The Human Microbiome and Its Potential Importance to Pediatrics

The human body is home to more than 1 trillion microbes, with the gastrointestinal tract alone harboring a diverse array of commensal microbes that are believed to contribute to host nutrition, developmental regulation of intestinal angiogenesis, protection from pathogens, and development of the immune response. Recent advances in genome sequencing technologies and metagenomic analysis are providing a broader understanding of these resident microbes and highlighting differences between healthy and disease states. The aim of this review is to provide a detailed summary of current pediatric microbiome studies in the literature, in addition to highlighting recent findings and advancements in studies of the adult microbiome. This review also seeks to elucidate the development of, and factors that could lead to changes in, the composition and function of the human microbiome.

[1]  Paul Forsythe,et al.  Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium‐dependent potassium channel opening , 2009, Journal of cellular and molecular medicine.

[2]  K. Mitsuyama,et al.  Germinated barley foodstuff ameliorates inflammation in mice with colitis through modulation of mucosal immune system , 2008, Scandinavian journal of gastroenterology.

[3]  V. Rotimi,et al.  The development of the bacterial flora in normal neonates. , 1981, Journal of medical microbiology.

[4]  Ruth Ley,et al.  Unravelling the effects of the environment and host genotype on the gut microbiome , 2011, Nature Reviews Microbiology.

[5]  Y. Onlen,et al.  High prevalence of Staphylococcus aureus cultivation and superantigen production in patients with psoriasis. , 2009, European journal of dermatology : EJD.

[6]  I. Strannegård,et al.  Reduced Enterobacterial and Increased Staphylococcal Colonization of the Infantile Bowel: An Effect of Hygienic Lifestyle? , 2006, Pediatric Research.

[7]  H. Yadav,et al.  Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilus and Lactobacillus casei in high fructose fed rats. , 2007, Nutrition.

[8]  S. Akira,et al.  Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. , 2004, Gastroenterology.

[9]  R. Knight,et al.  Bacterial Community Variation in Human Body Habitats Across Space and Time , 2009, Science.

[10]  A. Palva,et al.  Analysis of the Fecal Microbiota of Irritable Bowel Syndrome Patients and Healthy Controls with Real-Time PCR , 2005, The American Journal of Gastroenterology.

[11]  J. Knol,et al.  Colon Microflora in Infants Fed Formula with Galacto- and Fructo-Oligosaccharides: More Like Breast-Fed Infants , 2005, Journal of pediatric gastroenterology and nutrition.

[12]  J. Gordon,et al.  Analyzing the molecular foundations of commensalism in the mouse intestine. , 2000, Current opinion in microbiology.

[13]  J. Corander,et al.  The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. , 2007, Gastroenterology.

[14]  S. Mazmanian,et al.  The gut microbiota shapes intestinal immune responses during health and disease , 2009, Nature Reviews Immunology.

[15]  J. Gordon,et al.  Homeostasis and Inflammation in the Intestine , 2010, Cell.

[16]  U. Göbel,et al.  Investigation of the intestinal microbiota in preterm infants using different methods. , 2010, Anaerobe.

[17]  M. Kilian,et al.  Acne is Not Associated with Yet-Uncultured Bacteria , 2008, Journal of Clinical Microbiology.

[18]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[19]  M. Blaut,et al.  Development of the Intestinal Bacterial Composition in Hospitalized Preterm Infants in Comparison with Breast-Fed, Full-Term Infants , 2003, Pediatric Research.

[20]  L. Brandt,et al.  Treatment of Refractory/Recurrent C. difficile-associated Disease by Donated Stool Transplanted Via Colonoscopy: A Case Series of 12 Patients , 2010, Journal of clinical gastroenterology.

[21]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[22]  F. Greer,et al.  Probiotics and Prebiotics in Pediatrics , 2010, Pediatrics.

[23]  J. Chapman,et al.  The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome , 2008, Proceedings of the National Academy of Sciences.

[24]  E. Bezirtzoglou The intestinal microflora during the first weeks of life. , 1997, Anaerobe.

[25]  M. Tollenaar,et al.  Cortisol in the first year of life: normative values and intra-individual variability. , 2010, Early human development.

