Reframing the Teenage Wasteland: Adolescent Microbiota-Gut-Brain Axis

Human adolescence is arguably one of the most challenging periods of development. The young adult is exposed to a variety of stressors and environmental stimuli on a backdrop of significant physiological change and development, which is especially apparent in the brain. It is therefore unsurprising that many psychiatric disorders are first observable during this time. The human intestine is inhabited by trillions of microorganisms, and evidence from both preclinical and clinical research focusing on the established microbiota-gut-brain axis suggests that the etiology and pathophysiology of psychiatric disorders may be influenced by intestinal dysbiosis. Provocatively, many if not all of the challenges faced by the developing teen have a documented impact on these intestinal commensal microbiota. In this review, we briefly summarize what is known about the developing adolescent brain and intestinal microbiota, discuss recent research investigating the microbiota-gut-brain axis during puberty, and propose that pre- and probiotics may prove useful in both the prevention and treatment of psychiatric disorders specifically benefitting the young adult.

[1]  C. McCormick,et al.  Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats , 2008, Behavioural Brain Research.

[2]  M. Ventura,et al.  Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. , 2015, The Journal of pediatrics.

[3]  Carol A Tamminga,et al.  Frontal cortex function. , 2004, The American journal of psychiatry.

[4]  Adriana Galvan,et al.  The adolescent brain. , 2008, Developmental review : DR.

[5]  R. D. Romeo,et al.  Stress and the developing adolescent brain , 2013, Neuroscience.

[6]  John F. Cryan,et al.  Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour , 2015, Brain, Behavior, and Immunity.

[7]  M. L. Pucak,et al.  Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex , 1997, Neuroscience.

[8]  T. Dinan,et al.  Microbiota and neurodevelopmental windows: implications for brain disorders. , 2014, Trends in molecular medicine.

[9]  E. Miller,et al.  An integrative theory of prefrontal cortex function. , 2001, Annual review of neuroscience.

[10]  P. Rakić,et al.  Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  H. Loos,et al.  Synaptogenesis in human visual cortex — evidence for synapse elimination during normal development , 1982, Neuroscience Letters.

[12]  K. Aagaard,et al.  The microbiome, parturition, and timing of birth: more questions than answers. , 2014, Journal of reproductive immunology.

[13]  W. D. de Vos,et al.  Intestinal Microbiota in Healthy U.S. Young Children and Adults—A High Throughput Microarray Analysis , 2013, PloS one.

[14]  F. Perera,et al.  Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity , 2014, International Journal of Obesity.

[15]  T. Dinan,et al.  Mind-altering Microorganisms: the Impact of the Gut Microbiota on Brain and Behaviour , 2022 .

[16]  B. McEwen,et al.  Testosterone Cannot Activate an Adult-Like Stress Response in Prepubertal Male Rats , 2004, Neuroendocrinology.

[17]  J. Cryan,et al.  Adolescent Brain Vulnerability and Psychopathology Through the Generations: Role of Diet and Dopamine , 2014, Biological Psychiatry.

[18]  Stephen J. Smith,et al.  Neural activity and the dynamics of central nervous system development , 2004, Nature Neuroscience.

[19]  P. Scully,et al.  The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner , 2013, Molecular Psychiatry.

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

[21]  Ben A. Barres,et al.  Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner , 2012, Neuron.

[22]  R. Romeo.  Adolescence: a central event in shaping stress reactivity. , 2010, Developmental psychobiology.

[23]  Alan C. Evans,et al.  Brain development during childhood and adolescence: a longitudinal MRI study , 1999, Nature Neuroscience.

[24]  P. O’Toole,et al.  Next-generation sequencing technologies and their impact on microbial genomics. , 2013, Briefings in functional genomics.

[25]  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.

[26]  M. Messaoudi,et al.  Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers , 2011, Gut microbes.

[27]  D. Mathalon,et al.  A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. , 1994, Archives of neurology.

[28]  E. Bezirtzoglou,et al.  Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH). , 2011, Anaerobe.

[29]  B. J. Casey,et al.  Quantitative magnetic resonance imaging of human brain development: ages 4-18. , 1996, Cerebral cortex.

[30]  J. Foster,et al.  The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse , 2013, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[31]  L. Spear.  The adolescent brain and age-related behavioral manifestations , 2000, Neuroscience & Biobehavioral Reviews.

[32]  G. MacQueen,et al.  Bacterial infection causes stress-induced memory dysfunction in mice , 2010, Gut.

