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Symposium Article SSCI Presidential Symposium: The MicrobiomeSymposium Editor: C. Mel Wilcox, MD| Volume 356, ISSUE 5, P413-423, November 01, 2018

Development of the Pediatric Gut Microbiome: Impact on Health and Disease

Open AccessPublished:August 20, 2018DOI:https://doi.org/10.1016/j.amjms.2018.08.005

      Abstract

      The intestinal microbiota are important in human growth and development. 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 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 disease development. Dysbiosis is 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 in health and disease, beginning in the prenatal period and extending throughout childhood.

      Key Indexing Terms

      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 conserved.
      Human Microbiome Project C
      Structure, function and diversity of the healthy human microbiome.
      These microbes play important roles in mammalian homeostasis, including providing essential nutrients,
      • Flint HJ
      • Scott KP
      • Duncan SH
      • et al.
      Microbial degradation of complex carbohydrates in the gut.
      ,
      • LeBlanc JG
      • Milani C
      • de Giori GS
      • et al.
      Bacteria as vitamin suppliers to their host: a gut microbiota perspective.
      metabolizing dietary fiber into short chain fatty acids,
      • Russell WR
      • Hoyles L
      • Flint HJ
      • et al.
      Colonic bacterial metabolites and human health.
      and ensuring proper development of the immune system.
      • Round JL
      • Mazmanian SK
      The gut microbiota shapes intestinal immune responses during health and disease.
      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 infection,
      • Schubert AM
      • Rogers MA
      • Ring C
      • et al.
      Microbiome data distinguish patients with Clostridium difficile infection and non-C. Difficile-associated diarrhea from healthy controls.
      inflammatory bowel disease,
      • Sartor RB
      Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation.
      ,
      • Frank DN
      • Robertson CE
      • Hamm CM
      • et al.
      Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.
      irritable bowel syndrome,
      • Mayer EA
      • Savidge T
      • Shulman RJ
      Brain-gut microbiome interactions and functional bowel disorders.
      ,
      • Grenham S
      • Clarke G
      • Cryan JF
      • et al.
      Brain-gut-microbe communication in health and disease.
      asthma,
      • Marra F
      • Marra CA
      • Richardson K
      • et al.
      Antibiotic use in children is associated with increased risk of asthma.
      obesity,
      • Kalliomaki M
      • Collado MC
      • Salminen S
      • et al.
      Early differences in fecal microbiota composition in children may predict overweight.
      and neurodevelopmental disorders such as autism.
      • Finegold SM
      • Dowd SE
      • Gontcharova V
      • et al.
      Pyrosequencing study of fecal microflora of autistic and control children.
      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 meconium
      • Gosalbes MJ
      • Llop S
      • Valles Y
      • et al.
      Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants.
      ,
      • Jimenez E
      • Marin ML
      • Martin R
      • et al.
      Is meconium from healthy newborns actually sterile?.
      has challenged this notion. While still controversial,
      • Perez-Munoz ME
      • Arrieta MC
      • Ramer-Tait AE
      • et al.
      A critical assessment of the "sterile womb" and "in utero colonization" hypotheses: implications for research on the pioneer infant microbiome.
      it is now clear that microbial colonization of the infant gut may begin prior to birth as additional evidence suggests microbial colonization of the placenta,
      • Aagaard K
      • Ma J
      • Antony KM
      • et al.
      The placenta harbors a unique microbiome.
      ,
      • Zheng J
      • Xiao X
      • Zhang Q
      • et al.
      The placental microbiome varies in association with low birth weight in full-term neonates.
      amniotic fluid,
      • Rautava S
      • Collado MC
      • Salminen S
      • et al.
      Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial.
      ,
      • DiGiulio DB
      • Romero R
      • Amogan HP
      • et al.
      Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation.
      and the umbilical cord.
      • Jimenez E
      • Fernandez L
      • Marin ML
      • et al.
      Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section.
      Aagaard et al
      • Aagaard K
      • Ma J
      • Antony KM
      • et al.
      The placenta harbors a unique microbiome.
      collected 320 placental specimens under sterile conditions and found a unique placental microbiome niche, which most closely resembled the human oral microbiome.
      • Aagaard K
      • Ma J
      • Antony KM
      • et al.
      The placenta harbors a unique microbiome.
      Furthermore, a randomized, double blind, placebo-controlled trial demonstrated that maternal probiotic supplementation could affect the expression of Toll-like receptor-related genes in both the placenta and the fetal intestine.
      • Rautava S
      • Collado MC
      • Salminen S
      • et al.
      Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial.
      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.
      • Collado MC
      • Rautava S
      • Aakko J
      • et al.
      Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid.
      Importantly, variations in the placental microbiome have been shown to associate with preterm birth
      • Aagaard K
      • Ma J
      • Antony KM
      • et al.
      The placenta harbors a unique microbiome.
      as well as low birth weight in full term infants.
      • Zheng J
      • Xiao X
      • Zhang Q
      • et al.
      The placental microbiome varies in association with low birth weight in full-term neonates.
      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 infants,
      • Arboleya S
      • Sanchez B
      • Milani C
      • et al.
      Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics.
      with preterm infant microbiomes being dominated by Enterobacter, Staphylococcus, and Enterococcus.
      • Patel AL
      • Mutlu EA
      • Sun Y
      • et al.
      Longitudinal survey of microbiota in hospitalized preterm very-low-birth-weight infants.
      • Korpela K
      • Blakstad EW
      • Moltu SJ
      • et al.
      Intestinal microbiota development and gestational age in preterm neonates.
      Prematurity is associated with a high risk for neonatal complications and can lead to significant morbidity and mortality.
      • Kramer MS
      • Demissie K
      • Yang H
      • et al.
      The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System.
      These premature neonates are often exposed to prolonged hospitalizations, antibiotics, and formula feeding which may all disrupt the maturation of health-associated microbial communities.
      • Penders J
      • Thijs C
      • Vink C
      • et al.
      Factors influencing the composition of the intestinal microbiota in early infancy.
      Importantly, alterations in the microbiome of preterm infants have been correlated with increased risk for complications such as necrotizing enterocolitis
      • Pammi M
      • Cope J
      • Tarr PI
      • et al.
      Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.
      ,
      • Dobbler PT
      • Procianoy RS
      • Mai V
      • et al.
      Low microbial diversity and abnormal microbial succession is associated with necrotizing enterocolitis in preterm infants.
      and late-onset sepsis.
      • Stewart CJ
      • Embleton ND
      • Marrs ECL
      • et al.
      Longitudinal development of the gut microbiome and metabolome in preterm neonates with late onset sepsis and healthy controls.
      • Mai V
      • Torrazza RM
      • Ukhanova M
      • et al.
      Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants.
      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 Anaerostipes.
      • Backhed F
      • Roswall J
      • Peng Y
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      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 composition.
      • Penders J
      • Thijs C
      • Vink C
      • et al.
      Factors influencing the composition of the intestinal microbiota in early infancy.
      ,
      • Backhed F
      • Roswall J
      • Peng Y
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      • Heikkila MP
      • Saris PE
      Inhibition of Staphylococcus aureus by the commensal bacteria of human milk.
      • O'Sullivan A
      • Farver M
      • Smilowitz JT
      The influence of early infant-feeding practices on the intestinal microbiome and body composition in infants.
      Conversely, studies have shown that human milk isolates contain symbiotic and potentially probiotic microbes.
      • Backhed F
      • Roswall J
      • Peng Y
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      • Heikkila MP
      • Saris PE
      Inhibition of Staphylococcus aureus by the commensal bacteria of human milk.
      Human milk oligosaccharides, the 3rd largest component in human milk, are considered prebiotic, with antimicrobial and antiadhesive properties thought to be protective to the infant.
      • Ward RE
      • Ninonuevo M
      • Mills DA
      • et al.
      In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri.
      • Lin AE
      • Autran CA
      • Szyszka A
      • et al.
      Human milk oligosaccharides inhibit growth of group B Streptococcus.
      • Gonia S
      • Tuepker M
      • Heisel T
      • et al.
      Human milk oligosaccharides inhibit Candida albicans invasion of human premature intestinal epithelial cells.
      • Ruiz-Palacios GM
      • Cervantes LE
      • Ramos P
      • et al.
      Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligo saccharides of human milk inhibit its binding and infection.
      Interestingly, breast-fed infants have reduced microbial diversity than their formula-fed counterparts.
      • Praveen P
      • Jordan F
      • Priami C
      • et al.
      The role of breast-feeding in infant immune system: a systems perspective on the intestinal microbiome.
      However, this reduced diversity is associated with an increase in genes relevant for degradation of human milk oligosaccharides.
      • Praveen P
      • Jordan F
      • Priami C
      • et al.
      The role of breast-feeding in infant immune system: a systems perspective on the intestinal microbiome.
      Human milk oligosaccharides, in turn, are able to amplify the presence of specific bacterial populations in the infant gut.
      • Ward RE
      • Ninonuevo M
      • Mills DA
      • et al.
      In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri.