[26]  G. Ruiz-Palacios,et al.  Human milk glycans protect infants against enteric pathogens. , 2005, Annual review of nutrition.

[27]  J. Neu,et al.  Intestinal Microbial Ecology in Premature Infants Assessed with Non–Culture-Based Techniques , 2010 .

[28]  J. Fell Neonatal inflammatory intestinal diseases: necrotising enterocolitis and allergic colitis. , 2005, Early human development.

[29]  H. Hayashi,et al.  Characterization of skin microbiota in patients with atopic dermatitis and in normal subjects using 16S rRNA gene-based comprehensive analysis. , 2007, Journal of medical microbiology.

[30]  L. Morelli Postnatal development of intestinal microflora as influenced by infant nutrition. , 2008, The Journal of nutrition.

[31]  J. Parkhill,et al.  Partitioning core and satellite taxa from within cystic fibrosis lung bacterial communities , 2010, The ISME Journal.

[32]  C. Hill,et al.  Antimicrobial activity of lacticin 3,147 against clinical Clostridium difficile strains. , 2007, Journal of medical microbiology.

[33]  Chyong-hsin Hsu,et al.  Oral Probiotics Prevent Necrotizing Enterocolitis in Very Low Birth Weight Preterm Infants: A Multicenter, Randomized, Controlled Trial , 2008, Pediatrics.

[34]  H. Kong,et al.  Skin microbiome: genomics-based insights into the diversity and role of skin microbes. , 2011, Trends in molecular medicine.

[35]  J. Penders,et al.  Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. , 2005, FEMS microbiology letters.

[36]  Rudolf Grimm,et al.  A strategy for annotating the human milk glycome. , 2006, Journal of agricultural and food chemistry.

[37]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[38]  R. Ley,et al.  Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine , 2006, Cell.

[39]  S. Mazmanian,et al.  A microbial symbiosis factor prevents intestinal inflammatory disease , 2008, Nature.

[40]  C. Deming,et al.  Topographical and Temporal Diversity of the Human Skin Microbiome , 2009, Science.

[41]  P. Lichter,et al.  Painting of defined chromosomal regions by in situ suppression hybridization of libraries from laser-microdissected chromosomes. , 1991, Cytogenetics and cell genetics.

[42]  L. Morelli,et al.  Mode of delivery affects the bacterial community in the newborn gut. , 2010, Early human development.

[43]  Gary L. Andersen,et al.  High-Density Universal 16S rRNA Microarray Analysis Reveals Broader Diversity than Typical Clone Library When Sampling the Environment , 2007, Microbial Ecology.

[44]  M. Surette,et al.  Culture Enriched Molecular Profiling of the Cystic Fibrosis Airway Microbiome , 2011, PloS one.

[45]  J. Keiser,et al.  Aerobes isolated in fecal microflora of infants in the intensive care nursery: relationship to human milk use and systemic sepsis. , 1993, American journal of infection control.

[46]  E. Denou,et al.  The putative role of the intestinal microbiota in the irritable bowel syndrome. , 2009, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[47]  N. Pace,et al.  Molecular identification of bacteria in bronchoalveolar lavage fluid from children with cystic fibrosis , 2007, Proceedings of the National Academy of Sciences.

[48]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Mazmanian,et al.  An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System , 2005, Cell.

[50]  J. Jansson,et al.  Metabolomics Reveals Metabolic Biomarkers of Crohn's Disease , 2009, PloS one.

[51]  M. Floch Probiotics and Prebiotics. , 2014, Gastroenterology & hepatology.

[52]  M. Bulsara,et al.  Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates , 2010, Pediatrics.

[53]  E. Pamer,et al.  Role of the commensal microbiota in normal and pathogenic host immune responses. , 2011, Cell host & microbe.

[54]  E. Soppi,et al.  Enhancement of the Circulating Antibody Secreting Cell Response in Human Diarrhea by a Human Lactobacillus Strain , 1992, Pediatric Research.

[55]  R. Kliegman Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. , 2005, The Journal of pediatrics.

[56]  K. Barrett,et al.  Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC) , 2003, Gut.