[33]  M. Kavaliers,et al.  Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: Implications for autism spectrum disorders , 2014, International Journal of Developmental Neuroscience.

[34]  Ian B. Jeffery,et al.  The microbiota link to irritable bowel syndrome , 2012, Gut microbes.

[35]  M. Sears,et al.  Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months , 2013, Canadian Medical Association Journal.

[36]  J. Koolhaas,et al.  Social stress during adolescence in Wistar rats induces social anxiety in adulthood without affecting brain monoaminergic content and activity , 2007, Physiology & Behavior.

[37]  L. Steinberg.  A Social Neuroscience Perspective on Adolescent Risk-Taking. , 2008, Developmental review : DR.

[38]  P. Bercik.  The microbiota–gut–brain axis: learning from intestinal bacteria? , 2011, Gut.

[39]  Sébastien Matamoros,et al.  Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity , 2014, Proceedings of the National Academy of Sciences.

[40]  V. Menon,et al.  White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. , 2005, Cerebral cortex.

[41]  T. Paus,et al.  Why do many psychiatric disorders emerge during adolescence? , 2008, Nature Reviews Neuroscience.

[42]  Olga V. Demler,et al.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[43]  R. P. Ross,et al.  Parenteral Antibiotics Reduce Bifidobacteria Colonization and Diversity in Neonates , 2010, International journal of microbiology.

[44]  P. Scully,et al.  Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses , 2009, Biological Psychiatry.

[45]  Alexander V. Zhdanov,et al.  Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood , 2015, Psychoneuroendocrinology.

[46]  N. De Stefano,et al.  Longitudinal changes in grey and white matter during adolescence , 2010, NeuroImage.

[47]  A. Toga,et al.  Mapping Continued Brain Growth and Gray Matter Density Reduction in Dorsal Frontal Cortex: Inverse Relationships during Postadolescent Brain Maturation , 2001, The Journal of Neuroscience.

[48]  E. Mayer,et al.  Principles and clinical implications of the brain–gut–enteric microbiota axis , 2009, Nature Reviews Gastroenterology &Hepatology.

[49]  T. Dinan,et al.  Melancholic microbes: a link between gut microbiota and depression? , 2013, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[50]  Kathrin Cohen Kadosh,et al.  The social brain in adolescence: Evidence from functional magnetic resonance imaging and behavioural studies , 2011, Neuroscience & Biobehavioral Reviews.

[51]  K. Svoboda,et al.  Experience-dependent structural synaptic plasticity in the mammalian brain , 2009, Nature Reviews Neuroscience.

[52]  J. Giedd.  Linking adolescent sleep, brain maturation, and behavior. , 2009, Journal of Adolescent Health.

[53]  John F. Cryan,et al.  Psychobiotics: A Novel Class of Psychotropic , 2013, Biological Psychiatry.

[54]  S. Finegold.  State of the art; microbiology in health and disease. Intestinal bacterial flora in autism. , 2011, Anaerobe.

[55]  P. Ducrotte,et al.  Efficacy and safety profile of LCR35 complete freeze-dried culture in irritable bowel syndrome: a randomized, double-blind study. , 2012, World journal of gastroenterology.

[56]  L. Spear.  Adolescents and alcohol: acute sensitivities, enhanced intake, and later consequences. , 2014, Neurotoxicology and teratology.

[57]  S. Collins,et al.  The microbiota–gut–brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? , 2014, The Journal of physiology.

[58]  G. Macfarlane,et al.  Variation in human intestinal microbiota with age. , 2002, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

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

[60]  D. Navajas,et al.  Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea , 2014, European Respiratory Journal.

[61]  T. Dinan,et al.  Review article: probiotics for the treatment of irritable bowel syndrome – focus on lactic acid bacteria , 2012, Alimentary pharmacology & therapeutics.

[62]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[63]  J. Foster,et al.  Reduced anxiety‐like behavior and central neurochemical change in germ‐free mice , 2011, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[64]  Jay N. Giedd,et al.  The influence of puberty on subcortical brain development , 2014, NeuroImage.

[65]  A. Logan,et al.  A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome , 2009, Gut pathogens.

[66]  J. Huizinga,et al.  Intestinal microbiota influence the early postnatal development of the enteric nervous system , 2014, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[67]  L. Spear,et al.  Developmental Cognitive Neuroscience Review Rewards, Aversions and Affect in Adolescence: Emerging Convergences across Laboratory Animal and Human Data , 2022 .

[68]  A. Mohammadi,et al.  The effects of probiotics on mental health and hypothalamic–pituitary–adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical workers , 2016, Nutritional neuroscience.