      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 Firmicutes.
      • Backhed F
      • Roswall J
      • Peng Y
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      ,
      • Palmer C
      • Bik EM
      • DiGiulio DB
      • et al.
      Development of the human infant intestinal microbiota.
      During the first year of life, the infant's microbiome also gains functionality similar to their mother's gut metagenome, with decreasing interindividual variation over time.
      • Backhed F
      • Roswall J
      • Peng Y
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      ,
      • Palmer C
      • Bik EM
      • DiGiulio DB
      • et al.
      Development of the human infant intestinal microbiota.
      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 foods.
      • Koenig JE
      • Spor A
      • Scalfone N
      • et al.
      Succession of microbial consortia in the developing infant gut microbiome.
      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 degredation.
      • Koenig JE
      • Spor A
      • Scalfone N
      • et al.
      Succession of microbial consortia in the developing infant gut microbiome.
      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 structure.
      • Palmer C
      • Bik EM
      • DiGiulio DB
      • et al.
      Development of the human infant intestinal microbiota.
      • Koenig JE
      • Spor A
      • Scalfone N
      • et al.
      Succession of microbial consortia in the developing infant gut microbiome.
      • Martin R
      • Makino H
      • Cetinyurek Yavuz A
      • et al.
      Early-life events, including mode of delivery and type of feeding, siblings and gender, shape the developing gut microbiota.
      Similarly, exposure to less sanitary environments, including contact with household pets and siblings, have significant effects on the developing microbiome.
      • Martin R
      • Makino H
      • Cetinyurek Yavuz A
      • et al.
      Early-life events, including mode of delivery and type of feeding, siblings and gender, shape the developing gut microbiota.
      • Azad MB
      • Konya T
      • Maughan H
      • et al.
      Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity.
      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 siblings.
      • Laursen MF
      • Zachariassen G
      • Bahl MI
      • et al.
      Having older siblings is associated with gut microbiota development during early childhood.
      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 twin.
      • Smith MI
      • Yatsunenko T
      • Manary MJ
      • et al.
      Gut microbiomes of Malawian twin pairs discordant for kwashiorkor.
      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 metabolism.
      • Smith MI
      • Yatsunenko T
      • Manary MJ
      • et al.
      Gut microbiomes of Malawian twin pairs discordant for kwashiorkor.