[57]  Y. Benno,et al.  THE INTESTINAL MICROFLORA OF INFANTS; COMPOSITION OF FECAL FLORA IN BREAST AND BOTTLE FED INFANTS , 1985 .

[58]  F. Bushman,et al.  Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes , 2011, Science.

[59]  P. Gajer,et al.  Vaginal microbiome of reproductive-age women , 2010, Proceedings of the National Academy of Sciences.

[60]  M. Washington,et al.  Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. , 2007, Gastroenterology.

[61]  M. Blaser,et al.  Long-Term Persistence of Resistant Enterococcus Species after Antibiotics To Eradicate Helicobacter pylori , 2003, Annals of Internal Medicine.

[62]  Ronald W. Davis,et al.  Microbes on the human vaginal epithelium , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[63]  R. Knight,et al.  The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice , 2009, Science Translational Medicine.

[64]  Cecilia Jernberg,et al.  Long-term impacts of antibiotic exposure on the human intestinal microbiota. , 2010, Microbiology.

[65]  E. van Nood,et al.  Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? , 2009, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[66]  C. Mackay,et al.  Diet, gut microbiota and immune responses , 2010, Nature Immunology.

[67]  B. Björkstén The gut microbiota: a complex ecosystem , 2006, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[68]  D. Theriaque,et al.  Intestinal microbial ecology in premature infants assessed with non-culture-based techniques. , 2010, The Journal of pediatrics.

[69]  W. Walker,et al.  Neonatal microbial flora and disease outcome. , 2008, Nestle Nutrition workshop series. Paediatric programme.

[70]  W. D. de Vos,et al.  Molecular Monitoring of Succession of Bacterial Communities in Human Neonates , 2002, Applied and Environmental Microbiology.

[71]  I. Dotan,et al.  Probiotics in inflammatory bowel disease: possible mechanisms of action , 2005, Current opinion in gastroenterology.

[72]  F. Shanahan,et al.  Therapeutic implications of manipulating and mining the microbiota , 2009, The Journal of physiology.

[73]  D. Cook,et al.  Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. , 2006, The American journal of clinical nutrition.

[74]  H. Khamis,et al.  Distal gut microbiota of adolescent children is different from that of adults. , 2011, FEMS microbiology ecology.

[75]  Piet A van den Brandt,et al.  Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study , 2006, Gut.

[76]  Anders F. Andersson,et al.  Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome , 2010, PloS one.

[77]  Susan M. Huse,et al.  Variability and Diversity of Nasopharyngeal Microbiota in Children: A Metagenomic Analysis , 2011, PloS one.

[78]  G. Ruiz-Palacios,et al.  Protection of breast-fed infants against Campylobacter diarrhea by antibodies in human milk. , 1990, The Journal of pediatrics.

[79]  M. Caplan,et al.  Gram Negative Bacteria Are Associated with the Early Stages of Necrotizing Enterocolitis , 2011, PloS one.

[80]  A. Shane Applications of Probiotics for Neonatal Enteric Diseases , 2008, The Journal of perinatal & neonatal nursing.

[81]  J. Gordon,et al.  Commensal Host-Bacterial Relationships in the Gut , 2001, Science.

[82]  Eoin L. Brodie,et al.  Loss of Bacterial Diversity during Antibiotic Treatment of Intubated Patients Colonized with Pseudomonas aeruginosa , 2006, Journal of Clinical Microbiology.

[83]  J. Doré,et al.  Resilience of the Dominant Human Fecal Microbiota upon Short-Course Antibiotic Challenge , 2005, Journal of Clinical Microbiology.

[84]  L. Hooper,et al.  Symbiotic Bacteria Direct Expression of an Intestinal Bactericidal Lectin , 2006, Science.

[85]  George Casella,et al.  Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis , 2011, PloS one.

[86]  Vincent J. Denef,et al.  Strain-resolved community genomic analysis of gut microbial colonization in a premature infant , 2010, Proceedings of the National Academy of Sciences.

[87]  C. Lebrilla,et al.  In Vitro Fermentation of Breast Milk Oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri , 2006, Applied and Environmental Microbiology.

[88]  G. Wennergren,et al.  Neonatal Antibiotic Treatment Is a Risk Factor for Early Wheezing , 2008, Pediatrics.

