting gastrointestinal tract motor, sensory and secretory functions, and simultaneous visceral signaling from the GI tract affecting brain function61 (Figure 2).
Long-term treatment with the probiotic L. rhamnosus (JB-1) led to decreased levels of stressinduced corticosteroids, depressive symptoms, and anxiety62. Treatment with L. rhamnosus also induced region-specific alterations in expression of GABAB1b and GABAAα262. Alterations in GABA expression are implicated in depression and anxiety disorders. Importantly these changes were not found in vagotomized mice, implicating the vagus nerve as a direct line of communication between the gut bacteria and the brain62.
Another study has implicated the gut microbiome in pain perception. Certain strains of Lactobacillus induce increased expression of μ-opioid and cannabinoid receptors in intestinal epithelial cells, mimicking the analgesic effects of morphine63.
Similarly, the brain can affect the composition of the gut microbiota. These effects on the microbiota can be indirect, through changes in motility and secretion, or direct, through signaling molecules released into the gastrointestinal tract via enterochromaffin cells, neurons, and immune cells64. The autonomic nervous system (ANS) affects motility as well as mucus secretion into the gut lumen, both of which can alter the gastrointestinal environment, thereby changing the bacteria that are present65, 66. The ANS can also affect epithelial mechanisms involved in immune activation of the gut64. For example, exposure to stressful stimuli has been shown to increase permeability of the epithelium, allowing bacterial antigens to cross the epithelium and stimulate an immune response in the mucosa, which in turn alters the microbiome67. This increased permeability is secondary to mast cell degranulation, overproduction of interferon-γ, and decreased expression of mRNA encoding tight junction proteins68.
DYSBIOSIS AND DISEASE
While it is clear that the maintenance of the microbiome is vital for preservation of health, imbalances in the microbiome can shift the microbiome-host relationship from symbiotic to pathogenic. Below, we discuss some examples of communicable and noncommunicable disorders that are associated with a dysbiotic microbiome.
Clostridium difficile Infection
Clostridium difficile infection (CDI) is the leading nosocomial infection in the United States, affecting more than 500,000 people annually69. A complex microbial community in the intestine is vitally important to providing colonization resistance to CDI. Therefore, alterations to the microbiota increases the risk of infection from C. difficile. When comparing patients with CDI to diarrheal and nondiarrheal controls, Schubert et al6 determined that Ruminococcaceae, Lachnospiraceae, Bacteroides and Porphyromonadaceae were absent in patients with CDI, but highly associated with nondiarrheal controls. These compositional changes are even more pronounced in patients with recurrent CDI who have been exposed to multiple courses of antbiotics70. Recurrent CDI leads to increased abundance of Proteobacteria, with decreased abundances of Bacteroides and Firmicutes compared to healthy controls71.
Antibiotic use is the most common risk factor for the development of CDI, with often longlasting changes to the microbiota72. These antibiotic-related changes included decreased taxonomic and functional diversity of the gut microbiome as well as a decreased colonization resistance against invading pathogens73. Additionally, Denève et al74 discovered that exposure to subinhibitory concentrations of certain antibiotics upregulated the expression of genes encoding colonization factors in C. difficile, and increased the adherence of C. difficile to cultured cells.
Proton pump inhibitor (PPI) use also increases the risk of CDI75. PPI use has been shown to alter the gut microbiota by decreasing microbial diversity, and decreasing the abundances of commensal microorganisms76, 77. Chronic PPI use leads to decreased abundances of Bacteroidetes and increased abundances of Firmicutes at the phylum level, which may predispose patients to CDI78. PPIs also increase fecal Enterococcaceae and Streptococcaceae, taxa which have been associated with CDI77, 79.
Therapies aimed at correcting and restoring health-associated complex microbial communities have yielded successful outcomes in treating CDI. Fecal microbiota transplantation (FMT) is around 90% effective at curing recurrent CDI with one or more infusions80. The rationale behind FMT for CDI is that restoration of the fecal community structure could also restore function, including colonization resistance81. Weingarden et al71 demonstrated that FMT normalizes both bacterial community composition and metabolic capacity. Pre-FMT fecal samples had greater concentrations of primary bile acids and bile salts, while post-FMT samples contained mostly secondary bile acids71. Patients with recurrent CDI yielded disrupted abilities to convert primary bile acids to secondary bile acids. Primary bile acids have been shown to promote germination and growth of C. difficile, while secondary bile acids inhibit this growth82, 83. Therefore, it is possible that the correction of bile acid metabolism, and not just restoration of community structure, is a crucial mechanistic element in the efficacy of FMT against CDI71.