      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 life,
      • Backhed F
      • Roswall J
      • Peng Y
      • et al.
      Dynamics and stabilization of the human gut microbiome during the first year of life.
      ,
      • Yatsunenko T
      • Rey FE
      • Manary MJ
      • et al.
      Human gut microbiome viewed across age and geography.
      other studies have demonstrated continued development through childhood into the teenage years.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      • Ringel-Kulka T
      • Cheng J
      • Ringel Y
      • et al.
      Intestinal microbiota in healthy U.S. young children and adults–a high throughput microarray analysis.
      • Agans R
      • Rigsbee L
      • Kenche H
      • et al.
      Distal gut microbiota of adolescent children is different from that of adults.
      In a study comparing the intestinal microbiota of 1-4 year old children to healthy adults, the adult microbiome had significantly greater diversity (abundance and richness) than young children.
      • Ringel-Kulka T
      • Cheng J
      • Ringel Y
      • et al.
      Intestinal microbiota in healthy U.S. young children and adults–a high throughput microarray analysis.
      At the phylum level, the predominant bacterial groups were similar, including Firmicutes, Bacteroidetes, and Actinobacteria.
      • Ringel-Kulka T
      • Cheng J
      • Ringel Y
      • et al.
      Intestinal microbiota in healthy U.S. young children and adults–a high throughput microarray analysis.
      However, at the genus level, multiple phylogenetic groups were significantly different between the children and adult populations.
      • Ringel-Kulka T
      • Cheng J
      • Ringel Y
      • et al.
      Intestinal microbiota in healthy U.S. young children and adults–a high throughput microarray analysis.
      A study comparing the fecal microbiota of adolescents (11-18 years of age) to healthy adults found that the number of detected species was similar between groups, but the relative abundances of genera differentiated adolescents from adults, suggesting that the microbiomes differed, even into adolescence.
      • Agans R
      • Rigsbee L
      • Kenche H
      • et al.
      Distal gut microbiota of adolescent children is different from that of adults.
      Hollister et al
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      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 Actinobacteria.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      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 Bifidobacterium.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      Fig 1
      Figure 1Healthy 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.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      )
      Importantly, Hollister et al
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      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 metabolism.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      Meanwhile, adults were enriched in pathways previously linked to inflammation, including genes involved in oxidative phosphorylation, lipopolysaccharide biosynthesis, flagellar assembly, and steroid hormone biosynthesis.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      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 in the ortholog groups and pathways.
      • Hollister EB
      • Riehle K
      • Luna RA
      • et al.
      Structure and function of the healthy pre-adolescent pediatric gut microbiome.
      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 microbiota.
      • Koren O
      • Goodrich JK
      • Cullender TC
      • et al.
      Host remodeling of the gut microbiome and metabolic changes during pregnancy.
      Mothers demonstrate an increase in Proteobacteria and Actinobacteria, and a decreased richness as they progress from the first to the third trimester of pregnancy.
      • Koren O
      • Goodrich JK
      • Cullender TC
      • et al.
      Host remodeling of the gut microbiome and metabolic changes during pregnancy.
      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 fetus.
      • Koren O
      • Goodrich JK
      • Cullender TC
      • et al.
      Host remodeling of the gut microbiome and metabolic changes during pregnancy.
      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 development.
      • Migliarini S
      • Pacini G
      • Pelosi B
      • et al.
      Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation.
      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 disorders.
      • Migliarini S
      • Pacini G
      • Pelosi B
      • et al.
      Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation.
      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-HT.
      • Diaz Heijtz R
      • Wang S
      • Anuar F
      • et al.
      Normal gut microbiota modulates brain development and behavior.
      Importantly, these abnormalities can be prevented by exposing the mice to gut microbiota early in life.
      • Diaz Heijtz R
      • Wang S
      • Anuar F
      • et al.
      Normal gut microbiota modulates brain development and behavior.
      Germ-free mice also have a decreased kynurenine: tryptophan ratio compared to conventionally raised mice, which normalizes upon exposure to gut microbiota immediately after weaning.
      • Clarke G
      • Grenham S
      • Scully P
      • et al.
      The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
      Similarly, aberrant anxiety responses were corrected with bacterial colonization of the gut in these animals.
      • Clarke G
      • Grenham S
      • Scully P
      • et al.
      The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
      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 controls.
      • Desbonnet L
      • Garrett L
      • Clarke G
      • et al.
      The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.
      Gut bacteria can also have direct effects on the metabolism and synthesis of tryptophan and 5-HT.
      • O'Mahony SM
      • Clarke G
      • Borre YE
      • et al.
      Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.
      For example, there is in vitro evidence that some bacterial strains can produce 5-HT from tryptophan.
      • O'Mahony SM
      • Clarke G
      • Borre YE
      • et al.
      Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.
      Meanwhile, some bacteria are able to synthesize tryptophan using enzymes such as tryptophan synthase,
      • Raboni S
      • Bettati S
      • Mozzarelli A
      Tryptophan synthase: a mine for enzymologists.
      • Yanofsky C
      RNA-based regulation of genes of tryptophan synthesis and degradation, in bacteria.
      while others degrade tryptophan with tryptophanase enzyme.
      • Yanofsky C
      RNA-based regulation of genes of tryptophan synthesis and degradation, in bacteria.
      • Li G
      • Young KD
      Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan.
      Fig 2
      Figure 2The 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.
      • Collins SM
      • Surette M
      • Bercik P
      The interplay between the intestinal microbiota and the brain.
      )
      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 health.
      • Russell WR
      • Hoyles L
      • Flint HJ
      • et al.
      Colonic bacterial metabolites and human health.
      Erny et al determined that SCFA regulate microglial homeostasis.
      • Erny D
      • Hrabe de Angelis AL
      • Jaitin D
      • et al.
      Host microbiota constantly control maturation and function of microglia in the CNS.
      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 complexity.
      • Erny D
      • Hrabe de Angelis AL
      • Jaitin D
      • et al.
      Host microbiota constantly control maturation and function of microglia in the CNS.
      Exposure to an indigenous microbiota during early development is also crucial for the development of a normal hypothalamic-pituitary-adrenal system.
      • Sudo N
      • Chida Y
      • Aiba Y
      • et al.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      Germ-free mice display an exaggerated hypothalamic-pituitary-adrenal stress response, which was reversible with exposure to SPF feces during early development.
      • Sudo N
      • Chida Y
      • Aiba Y
      • et al.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      However, reconstitution with SPF feces at a later developmental stage was ineffective at reducing the aberrant stress response.
      • Sudo N
      • Chida Y
      • Aiba Y
      • et al.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      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 microbiota.
      • Grenham S
      • Clarke G
      • Cryan JF
      • et al.
      Brain-gut-microbe communication in health and disease.
      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 function
      • O'Mahony SM
      • Hyland NP
      • Dinan TG
      • et al.
      Maternal separation as a model of brain-gut axis dysfunction.
      (Figure 2).
      Long-term treatment with the probiotic Lactobacillus rhamnosus (JB-1) led to decreased levels of stress-induced corticosteroids, depressive symptoms, and anxiety.
      • Bravo JA
      • Forsythe P
      • Chew MV
      • et al.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      Treatment with L. rhamnosus also induced region-specific alterations in expression of GABAB1b and GABAAα2.
      • Bravo JA
      • Forsythe P
      • Chew MV
      • et al.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      Alterations in GABA production 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 brain.
      • Bravo JA
      • Forsythe P
      • Chew MV
      • et al.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      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 morphine.
      • Rousseaux C
      • Thuru X
      • Gelot A
      • et al.
      Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.
      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 cells.
      • Rhee SH
      • Pothoulakis C
      • Mayer EA
      Principles and clinical implications of the brain-gut-enteric microbiota axis.
      The autonomic nervous system 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 present.
      • Van Felius ID
      • Akkermans LM
      • Bosscha K
      • et al.
      Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis.
      ,
      • Macfarlane S
      • Dillon JF
      Microbial biofilms in the human gastrointestinal tract.
      The autonomic nervous system can also affect epithelial mechanisms involved in immune activation of the gut.
      • Rhee SH
      • Pothoulakis C
      • Mayer EA
      Principles and clinical implications of the brain-gut-enteric microbiota axis.
      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 microbiome.
      • Soderholm JD
      • Yates DA
      • Gareau MG
      • et al.
      Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress.
      This increased permeability is secondary to mast cell degranulation, overproduction of interferon gamma, and decreased expression of mRNA encoding tight junction proteins.
      • Demaude J
      • Salvador-Cartier C
      • Fioramonti J
      • et al.
      Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction.

      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 annually.
      • Lessa FC
      • Mu Y
      • Bamberg WM
      • et al.
      Burden of Clostridium difficile infection in the United States.
      A complex microbial community in the intestine is vitally important to providing colonization resistance to CDI. Therefore, alterations to the microbiota increase the risk of infection from C. difficile. When comparing patients with CDI to diarrheal and nondiarrheal controls, Schubert et al
      • Schubert AM
      • Rogers MA
      • Ring C
      • et al.
      Microbiome data distinguish patients with Clostridium difficile infection and non-C. Difficile-associated diarrhea from healthy controls.
      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 antbiotics.
      • Chang JY
      • Antonopoulos DA
      • Kalra A
      • et al.
      Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea.
      Recurrent CDI leads to increased abundance of Proteobacteria, with decreased abundances of Bacteroidetes and Firmicutes compared to healthy controls.
      • Weingarden AR
      • Chen C
      • Bobr A
      • et al.
      Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
      Antibiotic use is the most common risk factor for the development of CDI, with long-lasting changes to the microbiota.
      • Jernberg C
      • Lofmark S
      • Edlund C
      • et al.
      Long-term ecological impacts of antibiotic administration on the human intestinal microbiota.
      These antibiotic-related changes included decreased taxonomic and functional diversity of the gut microbiome as well as a decreased colonization resistance against invading pathogens.
      • Lange K
      • Buerger M
      • Stallmach A
      • et al.
      Effects of Antibiotics on Gut Microbiota.
      Additionally, Deneve et al
      • Deneve C
      • Delomenie C
      • Barc MC
      • et al.
      Antibiotics involved in Clostridium difficile-associated disease increase colonization factor gene expression.
      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 CDI.
      • Janarthanan S
      • Ditah I
      • Adler DG
      • et al.
      Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis.
      PPI use has been shown to alter the gut microbiota by decreasing microbial diversity, and decreasing the abundances of commensal microorganisms.
      • Jackson MA
      • Goodrich JK
      • Maxan ME
      • et al.
      Proton pump inhibitors alter the composition of the gut microbiota.
      • Imhann F
      • Bonder MJ
      • Vich Vila A
      • et al.
      Proton pump inhibitors affect the gut microbiome.
      Chronic PPI use leads to decreased abundances of Bacteroidetes and increased abundances of Firmicutes at the phylum level, which may predispose patients to CDI.
      • Clooney AG
      • Bernstein CN
      • Leslie WD
      • et al.
      A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors.
      PPIs also increase fecal Enterococcaceae and Streptococcaceae, taxa which have been associated with CDI.
      • Imhann F
      • Bonder MJ
      • Vich Vila A
      • et al.
      Proton pump inhibitors affect the gut microbiome.
      • Freedberg DE
      • Toussaint NC
      • Chen SP
      • et al.
      Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial.
      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 infusions.
      • Cammarota G
      • Ianiro G
      • Gasbarrini A
      Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review.
      The rationale behind FMT for CDI is that restoration of the fecal community structure could also restore function, including colonization resistance.
      • Khanna S.
      Microbiota replacement therapies: innovation in gastrointestinal care.
      Weingarden et al
      • Weingarden AR
      • Chen C
      • Bobr A
      • et al.
      Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
      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 acids.
      • Weingarden AR
      • Chen C
      • Bobr A
      • et al.
      Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
      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 growth.
      • Giel JL
      • Sorg JA
      • Sonenshein AL
      • et al.
      Metabolism of bile salts in mice influences spore germination in Clostridium difficile.
      • Sorg JA
      • Sonenshein AL
      Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid.
      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 CDI.
      • Weingarden AR
      • Chen C
      • Bobr A
      • et al.
      Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.