[89]  Eoin L. Brodie,et al.  Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa. , 2010, Environmental microbiology.

[90]  A. Ouwehand,et al.  Human intestinal microbiota and healthy ageing , 2010, Ageing Research Reviews.

[91]  L. T. Angenent,et al.  Succession of microbial consortia in the developing infant gut microbiome , 2010, Proceedings of the National Academy of Sciences.

[92]  D. P. Strachan,et al.  Hay fever, hygiene, and household size. , 1989, BMJ.

[93]  R. Knight,et al.  UniFrac: a New Phylogenetic Method for Comparing Microbial Communities , 2005, Applied and Environmental Microbiology.

[94]  K. Desager,et al.  The importance of the development of the intestinal microbiota in infancy , 2009, Current opinion in pediatrics.

[95]  R. Knight,et al.  Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns , 2010, Proceedings of the National Academy of Sciences.

[96]  C. Surawicz,et al.  Fecal Flora Reconstitution for Recurrent Clostridium difficile Infection: Results and Methodology , 2010, Journal of clinical gastroenterology.

[97]  N. Wight Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review. , 2003, The Journal of pediatrics.

[98]  P. A. van den Brandt,et al.  Factors Influencing the Composition of the Intestinal Microbiota in Early Infancy , 2006, Pediatrics.

[99]  J. Jansson,et al.  Molecular analysis of the gut microbiota of identical twins with Crohn's disease , 2008, The ISME Journal.

[100]  J. Gordon,et al.  Honor thy symbionts , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[101]  N. Kollias,et al.  Infant Skin Microstructure Assessed In Vivo Differs from Adult Skin in Organization and at the Cellular Level , 2010, Pediatric dermatology.

[102]  L. Mcfarland,et al.  Epidemiology, Risk Factors and Treatments for Antibiotic-Associated Diarrhea , 1998, Digestive Diseases.

[103]  A. Andoh,et al.  Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease. , 2006, World journal of gastroenterology.

[104]  P. L. Stark,et al.  The microbial ecology of the large bowel of breast-fed and formula-fed infants during the first year of life. , 1982, Journal of medical microbiology.

[105]  P. Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[106]  Jeffrey I. Gordon,et al.  Angiogenins: a new class of microbicidal proteins involved in innate immunity , 2003, Nature Immunology.

[107]  P. Kero,et al.  Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months , 2000, Archives of disease in childhood. Fetal and neonatal edition.

[108]  D. Cook,et al.  Effect of Infant Feeding on the Risk of Obesity Across the Life Course: A Quantitative Review of Published Evidence , 2005, Pediatrics.

[109]  B. Stoll,et al.  Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated With Increased Rates of Necrotizing Enterocolitis and Death for Extremely Low Birth Weight Infants , 2009, Pediatrics.

[110]  S. Walsh,et al.  Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial , 2005, Gut.

[111]  D. Relman,et al.  Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation , 2010, Proceedings of the National Academy of Sciences.

[112]  P. Huovinen,et al.  Long-term antimicrobial resistance in Escherichia coli from human intestinal microbiota after administration of clindamycin , 2007, Scandinavian journal of infectious diseases.

[113]  K. Wilson The microecology of Clostridium difficile. , 1993, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[114]  H. Wichmann,et al.  Mode of delivery and development of atopic disease during the first 2 years of life , 2004, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[115]  M. Pop,et al.  Metagenomic Analysis of the Human Distal Gut Microbiome , 2006, Science.

[116]  C. Di Lorenzo,et al.  Childhood Functional Gastrointestinal Disorders : Child / Adolescent , 2022 .

[117]  Camilia R. Martin,et al.  Intestinal immune defences and the inflammatory response in necrotising enterocolitis. , 2006, Seminars in fetal & neonatal medicine.

[118]  H. Harmsen,et al.  Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. , 2000, Journal of pediatric gastroenterology and nutrition.

[119]  D. Antonopoulos,et al.  Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. , 2008, The Journal of infectious diseases.

[120]  Howard Ochman,et al.  Comparative Metagenomics and Population Dynamics of the Gut Microbiota in Mother and Infant , 2010, Genome biology and evolution.