Inflammatory bowel disease
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, are also associated with a dysbiotic microbiome7, 8. However, it is unclear if this dysbiosis plays a role in the etiology of the disease, is a result of the disease, or both. Patients with IBD demonstrated exaggerated immune responses against commensal intestinal microbes, which may be essential for the development of intestinal inflammation84, 85. However, others theorize that an aberrant intestinal microbiota is the primary driver of inflammation in IBD86. In support of this theory, studies have shown that treatment with antibiotics can substantially decrease intestinal inflammation and improve IBD symptoms87. Also, many microbes which are enriched in IBD may be able to potentiate disease88. For example, Ohkusa et al89 demonstrated that the abundance of Fusobacterium species is increased in patients with ulcerative colitis compared with healthy controls. In a separate study, Ohkusa et al90 showed that when given as an enema, the isolated human strain of Fusobacterium varium caused UC-like colonic ulcerations in mice, indicating that this bacterium may play a role in the pathogenesis of ulcerative colitis.
Patients with IBD have a variety of changes in the fecal microbiota including decreased abundances of Bacteroides, Firmicutes, Clostridia, Bifidobacterium and Lactobacillus, as well as increased abundances of Fusobacterium and adherent-invasive Escherichia coli88, 91, 92. Patients with IBD have reduced diversity of the microbiome, which becomes more pronounced in inflamed as compared to noninflamed tissue93. Additionally, the functional composition of the gut microbiota is altered in IBD, with one study showing an alteration of 12% of pathways analyzed compared to 2% of genera between IBD and healthy individuals94. Functional alterations in IBD patients include diminished carbohydrate metabolism and decreased production of butyrate and other short chain fatty acids88, 94, 95.
Given the importance of the microbiome in IBD, therapies aimed at manipulating the microbiome have gained popularity. While there are some promising studies demonstrating the efficacy of certain antibiotic combinations in treating IBD, more controlled trials are needed96. Similarly, while studies exploring the use of probiotics in IBD have yielded encouraging results, results vary across studies and more randomized controlled trials are needed97–99. Finally, fecal microbiota transplantation (FMT) is a possible therapy for IBD, given its success in treating recurrent C. difficile infection100. Few randomized controlled trials have been conducted in patients with IBD, with varying results101–104, and more controlled trials are needed to fully understand the therapeutic potential of FMT for the treatment of IBD.
Irritable Bowel Syndrome
Evidence for the microbiome’s influence on disease is found in irritable bowel syndrome (IBS)9, 10. IBS is diagnosed based on the presence of chronic recurrent abdominal pain related to defecation or associated with changes in frequency or form of stool, without accompanying warning signs105. Multiple studies have demonstrated differences in the fecal microbial communities of patients with IBS compared to healthy controls106. Patient with IBS show reductions in the relative abundance of Bifidobacterium and Lactobacillus, as well as increased abundances in the Firmicutes:Bacteroidetes ratio9, 107. Similarly, a small number of studies have shown shifts in the small intestinal microbiota in patients with IBS108, including evidence that small intestinal bacterial overgrowth may play a role109. While the majority of work has been done in adults with IBS, Saulnier et al110 confirmed differences in microbiome signatures in pediatric IBS compared to healthy controls. Additionally, they were able to classify different subtypes of IBS using a limited set of discriminatory species, with a success rate of 98.5%110.
Further support for the role of gut microbiome perturbations in the development of IBS is the persistence of IBS-like symptoms following confirmed bacterial or viral gastroenteritis, a term called post-infectious IBS111. Proposed mechanisms for post-infectious IBS include enteroendocrine cell hyperplasia, elevated T-lymphocytes, and increased gut permeability following infection112, 113.
To further elucidate the role of the intestinal microbiota in IBS, multiple studies have examined the effects of probiotic supplementation in this disorder. Based on several meta-analyses and systematic reviews, probiotic use for treatment of IBS appears more effective than placebo114–116. However, many of these studies vary in their specific conclusions, likely due to inadequate sample sizes, weak study design, and the use of various probiotic strains making comparisons difficult117. In an effort to clarify which organisms were potentially effective in improving IBS symptoms, Ortiz-Lucas et al118specifically examined 10 randomized controlled trials. They found that probiotic combinations containing Bifidobacterium breve, Bifidobacterium longum, or Lactobacillus acidophilus improved pain scores118. Meanwhile, probiotics containing Bifidobacterium breve, Bifidobacterium longum, Lactobacillus casei, or Lactobacillus plantarum improved distension scores118.
Another therapeutic avenue for the treatment of IBS has included dietary changes. Fermentable carbohydrates can be difficult to absorb and have been shown to contribute to symptoms in IBS. Consistent with this finding, a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet has been shown to decrease symptoms in adults with IBS119, 120. Chumpitazi et al121 confirmed that this response was also true in pediatric IBS. Additionally, they demonstrated that specific microbial signatures were associated with the efficacy of the FODMAP diet121. Specifically, FONDMAP responders had baseline microbiomes enriched with taxa with greater saccharolytic metabolic capacity and metabolic pathways related to carbohydrate metabolism121.