      Inflammatory Bowel Disease

      Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are also associated with a dysbiotic microbiome.
      • Sartor RB
      Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation.
      • Frank DN
      • Robertson CE
      • Hamm CM
      • et al.
      Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.
      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 inflammation.
      • Strober W
      • Fuss I
      • Mannon P
      The fundamental basis of inflammatory bowel disease.
      • Edwards LA
      • Lucas M
      • Edwards EA
      • et al.
      Aberrant response to commensal Bacteroides thetaiotaomicron in Crohn's disease: an ex vivo human organ culture study.
      However, others theorize that aberrant intestinal microbiota are the primary driver of inflammation in IBD.
      • Sartor RB
      Microbial influences in inflammatory bowel diseases.
      In support of this theory, studies have shown that treatment with antibiotics can substantially decrease intestinal inflammation and improve IBD symptoms.
      • Sartor RB.
      Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics.
      Also, many microbes which are enriched in IBD may be able to potentiate disease.
      • Kostic AD
      • Xavier RJ
      • Gevers D
      The microbiome in inflammatory bowel disease: current status and the future ahead.
      For example, Ohkusa et al
      • Ohkusa T
      • Sato N
      • Ogihara T
      • et al.
      Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody.
      demonstrated that the abundance of Fusobacterium species is increased in patients with ulcerative colitis compared with healthy controls. In a separate study, Ohkusa et al
      • Ohkusa T
      • Okayasu I
      • Ogihara T
      • et al.
      Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis.
      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, Bidifdobacterium, Clostridium, and Lactobacillus, as well as increased abundances of Fusobacterium and adherent-invasive Escherichia coli.
      • Kostic AD
      • Xavier RJ
      • Gevers D
      The microbiome in inflammatory bowel disease: current status and the future ahead.
      • Manichanh C
      • Rigottier-Gois L
      • Bonnaud E
      • et al.
      Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach.
      ,
      • Dicksved J
      • Halfvarson J
      • Rosenquist M
      • et al.
      Molecular analysis of the gut microbiota of identical twins with Crohn's disease.
      Patients with IBD have reduced diversity of the microbiome, which becomes more pronounced in inflamed as compared to noninflamed tissue.
      • Sepehri S
      • Kotlowski R
      • Bernstein CN
      • et al.
      Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease.
      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 individuals.
      • Morgan XC
      • Tickle TL
      • Sokol H
      • et al.
      Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.
      Functional alterations in IBD patients include diminished carbohydrate metabolism and decreased production of butyrate and other short chain fatty acids.
      • Kostic AD
      • Xavier RJ
      • Gevers D
      The microbiome in inflammatory bowel disease: current status and the future ahead.
      • Morgan XC
      • Tickle TL
      • Sokol H
      • et al.
      Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.
      ,
      • Erickson AR
      • Cantarel BL
      • Lamendella R
      • et al.
      Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease.
      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 needed.
      • Khan KJ
      • Ullman TA
      • Ford AC
      • et al.
      Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis.
      Similarly, while studies exploring the use of probiotics in IBD have yielded encouraging results, results vary across studies and more randomized controlled trials are needed.
      • Kruis W
      • Fric P
      • Pokrotnieks J
      • et al.
      Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine.
      • Sood A
      • Midha V
      • Makharia GK
      • et al.
      The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis.
      • Tursi A
      • Brandimarte G
      • Papa A
      • et al.
      Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study.
      Finally, fecal microbiota transplantation (FMT) is a possible therapy for IBD, given its success in treating recurrent C. difficile infection.
      • Van Nood E
      • Dijkgraaf MG
      • Keller JJ
      Duodenal infusion of feces for recurrent Clostridium difficile.
      Few randomized controlled trials have been conducted in patients with IBD, with varying results,
      • Rossen NG
      • Fuentes S
      • van der Spek MJ
      • et al.
      Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis.
      • Moayyedi P
      • Surette M
      • Wolfe M
      • et al.
      A Randomized, Placebo Controlled Trial of Fecal Microbiota Therapy in Active Ulcerative Colitis.
      • Moayyedi P
      • Surette MG
      • Kim PT
      • et al.
      Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized, controlled trial.
      • Paramsothy S
      • Kamm MA
      • Kaakoush NO
      • et al.
      Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.
      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).
      • Mayer EA
      • Savidge T
      • Shulman RJ
      Brain-gut microbiome interactions and functional bowel disorders.
      • Grenham S
      • Clarke G
      • Cryan JF
      • et al.
      Brain-gut-microbe communication in health and disease.
      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 signs.
      • Mearin F
      • Lacy BE
      • Chang L
      • et al.
      Bowel disorders.
      Multiple studies have demonstrated differences in the fecal microbial communities of patients with IBS compared to healthy controls.
      • Simren M
      • Barbara G
      • Flint HJ
      • et al.
      Intestinal microbiota in functional bowel disorders: a Rome foundation report.
      Patient with IBS show reductions in the relative abundance of Bifidobacterium and Lactobacillus, as well as increased abundances in the Firmicutes: Bacteroidetes ratio.
      • Mayer EA
      • Savidge T
      • Shulman RJ
      Brain-gut microbiome interactions and functional bowel disorders.
      • Rajilic-Stojanovic M
      • Biagi E
      • Heilig HG
      • et al.
      Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome.
      Similarly, a small number of studies have shown shifts in the small intestinal microbiota in patients with IBS,
      • Kerckhoffs AP
      • Ben-Amor K
      • Samsom M
      • et al.
      Molecular analysis of faecal and duodenal samples reveals significantly higher prevalence and numbers of Pseudomonas aeruginosa in irritable bowel syndrome.
      including evidence that small intestinal bacterial overgrowth may play a role.
      • Giamarellos-Bourboulis EJ
      • Pyleris E
      • Barbatzas C
      • et al.
      Small intestinal bacterial overgrowth is associated with irritable bowel syndrome and is independent of proton pump inhibitor usage.
      While the majority of work has been done in adults with IBS, Saulnier et al
      • Saulnier DM
      • Riehle K
      • Mistretta TA
      • et al.
      Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome.
      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%.
      • Saulnier DM
      • Riehle K
      • Mistretta TA
      • et al.
      Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome.
      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 postinfectious IBS.
      • Lee YY
      • Annamalai C
      • Rao SSC
      Post-infectious irritable bowel syndrome.
      Proposed mechanisms for postinfectious IBS include enteroendocrine cell hyperplasia, elevated T-lymphocytes, and increased gut permeability following infection.
      • Dunlop SP
      • Jenkins D
      • Neal KR
      • et al.
      Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.
      • Spiller RC
      • Jenkins D
      • Thornley JP
      • et al.
      Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome.
      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 placebo.
      • Moayyedi P
      • Ford AC
      • Talley NJ
      • et al.
      The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review.
      • Clarke G
      • Cryan JF
      • Dinan TG
      • et al.
      Review article: probiotics for the treatment of irritable bowel syndrome–focus on lactic acid bacteria.
      • Brenner DM
      • Moeller MJ
      • Chey WD
      • et al.
      The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review.
      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 difficult.
      • Sanders ME
      • Guarner F
      • Guerrant R
      • et al.
      An update on the use and investigation of probiotics in health and disease.
      In an effort to clarify which organisms were potentially effective in improving IBS symptoms, Ortiz-Lucas et al
      • Ortiz-Lucas M
      • Tobias A
      • Saz P
      • et al.
      Effect of probiotic species on irritable bowel syndrome symptoms: a bring up to date meta-analysis.
      specifically examined 10 randomized controlled trials. They found that probiotic combinations containing Bifidobacterium breve, Bifidobacterium longum, or Lactobacillus acidophilus improved pain scores.
      • Ortiz-Lucas M
      • Tobias A
      • Saz P
      • et al.
      Effect of probiotic species on irritable bowel syndrome symptoms: a bring up to date meta-analysis.
      Meanwhile, probiotics containing Bifidobacterium breve, Bifidobacterium longum, Lactobacillus casei, or Lactobacillus plantarum improved distension scores.
      • Ortiz-Lucas M
      • Tobias A
      • Saz P
      • et al.
      Effect of probiotic species on irritable bowel syndrome symptoms: a bring up to date meta-analysis.
      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 IBS.
      • Halmos EP
      • Power VA
      • Shepherd SJ
      • et al.
      A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
      • Bohn L
      • Storsrud S
      • Liljebo T
      • et al.
      Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial.
      Chumpitazi et al
      • Chumpitazi BP
      • Cope JL
      • Hollister EB
      • et al.
      Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.
      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 diet.
      • Chumpitazi BP
      • Cope JL
      • Hollister EB
      • et al.
      Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.
      Specifically, FODMAP responders had baseline microbiomes enriched with taxa with greater saccharolytic metabolic capacity and metabolic pathways related to carbohydrate metabolism.
      • Chumpitazi BP
      • Cope JL
      • Hollister EB
      • et al.
      Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.