[121]  J. Meinzen-Derr,et al.  Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death , 2009, Journal of Perinatology.

[122]  J. Vederas,et al.  Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile , 2010, Proceedings of the National Academy of Sciences.

[123]  J. Picaud,et al.  Dynamics and clinical evolution of bacterial gut microflora in extremely premature patients. , 2011, The Journal of pediatrics.

[124]  R. Knight,et al.  The Human Microbiome Project , 2007, Nature.

[125]  J. Neu,et al.  Intestinal microbiota development in the premature neonate: establishment of a lasting commensal relationship? , 2008, Nutrition reviews.

[126]  R Balfour Sartor,et al.  Microbial influences in inflammatory bowel diseases. , 2008, Gastroenterology.

[127]  D. Beard,et al.  Effects of metronidazole and oligofructose on faecal concentrations of sulphate-reducing bacteria and their activity in human volunteers , 2005, Scandinavian journal of gastroenterology.

[128]  Martin J. Blaser,et al.  Substantial Alterations of the Cutaneous Bacterial Biota in Psoriatic Lesions , 2008, PloS one.

[129]  P. V. Tearle,et al.  Bifidobacteria in the intestinal tract of infants: an in-vivo study. , 1976, Journal of medical microbiology.

[130]  A. Servin,et al.  Adhesion of probiotic strains to the intestinal mucosa and interaction with pathogens. , 2003, Best practice & research. Clinical gastroenterology.

[131]  M. Clerici,et al.  Early Impairment of Gut Function and Gut Flora Supporting a Role for Alteration of Gastrointestinal Mucosa in Human Immunodeficiency Virus Pathogenesis , 2007, Journal of Clinical Microbiology.

[132]  S. Massart,et al.  Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa , 2010, Proceedings of the National Academy of Sciences.

[133]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[134]  I. Adlerberth,et al.  Establishment of the gut microbiota in Western infants , 2009, Acta paediatrica.

[135]  P. Semik,et al.  Prevalence of Clostridium difficile colonization at admission to rehabilitation. , 2006, Archives of physical medicine and rehabilitation.

[136]  Walker Wa,et al.  Neonatal microbial flora and disease outcome. , 2008, Nestle Nutrition workshop series. Paediatric programme.

[137]  E. Telemo,et al.  Breast-feeding, infant formulas, and the immune system. , 2003, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[138]  J. Doré,et al.  Low counts of Faecalibacterium prausnitzii in colitis microbiota , 2009, Inflammatory bowel diseases.

[139]  A. Schuller,et al.  Exploring the oral microbiota of children at various developmental stages of their dentition in the relation to their oral health , 2011, BMC Medical Genomics.

[140]  Jeffrey I. Gordon,et al.  Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[141]  Daniel B. DiGiulio,et al.  Development of the Human Infant Intestinal Microbiota , 2007, PLoS biology.

[142]  P. Turnbaugh,et al.  The core gut microbiome, energy balance and obesity , 2009, The Journal of physiology.

[143]  S. Dowd,et al.  Diversity of the Human Skin Microbiome Early in Life , 2011, The Journal of investigative dermatology.

[144]  G. Redding,et al.  Childhood asthma hospitalization risk after cesarean delivery in former term and premature infants. , 2005, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[145]  D. Antonopoulos,et al.  16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis , 2009, The ISME Journal.

[146]  M. Ronaghi Pyrosequencing sheds light on DNA sequencing. , 2001, Genome research.

[147]  Aleksandar Milosavljevic,et al.  Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. , 2011, Gastroenterology.

[148]  N. Pace,et al.  Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases , 2007, Proceedings of the National Academy of Sciences.

[149]  H. Wichmann,et al.  Caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitisation during the first year of life , 2004, Archives of Disease in Childhood.

[150]  R. Vuento,et al.  Effects of mode of delivery and necrotising enterocolitis on the intestinal microflora in preterm infants , 2004, European Journal of Clinical Microbiology and Infectious Diseases.

[151]  J. Neu,et al.  The developing intestinal microbiome and its relationship to health and disease in the neonate , 2011, Journal of Perinatology.