[69]  H. Forssberg,et al.  Normal gut microbiota modulates brain development and behavior , 2011, Proceedings of the National Academy of Sciences.

[70]  G. Boudry,et al.  Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects , 2010, Nutrition Research Reviews.

[71]  Suzanne E. Welcome,et al.  Mapping cortical change across the human life span , 2003, Nature Neuroscience.

[72]  L. Desbonnet,et al.  Microbiota is essential for social development in the mouse , 2013, Molecular Psychiatry.

[73]  A. Reiss,et al.  Brain development, gender and IQ in children. A volumetric imaging study. , 1996, Brain : a journal of neurology.

[74]  J. Doré,et al.  Intestinal Microbiota of 6-week-old Infants Across Europe: Geographic Influence Beyond Delivery Mode, Breast-feeding, and Antibiotics , 2010, Journal of pediatric gastroenterology and nutrition.

[75]  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.

[76]  L. Steinberg.  A dual systems model of adolescent risk-taking. , 2010, Developmental psychobiology.

[77]  Y. Chida,et al.  Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice , 2004, The Journal of physiology.

[78]  B. McEwen,et al.  Stress and the Adolescent Brain , 2006, Annals of the New York Academy of Sciences.

[79]  B. Cragg,et al.  The development of synapses in the visual system of the cat , 1975, The Journal of comparative neurology.

[80]  J. Ferreira,et al.  Adrenarche in the rat. , 2006, The Journal of endocrinology.

[81]  H. Akil,et al.  Pituitary-Adrenal Response to Ether Vapor in the Weanling Animal: Characterization of the Inhibitory Effect of Glucocorticoids on Adrenocorticotropin Secretion , 1993, Pediatric Research.

[82]  S. Levine,et al.  Postweaning development of negative feedback in the pituitary-adrenal system of the rat. , 1973, Neuroendocrinology.

[83]  S. Blakemore,et al.  Development of the adolescent brain: implications for executive function and social cognition. , 2006 .

[84]  P. Huttenlocher.  Synaptic density in human frontal cortex - developmental changes and effects of aging. , 1979, Brain research.

[85]  M. Sekelja,et al.  Correlation between the human fecal microbiota and depression , 2014, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[86]  David Padua,et al.  Altered brain‐gut axis in autism: Comorbidity or causative mechanisms? , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[87]  L. Hoyles,et al.  Examination of faecal Bifidobacterium populations in breast- and formula-fed infants during the first 18 months of life. , 2010, Microbiology.

[88]  J. Groeger,et al.  Cognitive performance in irritable bowel syndrome: evidence of a stress-related impairment in visuospatial memory , 2013, Psychological Medicine.

[89]  P. Cotter,et al.  Composition of the early intestinal microbiota , 2012, Gut microbes.

[90]  F. Benes,et al.  Myelination of cortical-hippocampal relays during late adolescence. , 1989, Schizophrenia bulletin.

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

[92]  P S Goldman-Rakic,et al.  Synaptogenesis in the prefrontal cortex of rhesus monkeys. , 1994, Cerebral cortex.

[93]  Bita Moghaddam,et al.  The neurobiology of adolescence: Changes in brain architecture, functional dynamics, and behavioral tendencies , 2011, Neuroscience & Biobehavioral Reviews.

[94]  B. McEwen,et al.  Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity. , 2006, Endocrinology.

[95]  Sarah-Jayne Blakemore,et al.  Brain development during puberty: state of the science. , 2006, Developmental science.

[96]  P. Portincasa,et al.  Microbiota in health and irritable bowel syndrome: current knowledge, perspectives and therapeutic options , 2013, Scandinavian journal of gastroenterology.

[97]  A. Kraneveld,et al.  Altered gut microbiota and activity in a murine model of autism spectrum disorders , 2014, Brain, Behavior, and Immunity.

[98]  S. Andersen,et al.  Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model , 2008, Synapse.

[99]  S. Collins.  A role for the gut microbiota in IBS , 2014, Nature Reviews Gastroenterology &Hepatology.

[100]  L. Colzato,et al.  A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood , 2015, Brain, Behavior, and Immunity.

[101]  C. McCormick,et al.  HPA function in adolescence: Role of sex hormones in its regulation and the enduring consequences of exposure to stressors , 2007, Pharmacology Biochemistry and Behavior.

[102]  J. Cryan,et al.  The microbiome‐gut‐brain axis: from bowel to behavior , 2011, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.