      Allergy and Asthma

      The development of asthma and allergies has been associated with deviations in the developing microbiota. For example, infants colonized with E. coli were at an increased risk of developing eczema, while infants colonized with C. difficile were at increased risk of all atopic outcomes (eczema, recurrent wheeze, and allergic sensitization).
      • Penders J
      • Thijs C
      • van den Brandt PA
      • et al.
      Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.
      Similarly, C. difficile colonization at 1 month of age was associated with asthma at 6 to 7 years of age.
      • Van Nimwegen FA
      • Penders J
      • Stobberingh EE
      • et al.
      Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.
      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 prescribed.
      • Marra F
      • Marra CA
      • Richardson K
      • et al.
      Antibiotic use in children is associated with increased risk of asthma.
      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 controls.
      • Herbst T
      • Sichelstiel A
      • Schar C
      • et al.
      Dysregulation of allergic airway inflammation in the absence of microbial colonization.
      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 conditions.
      • Herbst T
      • Sichelstiel A
      • Schar C
      • et al.
      Dysregulation of allergic airway inflammation in the absence of microbial colonization.
      Furthermore, in a mouse model of allergic airway inflammation (asthma), symptoms could be attenuated by exposure to Lactobacillus reuteri, but not Lactobacillus salivarius,
      • Forsythe P
      • Inman MD
      • Bienenstock J
      Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice.
      signifying the importance of the bacterial species and strains that are present. In line with these findings, Russell et al
      • Russell SL
      • Gold MJ
      • Hartmann M
      • et al.
      Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.
      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 prevalence.
      • Ng M
      • Fleming T
      • Robinson M
      • et al.
      Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.
      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 age.
      • Tun HM
      • Bridgman SL
      • Chari R
      • et al.
      Roles of birth mode and infant gut microbiota in intergenerational transmission of overweight and obesity from mother to offspring.
      Another study found that low levels of Bifidobacterium spp. and increased Staphylococcus aureas in infancy were associated with being overweight by age seven.
      • Kalliomaki M
      • Collado MC
      • Salminen S
      • et al.
      Early differences in fecal microbiota composition in children may predict overweight.
      Further support for the microbiome's role in obesity was demonstrated by Cho et al.
      • Cho I
      • Yamanishi S
      • Cox L
      • et al.
      Antibiotics in early life alter the murine colonic microbiome and adiposity.
      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 cholesterol.
      • Cho I
      • Yamanishi S
      • Cox L
      • et al.
      Antibiotics in early life alter the murine colonic microbiome and adiposity.
      Additional work by Cox et al
      • Cox LM
      • Yamanishi S
      • Sohn J
      • et al.
      Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.
      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 microbiome,
      • Cox LM
      • Yamanishi S
      • Sohn J
      • et al.
      Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.
      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 controls.
      • Finegold SM
      • Dowd SE
      • Gontcharova V
      • et al.
      Pyrosequencing study of fecal microflora of autistic and control children.
      Luna et al
      • Luna RA
      • Oezguen N
      • Balderas M
      • et al.
      Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder.
      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 nonspore-forming anaerobes and microaerophilic bacteria, which were absent in control children.
      • Finegold SM
      • Molitoris D
      • Song Y
      • et al.
      Gastrointestinal microflora studies in late-onset autism.
      Due to frequent parental reports of an antecedent antibiotic exposure followed by chronic diarrhea in regressive autism, Sandler et al
      • Sandler RH
      • Finegold SM
      • Bolte ER
      • et al.
      Short-term benefit from oral vancomycin treatment of regressive-onset autism.
      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 symptoms.
      • Sandler RH
      • Finegold SM
      • Bolte ER
      • et al.
      Short-term benefit from oral vancomycin treatment of regressive-onset autism.
      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 al
      • Buffington SA
      • Di Prisco GV
      • Auchtung TA
      • et al.
      Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring.
      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 was notable for a significant reduction in L. reuteri, supplementation with this bacterium reversed the observed social deficits.
      • Buffington SA
      • Di Prisco GV
      • Auchtung TA
      • et al.
      Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring.
      deTheije et al
      • de Theije CG
      • Wopereis H
      • Ramadan M
      • et al.
      Altered gut microbiota and activity in a murine model of autism spectrum disorders.
      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.

      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.).