Allergy and Asthma
The development of asthma and allergies has been associated with deviations in the developing microbiota. For example, infants colonized with Escherichia coli were at an increased risk of developing eczema, while infants colonized with Clostridium difficile were at increased risk of all atopic outcomes (eczema, recurrent wheeze, and allergic sensitization)122. Similarly, Clostridium difficile colonization at 1 month of age was associated with asthma at 6 to 7 years of age123. Antibiotic exposure in the first year of life has also been associated with an increased risk for the development of asthma in children, with this risk increasing in parallel with the number of courses of antibiotics prescribed11.
These human findings have been further explored using mouse models of allergy and atopy. Allergic germ-free mice developed more severe disease than conventionally housed controls124. Importantly, this phenotype could be reversed by recolonization of the germ-free mice with conventional microbiota, demonstrating the important and influential role of the microbiota in allergic conditions124. Furthermore, in a mouse model of allergic airway inflammation (asthma), symptoms could be attenuated by exposure to Lactobacillus reuteri, but not Lactobacillus salivarius125, signifying the importance of the bacterial species and strains that are present. In line with these findings, Russell et al126 demonstrated that exposure to vancomycin, but not streptomycin, increased the severity of murine allergic asthma.
Obesity
Obesity has become a major global health problem, with increasing prevalence127. The patterns of maturation of microbial communities in infancy can affect the relative risk of becoming overweight and obese in later childhood. A recent longitudinal study of more than 900 infants found that mode of delivery and infant gut microbiota (specifically belonging to the Lachnospiraceae family) mediated the association between prepregnancy maternal overweight status and overweight status of children at 1 and 3 years of age128. Another study found that low levels of Bifidobacterium spp. and increased Staphlococcus aureas in infancy was associated with being overweight by age seven12.
Further support for the microbiome’s role in obesity was demonstrated by Cho et al129. In this study low dose antibiotic exposure in young mice led to increased adiposity, metabolic hormone levels, and SCFA levels, as well as changes to the hepatic metabolism of lipids and cholesterol129. Additional work by Cox et al130 found that low dose penicillin given at birth can induce sustained effects on body composition and enhance high fat diet-induced obesity in mice. Furthermore, the obese phenotype was transferable to germ-free mice by transfer of low-dose penicillin microbiome130, implicating the microbiome as the driver of this phenotype as opposed to antibiotics.
Autism Spectrum Disorder
While the underlying etiology of autism or autism spectrum disorder is not well understood, the intestinal microbiota is proposed to play a role in the development of autism. Children with autism have dysbiotic fecal microbiota, with greater abundances of Bacteroidetes and lesser abundances of Firmicutes compared to controls13. Luna et al131 compared the mucosal microbiome of autistic children with functional abdominal pain to neurotypical children with function abdominal pain, and found distinct microbial signatures in autistic children that correlate with cytokine quantities and tryptophan homeostasis.
Children with regressive (late-onset) autism have increased numbers of fecal clostridial species, as well as the presence of non-spore-forming anaerobes and microaerophilic bacteria, which were absent in control children132. Due to frequent parental reports of an antecedent antibiotic exposure followed by chronic diarrhea in regressive autism, Sandler et al133 hypothesized that, in some children, antibiotic-induced disruption of the microbiome may facilitate colonization by autism-promoting bacterial species. They tested this hypothesis by treating 10 autistic children with minimally absorbed oral vancomycin, and found that 8 of 10 children had short-term improvement in autistic symptoms133. While the improvements were not long-lasting, this report indicates a potential role for the gut microbiota in the symptomatology of autism spectrum disorder and thus warrants further investigation.
Murine studies have also supported a role of the microbiome in autism. Buffington et al134 demonstrated impaired social behavior in the offspring of dams fed a high-fat diet, which were mediated by changes in the offspring’s microbiota. While these pups’ microbiota were notable for a significant reduction in Lactobacillus reuteri, supplementation with this bacterium reversed the observed social deficits134. deTheije et al135 found that in utero valproic acid exposure resulted in decreased social behavior scores and impacted the gut microbiota of mice, with specific changes in Bacteroidetes and Firmicutes, similar to human autism studies. Together these results establish that in murine models of autism, behavioral alterations have been associated with altered microbial colonization.
CONCLUSIONS
In this review, we summarized the current understanding of the development of the pediatric microbiome, the impact of the microbiome on the developing brain and brain function through the gut-brain axis, and the impact of dysbiosis on disease development. The intestinal microbiome is an important factor in human growth and development, and the appropriate balance of microbes throughout life plays a crucial role in the both health and disease. As emerging technology allows us to understand more about the microbiome and its many important functions, we in turn begin to understand the disease processes that the microbes impact. With this deeper knowledge and understanding comes the hope of new therapeutic targets and avenues through which to treat these diseases and promote human health across life stages and ages.
Acknowledgments
Funding Sources Statement: This work was supported by the National Institutes of Health (U01 CA170930), Texas Medical Center Digestive Disease Center (P30 DK56338), and unrestricted research support from BioGaia AB (Stockholm, Sweden) (J.V.).
Footnotes
Conflict of Interest Statement: FDI has no conflicts to disclose. J.V. receives unrestricted research support from BioGaia AB.
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