      References

        • Human Microbiome Project C
        Structure, function and diversity of the healthy human microbiome.
        Nature. 2012; 486: 207-214
        • Flint HJ
        • Scott KP
        • Duncan SH
        • et al.
        Microbial degradation of complex carbohydrates in the gut.
        Gut Microbes. 2012; 3: 289-306
        • LeBlanc JG
        • Milani C
        • de Giori GS
        • et al.
        Bacteria as vitamin suppliers to their host: a gut microbiota perspective.
        Curr Opin Biotechnol. 2013; 24: 160-168
        • Russell WR
        • Hoyles L
        • Flint HJ
        • et al.
        Colonic bacterial metabolites and human health.
        Curr Opin Microbiol. 2013; 16 (246-154)
        • Round JL
        • Mazmanian SK
        The gut microbiota shapes intestinal immune responses during health and disease.
        Nat Rev Immunol. 2009; 9: 313-323
        • Schubert AM
        • Rogers MA
        • Ring C
        • et al.
        Microbiome data distinguish patients with Clostridium difficile infection and non-C. Difficile-associated diarrhea from healthy controls.
        MBio. 2014; 5 (e01021-14)
        • Sartor RB
        Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation.
        Mucosal Immunol. 2011; 4: 127-132
        • Frank DN
        • Robertson CE
        • Hamm CM
        • et al.
        Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.
        Inflammatory Bowel Dis. 2011; 17: 179-184
        • Mayer EA
        • Savidge T
        • Shulman RJ
        Brain-gut microbiome interactions and functional bowel disorders.
        Gastroenterology. 2014; 146: 1500-1512
        • Grenham S
        • Clarke G
        • Cryan JF
        • et al.
        Brain-gut-microbe communication in health and disease.
        Front Physiol. 2011; 2: 94
        • Marra F
        • Marra CA
        • Richardson K
        • et al.
        Antibiotic use in children is associated with increased risk of asthma.
        Pediatrics. 2009; 123: 1003-1010
        • Kalliomaki M
        • Collado MC
        • Salminen S
        • et al.
        Early differences in fecal microbiota composition in children may predict overweight.
        Am J Clin Nutr. 2008; 87: 534-538
        • Finegold SM
        • Dowd SE
        • Gontcharova V
        • et al.
        Pyrosequencing study of fecal microflora of autistic and control children.
        Anaerobe. 2010; 16: 444-453
        • Gosalbes MJ
        • Llop S
        • Valles Y
        • et al.
        Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants.
        Clin Exp Allergy. 2013; 43: 198-211
        • Jimenez E
        • Marin ML
        • Martin R
        • et al.
        Is meconium from healthy newborns actually sterile?.
        Res Microbiol. 2008; 159: 187-193
        • Perez-Munoz ME
        • Arrieta MC
        • Ramer-Tait AE
        • et al.
        A critical assessment of the "sterile womb" and "in utero colonization" hypotheses: implications for research on the pioneer infant microbiome.
        Microbiome. 2017; 5: 48
        • Aagaard K
        • Ma J
        • Antony KM
        • et al.
        The placenta harbors a unique microbiome.
        Sci Transl Med. 2014; 6 (237ra65)
        • Zheng J
        • Xiao X
        • Zhang Q
        • et al.
        The placental microbiome varies in association with low birth weight in full-term neonates.
        Nutrients. 2015; 7: 6924-6937
        • Rautava S
        • Collado MC
        • Salminen S
        • et al.
        Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial.
        Neonatology. 2012; 102: 178-184
        • DiGiulio DB
        • Romero R
        • Amogan HP
        • et al.
        Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation.
        PLoS One. 2008; 3: e3056
        • Jimenez E
        • Fernandez L
        • Marin ML
        • et al.
        Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section.
        Curr Microbiol. 2005; 51: 270-274
        • Collado MC
        • Rautava S
        • Aakko J
        • et al.
        Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid.
        Sci Rep. 2016; 6: 23129
        • Arboleya S
        • Sanchez B
        • Milani C
        • et al.
        Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics.
        J Pediatr. 2015; 166: 538-544
        • Patel AL
        • Mutlu EA
        • Sun Y
        • et al.
        Longitudinal survey of microbiota in hospitalized preterm very-low-birth-weight infants.
        J Pediatr Gastroenterol Nutr. 2016; 62: 292-303
        • Korpela K
        • Blakstad EW
        • Moltu SJ
        • et al.
        Intestinal microbiota development and gestational age in preterm neonates.
        Sci Rep. 2018; 8: 2453
        • Kramer MS
        • Demissie K
        • Yang H
        • et al.
        The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System.
        JAMA. 2000; 284: 843-849
        • Penders J
        • Thijs C
        • Vink C
        • et al.
        Factors influencing the composition of the intestinal microbiota in early infancy.
        Pediatrics. 2006; 118: 511-521
        • Pammi M
        • Cope J
        • Tarr PI
        • et al.
        Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.
        Microbiome. 2017; 5: 31
        • Dobbler PT
        • Procianoy RS
        • Mai V
        • et al.
        Low microbial diversity and abnormal microbial succession is associated with necrotizing enterocolitis in preterm infants.
        Front Microbiol. 2017; 8: 2243
        • Stewart CJ
        • Embleton ND
        • Marrs ECL
        • et al.
        Longitudinal development of the gut microbiome and metabolome in preterm neonates with late onset sepsis and healthy controls.
        Microbiome. 2017; 5: 75
        • Mai V
        • Torrazza RM
        • Ukhanova M
        • et al.
        Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants.
        PLoS One. 2013; 8: e52876
        • Backhed F
        • Roswall J
        • Peng Y
        • et al.
        Dynamics and stabilization of the human gut microbiome during the first year of life.
        Cell Host Microbe. 2015; 17: 852
        • Heikkila MP
        • Saris PE
        Inhibition of Staphylococcus aureus by the commensal bacteria of human milk.
        J Appl Microbiol. 2003; 95: 471-478
        • O'Sullivan A
        • Farver M
        • Smilowitz JT
        The influence of early infant-feeding practices on the intestinal microbiome and body composition in infants.
        Nutr Metab Insights. 2015; 8: 1-9
        • Ward RE
        • Ninonuevo M
        • Mills DA
        • et al.
        In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri.
        Appl Environ Microbiol. 2006; 72: 4497-4499
        • Lin AE
        • Autran CA
        • Szyszka A
        • et al.
        Human milk oligosaccharides inhibit growth of group B Streptococcus.
        J Biol Chem. 2017; 292: 11243-11249
        • Gonia S
        • Tuepker M
        • Heisel T
        • et al.
        Human milk oligosaccharides inhibit Candida albicans invasion of human premature intestinal epithelial cells.
        J Nutr. 2015; 145: 1992-1998
        • Ruiz-Palacios GM
        • Cervantes LE
        • Ramos P
        • et al.
        Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligo saccharides of human milk inhibit its binding and infection.
        J Biol Chem. 2003; 278: 14112-14120
        • Praveen P
        • Jordan F
        • Priami C
        • et al.
        The role of breast-feeding in infant immune system: a systems perspective on the intestinal microbiome.
        Microbiome. 2015; 3: 41
        • Palmer C
        • Bik EM
        • DiGiulio DB
        • et al.
        Development of the human infant intestinal microbiota.
        PLoS Biol. 2007; 5: e177
        • Koenig JE
        • Spor A
        • Scalfone N
        • et al.
        Succession of microbial consortia in the developing infant gut microbiome.
        Proc Natl Acad Sci USA. 2011; 108: 4578-4585
        • Martin R
        • Makino H
        • Cetinyurek Yavuz A
        • et al.
        Early-life events, including mode of delivery and type of feeding, siblings and gender, shape the developing gut microbiota.
        PLoS One. 2016; 11e0158498
        • Azad MB
        • Konya T
        • Maughan H
        • et al.
        Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity.
        Allergy Asthma Clin Immunol. 2013; 9: 15
        • Laursen MF
        • Zachariassen G
        • Bahl MI
        • et al.
        Having older siblings is associated with gut microbiota development during early childhood.
        BMC Microbiol. 2015; 15: 154
        • Smith MI
        • Yatsunenko T
        • Manary MJ
        • et al.
        Gut microbiomes of Malawian twin pairs discordant for kwashiorkor.
        Science. 2013; 339: 548-554
        • Yatsunenko T
        • Rey FE
        • Manary MJ
        • et al.
        Human gut microbiome viewed across age and geography.
        Nature. 2012; 486: 222-227
        • Hollister EB
        • Riehle K
        • Luna RA
        • et al.
        Structure and function of the healthy pre-adolescent pediatric gut microbiome.
        Microbiome. 2015; 3: 36
        • Ringel-Kulka T
        • Cheng J
        • Ringel Y
        • et al.
        Intestinal microbiota in healthy U.S. young children and adults–a high throughput microarray analysis.
        PLoS One. 2013; 8: e64315
        • Agans R
        • Rigsbee L
        • Kenche H
        • et al.
        Distal gut microbiota of adolescent children is different from that of adults.
        FEMS Microbiol Ecol. 2011; 77: 404-412
        • Koren O
        • Goodrich JK
        • Cullender TC
        • et al.
        Host remodeling of the gut microbiome and metabolic changes during pregnancy.
        Cell. 2012; 150: 470-480
        • Migliarini S
        • Pacini G
        • Pelosi B
        • et al.
        Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation.
        Mol Psychiatry. 2013; 18: 1106-1118
        • Diaz Heijtz R
        • Wang S
        • Anuar F
        • et al.
        Normal gut microbiota modulates brain development and behavior.
        Proc Natl Acad Sci USA. 2011; 108: 3047-3052
        • Clarke G
        • Grenham S
        • Scully P
        • et al.
        The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
        Mol Psychiatry. 2013; 18: 666-673
        • Desbonnet L
        • Garrett L
        • Clarke G
        • et al.
        The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.
        J Psychiatr Res. 2008; 43: 164-174
        • O'Mahony SM
        • Clarke G
        • Borre YE
        • et al.
        Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.
        Behav Brain Res. 2015; 277: 32-48
        • Raboni S
        • Bettati S
        • Mozzarelli A
        Tryptophan synthase: a mine for enzymologists.
        Cell Mol Life Sci. 2009; 66: 2391-2403
        • Yanofsky C
        RNA-based regulation of genes of tryptophan synthesis and degradation, in bacteria.
        RNA. 2007; 13: 1141-1154
        • Li G
        • Young KD
        Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan.
        Microbiology. 2013; 159: 402-410
        • Erny D
        • Hrabe de Angelis AL
        • Jaitin D
        • et al.
        Host microbiota constantly control maturation and function of microglia in the CNS.
        Nat Neurosci. 2015; 18: 965-977
        • Sudo N
        • Chida Y
        • Aiba Y
        • et al.
        Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
        J Physiol. 2004; 558: 263-275
        • O'Mahony SM
        • Hyland NP
        • Dinan TG
        • et al.
        Maternal separation as a model of brain-gut axis dysfunction.
        Psychopharmacology (Berl). 2011; 214: 71-88
        • Bravo JA
        • Forsythe P
        • Chew MV
        • et al.
        Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
        Proc Natl Acad Sci USA. 2011; 108: 16050-16055
        • Rousseaux C
        • Thuru X
        • Gelot A
        • et al.
        Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.
        Nat Med. 2007; 13: 35-37
        • Rhee SH
        • Pothoulakis C
        • Mayer EA
        Principles and clinical implications of the brain-gut-enteric microbiota axis.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 306-314
        • Van Felius ID
        • Akkermans LM
        • Bosscha K
        • et al.
        Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis.
        Neurogastroenterol Motil. 2003; 15: 267-276
        • Macfarlane S
        • Dillon JF
        Microbial biofilms in the human gastrointestinal tract.
        J Appl Microbiol. 2007; 102: 1187-1196
        • Soderholm JD
        • Yates DA
        • Gareau MG
        • et al.
        Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress.
        Am J Physiol Gastrointest Liver Physiol. 2002; 283: G1257-G1263
        • Demaude J
        • Salvador-Cartier C
        • Fioramonti J
        • et al.
        Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction.
        Gut. 2006; 55: 655-661
        • Lessa FC
        • Mu Y
        • Bamberg WM
        • et al.
        Burden of Clostridium difficile infection in the United States.
        N Engl J Med. 2015; 372: 825-834
        • Chang JY
        • Antonopoulos DA
        • Kalra A
        • et al.
        Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea.
        J Infect Dis. 2008; 197: 435-438
        • Weingarden AR
        • Chen C
        • Bobr A
        • et al.
        Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.
        Am J Physiol Gastrointest Liver Physiol. 2014; 306: G310-G319
        • Jernberg C
        • Lofmark S
        • Edlund C
        • et al.
        Long-term ecological impacts of antibiotic administration on the human intestinal microbiota.
        ISME J. 2007; 1: 56-66
        • Lange K
        • Buerger M
        • Stallmach A
        • et al.
        Effects of Antibiotics on Gut Microbiota.
        Dig Dis. 2016; 34: 260-268
        • Deneve C
        • Delomenie C
        • Barc MC
        • et al.
        Antibiotics involved in Clostridium difficile-associated disease increase colonization factor gene expression.
        J Med Microbiol. 2008; 57: 732-738
        • Janarthanan S
        • Ditah I
        • Adler DG
        • et al.
        Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis.
        Am J Gastroenterol. 2012; 107: 1001-1010
        • Jackson MA
        • Goodrich JK
        • Maxan ME
        • et al.
        Proton pump inhibitors alter the composition of the gut microbiota.
        Gut. 2016; 65: 749-756
        • Imhann F
        • Bonder MJ
        • Vich Vila A
        • et al.
        Proton pump inhibitors affect the gut microbiome.
        Gut. 2016; 65: 740-748
        • Clooney AG
        • Bernstein CN
        • Leslie WD
        • et al.
        A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors.
        Aliment Pharmacol Ther. 2016; 43: 974-984
        • Freedberg DE
        • Toussaint NC
        • Chen SP
        • et al.
        Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial.
        Gastroenterology. 2015; 149 (e9): 883-885
        • Cammarota G
        • Ianiro G
        • Gasbarrini A
        Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review.
        J Clin Gastroenterol. 2014; 48: 693-702
        • Khanna S.
        Microbiota replacement therapies: innovation in gastrointestinal care.
        Clin Pharmacol Ther. 2018; 103: 102-111
        • Giel JL
        • Sorg JA
        • Sonenshein AL
        • et al.
        Metabolism of bile salts in mice influences spore germination in Clostridium difficile.
        PLoS One. 2010; 5: e8740
        • Sorg JA
        • Sonenshein AL
        Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid.
        J Bacteriol. 2010; 192: 4983-4990
        • Strober W
        • Fuss I
        • Mannon P
        The fundamental basis of inflammatory bowel disease.
        J Clin Invest. 2007; 117: 514-521
        • Edwards LA
        • Lucas M
        • Edwards EA
        • et al.
        Aberrant response to commensal Bacteroides thetaiotaomicron in Crohn's disease: an ex vivo human organ culture study.
        Inflammatory Bowel Dis. 2011; 17: 1201-1208
        • Sartor RB
        Microbial influences in inflammatory bowel diseases.
        Gastroenterology. 2008; 134: 577-594
        • Sartor RB.
        Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics.
        Gastroenterology. 2004; 126: 1620-1633
        • Kostic AD
        • Xavier RJ
        • Gevers D
        The microbiome in inflammatory bowel disease: current status and the future ahead.
        Gastroenterology. 2014; 146: 1489-1499
        • Ohkusa T
        • Sato N
        • Ogihara T
        • et al.
        Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody.
        J Gastroenterol Hepatol. 2002; 17: 849-853
        • Ohkusa T
        • Okayasu I
        • Ogihara T
        • et al.
        Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis.
        Gut. 2003; 52: 79-83
        • Manichanh C
        • Rigottier-Gois L
        • Bonnaud E
        • et al.
        Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach.
        Gut. 2006; 55: 205-211
        • Dicksved J
        • Halfvarson J
        • Rosenquist M
        • et al.
        Molecular analysis of the gut microbiota of identical twins with Crohn's disease.
        ISME J. 2008; 2: 716-727
        • Sepehri S
        • Kotlowski R
        • Bernstein CN
        • et al.
        Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease.
        Inflammatory Bowel Dis. 2007; 13: 675-683
        • Morgan XC
        • Tickle TL
        • Sokol H
        • et al.
        Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.
        Genome Biol. 2012; 13: R79
        • Erickson AR
        • Cantarel BL
        • Lamendella R
        • et al.
        Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease.
        PLoS One. 2012; 7: e49138
        • Khan KJ
        • Ullman TA
        • Ford AC
        • et al.
        Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis.
        Am J Gastroenterol. 2011; 106: 661-673
        • Kruis W
        • Fric P
        • Pokrotnieks J
        • et al.
        Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine.
        Gut. 2004; 53: 1617-1623
        • Sood A
        • Midha V
        • Makharia GK
        • et al.
        The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis.
        Clin Gastroenterol Hepatol. 2009; 7 (1209 e1): 1202-1209
        • Tursi A
        • Brandimarte G
        • Papa A
        • et al.
        Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study.
        Am J Gastroenterol. 2010; 105: 2218-2227
        • Van Nood E
        • Dijkgraaf MG
        • Keller JJ
        Duodenal infusion of feces for recurrent Clostridium difficile.
        N Engl J Med. 2013; 368: 2145
        • Rossen NG
        • Fuentes S
        • van der Spek MJ
        • et al.
        Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis.
        Gastroenterology. 2015; 149 (e4): 110-118
        • Moayyedi P
        • Surette M
        • Wolfe M
        • et al.
        A Randomized, Placebo Controlled Trial of Fecal Microbiota Therapy in Active Ulcerative Colitis.
        DDW, 2014 (Abstract 929c)
        • Moayyedi P
        • Surette MG
        • Kim PT
        • et al.
        Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized, controlled trial.
        Gastroenterology. 2015; 149: 102-109
        • Paramsothy S
        • Kamm MA
        • Kaakoush NO
        • et al.
        Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.
        Lancet. 2017; 389: 1218-1228
        • Mearin F
        • Lacy BE
        • Chang L
        • et al.
        Bowel disorders.
        Gastroenterology. 2016; 150: 1393-1407
        • Simren M
        • Barbara G
        • Flint HJ
        • et al.
        Intestinal microbiota in functional bowel disorders: a Rome foundation report.
        Gut. 2013; 62: 159-176
        • Rajilic-Stojanovic M
        • Biagi E
        • Heilig HG
        • et al.
        Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome.
        Gastroenterology. 2011; 141: 1792-1801
        • Kerckhoffs AP
        • Ben-Amor K
        • Samsom M
        • et al.
        Molecular analysis of faecal and duodenal samples reveals significantly higher prevalence and numbers of Pseudomonas aeruginosa in irritable bowel syndrome.
        J Med Microbiol. 2011; 60: 236-245
        • Giamarellos-Bourboulis EJ
        • Pyleris E
        • Barbatzas C
        • et al.
        Small intestinal bacterial overgrowth is associated with irritable bowel syndrome and is independent of proton pump inhibitor usage.
        BMC Gastroenterol. 2016; 16: 67
        • Saulnier DM
        • Riehle K
        • Mistretta TA
        • et al.
        Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome.
        Gastroenterology. 2011; 141: 1782-1791
        • Lee YY
        • Annamalai C
        • Rao SSC
        Post-infectious irritable bowel syndrome.
        Curr Gastroenterol Rep. 2017; 19: 56
        • Dunlop SP
        • Jenkins D
        • Neal KR
        • et al.
        Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.
        Gastroenterology. 2003; 125: 1651-1659
        • Spiller RC
        • Jenkins D
        • Thornley JP
        • et al.
        Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome.
        Gut. 2000; 47: 804-811
        • Moayyedi P
        • Ford AC
        • Talley NJ
        • et al.
        The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review.
        Gut. 2010; 59: 325-332
        • Clarke G
        • Cryan JF
        • Dinan TG
        • et al.
        Review article: probiotics for the treatment of irritable bowel syndrome–focus on lactic acid bacteria.
        Aliment Pharmacol Ther. 2012; 35: 403-413
        • Brenner DM
        • Moeller MJ
        • Chey WD
        • et al.
        The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review.
        Am J Gastroenterol. 2009; 104 (quiz 1050): 1033-1049
        • Sanders ME
        • Guarner F
        • Guerrant R
        • et al.
        An update on the use and investigation of probiotics in health and disease.
        Gut. 2013; 62: 787-796
        • Ortiz-Lucas M
        • Tobias A
        • Saz P
        • et al.
        Effect of probiotic species on irritable bowel syndrome symptoms: a bring up to date meta-analysis.
        Rev Esp Enferm Dig. 2013; 105: 19-36
        • Halmos EP
        • Power VA
        • Shepherd SJ
        • et al.
        A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
        Gastroenterology. 2014; 146 (e5): 67-75
        • Bohn L
        • Storsrud S
        • Liljebo T
        • et al.
        Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial.
        Gastroenterology. 2015; 149 (e2): 1399-1407
        • Chumpitazi BP
        • Cope JL
        • Hollister EB
        • et al.
        Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.
        Aliment Pharmacol Ther. 2015; 42: 418-427
        • Penders J
        • Thijs C
        • van den Brandt PA
        • et al.
        Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.
        Gut. 2007; 56: 661-667
        • Van Nimwegen FA
        • Penders J
        • Stobberingh EE
        • et al.
        Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.
        J Allergy Clin Immunol. 2011; 128 (e1-3): 948-955
        • Herbst T
        • Sichelstiel A
        • Schar C
        • et al.
        Dysregulation of allergic airway inflammation in the absence of microbial colonization.
        Am J Respir Crit Care Med. 2011; 184: 198-205
        • Forsythe P
        • Inman MD
        • Bienenstock J
        Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice.
        Am J Respir Crit Care Med. 2007; 175: 561-569
        • Russell SL
        • Gold MJ
        • Hartmann M
        • et al.
        Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.
        EMBO Rep. 2012; 13: 440-447
        • Ng M
        • Fleming T
        • Robinson M
        • et al.
        Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2014; 384: 766-781
        • Tun HM
        • Bridgman SL
        • Chari R
        • et al.
        Roles of birth mode and infant gut microbiota in intergenerational transmission of overweight and obesity from mother to offspring.
        JAMA Pediatr. 2018;
        • Cho I
        • Yamanishi S
        • Cox L
        • et al.
        Antibiotics in early life alter the murine colonic microbiome and adiposity.
        Nature. 2012; 488: 621-626
        • Cox LM
        • Yamanishi S
        • Sohn J
        • et al.
        Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.
        Cell. 2014; 158: 705-721
        • Luna RA
        • Oezguen N
        • Balderas M
        • et al.
        Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder.
        Cell Mol Gastroenterol Hepatol. 2017; 3: 218-230
        • Finegold SM
        • Molitoris D
        • Song Y
        • et al.
        Gastrointestinal microflora studies in late-onset autism.
        Clin Infect Dis. 2002; 35: S6-S16
        • Sandler RH
        • Finegold SM
        • Bolte ER
        • et al.
        Short-term benefit from oral vancomycin treatment of regressive-onset autism.
        J Child Neurol. 2000; 15: 429-435
        • Buffington SA
        • Di Prisco GV
        • Auchtung TA
        • et al.
        Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring.
        Cell. 2016; 165: 1762-1775
        • de Theije CG
        • Wopereis H
        • Ramadan M
        • et al.
        Altered gut microbiota and activity in a murine model of autism spectrum disorders.
        Brain Behav Immun. 2014; 37: 197-206
        • Collins SM
        • Surette M
        • Bercik P
        The interplay between the intestinal microbiota and the brain.
        Nat Rev Microbiol. 2012; 10: 735-742