The Impact of Microbiota on Brain and Behavior: Mechanisms & Therapeutic Potential

  • Yuliya E. Borre
  • Rachel D. Moloney
  • Gerard Clarke
  • Timothy G. Dinan
  • John F. Cryan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 817)

Abstract

There is increasing evidence that host-microbe interactions play a key role in maintaining homeostasis. Alterations in gut microbial composition is associated with marked changes in behaviors relevant to mood, pain and cognition, establishing the critical importance of the bi-directional pathway of communication between the microbiota and the brain in health and disease. Dysfunction of the microbiome-brain-gut axis has been implicated in stress-related disorders such as depression, anxiety and irritable bowel syndrome and neurodevelopmental disorders such as autism. Bacterial colonization of the gut is central to postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Moreover, there is now expanding evidence for the view that enteric microbiota plays a role in early programming and later response to acute and chronic stress. This view is supported by studies in germ-free mice and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics. Although communication between gut microbiota and the CNS are not fully elucidated, neural, hormonal, immune and metabolic pathways have been suggested. Thus, the concept of a microbiome-brain-gut axis is emerging, suggesting microbiota-modulating strategies may be a tractable therapeutic approach for developing novel treatments for CNS disorders.

Keywords

Fatigue Fermentation Depression Schizophrenia Serotonin 

Abbreviations

5-HT

5-Hydroxytryptamine

APC

Antigen presenting cell

ASD

Autism spectrum disorder

BDNF

Brain derived neurotrophic factor

CNS

Central nervous system

DC

Dendritic cell

DHA

Docosahexaenoic acid

DSS

Dextran sodium sulphate

EC

Enteroendocrine cells

ECC

Enterochromaffin cells

ENS

Enteric nervous system

EPA

Eicosapentaenoic acid

GABA

Gamma-aminobutyric acid

GALT

Gut-associated lymphoid tissues

GI

Gastrointestinal

HDAC

Histone deacetylase

HPA

Hypothalamic-pituitary-adrenal axis

IBS

Irritable bowel syndrome

IDO

Indoleamine-2,3-dioxygenase

NMDAR

N-methyl-d-aspartate receptor

NPY

Neuropeptide Y

SCFA

Short chain fatty acid

SSRI

Selective serotonin reuptake inhibitor

TCA

Tricyclic antidepressant

TDO

Tryptophan 2,3-dioxygenase

Treg

The regulatory T cells

References

  1. 1.
    Gill SR et al (2006) Metagenomic analysis of the human distal gut microbiome. Science 312(5778):1355–1359PubMedCentralPubMedGoogle Scholar
  2. 2.
    De Filippo C et al (2010) Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 107(33):14691–14696PubMedCentralPubMedGoogle Scholar
  3. 3.
    Arumugam M et al (2011) Enterotypes of the human gut microbiome. Nature 473(7346):174–180PubMedCentralPubMedGoogle Scholar
  4. 4.
    Eckburg PB et al (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638PubMedCentralPubMedGoogle Scholar
  5. 5.
    Benno Y, Sawada K, Mitsuoka T (1984) The intestinal microflora of infants: composition of fecal flora in breast-fed and bottle-fed infants. Microbiol Immunol 28(9):975–986PubMedGoogle Scholar
  6. 6.
    Douglas-Escobar M, Elliott E, Neu J (2013) Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr 167(4):374–379PubMedGoogle Scholar
  7. 7.
    Metchnikoff E. Essais optimistes. 1907, Paris,: A. Maloine. 3 p. l., iii, 438 pGoogle Scholar
  8. 8.
    Bengmark S (2013) Gut microbiota, immune development and function. Pharmacol Res 69(1):87–113PubMedGoogle Scholar
  9. 9.
    Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10(11):735–742PubMedGoogle Scholar
  10. 10.
    Diamond B et al (2011) It takes guts to grow a brain: increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. Bioessays 33(8):588–591PubMedGoogle Scholar
  11. 11.
    Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behavior. Nat Rev Neurosci 13(10):701–712PubMedGoogle Scholar
  12. 12.
    Desbonnet L et al (2010) Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170(4):1179–1188PubMedGoogle Scholar
  13. 13.
    Bravo JA et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108(38):16050–16055PubMedCentralPubMedGoogle Scholar
  14. 14.
    Savignac HM et al (2013) Prebiotic feeding elevates central, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem Int 63(8):756–764PubMedCentralPubMedGoogle Scholar
  15. 15.
    Messaoudi M et al (2011) Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr 105(5):755–764PubMedGoogle Scholar
  16. 16.
    Rao AV et al (2009) A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog 1(1):6PubMedCentralPubMedGoogle Scholar
  17. 17.
    Tillisch K et al (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144(7):1394–1401, 1401 e1–e4Google Scholar
  18. 18.
    Fouhy F et al (2012) Composition of the early intestinal microbiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps. Gut Microbes 3(3):203–220PubMedCentralPubMedGoogle Scholar
  19. 19.
    Fanca-Berthon P et al (2010) Intrauterine growth restriction not only modifies the cecocolonic microbiota in neonatal rats but also affects its activity in young adult rats. J Pediatr Gastroenterol Nutr 51(4):402–413PubMedGoogle Scholar
  20. 20.
    Costello EK et al (2012) The application of ecological theory toward an understanding of the human microbiome. Science 336(6086):1255–1262PubMedGoogle Scholar
  21. 21.
    Relman DA (2012) The human microbiome: ecosystem resilience and health. Nutr Rev 70(Suppl 1):S2–S9PubMedCentralPubMedGoogle Scholar
  22. 22.
    Gregory KE (2011) Microbiome aspects of perinatal and neonatal health. J Perinat Neonatal Nurs 25(2):158–162, quiz 163–164PubMedCentralPubMedGoogle Scholar
  23. 23.
    Adlerberth I, Wold AE (2009) Establishment of the gut microbiota in Western infants. Acta Paediatr 98(2):229–238PubMedGoogle Scholar
  24. 24.
    Funkhouser LJ, Bordenstein SR (2013) Mom knows best: the universality of maternal microbial transmission. PLoS Biol 11(8):e1001631PubMedCentralPubMedGoogle Scholar
  25. 25.
    DiGiulio DB et al (2010) Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 64(1):38–57PubMedCentralPubMedGoogle Scholar
  26. 26.
    Dominguez-Bello MG et al (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107(26):11971–11975PubMedCentralPubMedGoogle Scholar
  27. 27.
    Gronlund MM et al (2007) Maternal breast-milk and intestinal bifidobacteria guide the compositional development of the Bifidobacterium microbiota in infants at risk of allergic disease. Clin Exp Allergy 37(12):1764–1772PubMedGoogle Scholar
  28. 28.
    Guaraldi F, Salvatori G (2012) Effect of breast and formula feeding on gut microbiota shaping in newborns. Front Cell Infect Microbiol 2:94PubMedCentralPubMedGoogle Scholar
  29. 29.
    Hegde S, Munshi AK (1998) Influence of the maternal vaginal microbiota on the oral microbiota of the newborn. J Clin Pediatr Dent 22(4):317–321PubMedGoogle Scholar
  30. 30.
    Fanaro S et al (2003) Fecal flora measurements of breastfed infants using an integrated transport and culturing system. Acta Paediatr 92(5):634–635PubMedGoogle Scholar
  31. 31.
    Cho CE, Norman M (2013) Cesarean section and development of the immune system in the offspring. Am J Obstet Gynecol 208(4):249–254PubMedGoogle Scholar
  32. 32.
    Romero R, Korzeniewski SJ (2013) Are infants born by elective cesarean delivery without labor at risk for developing immune disorders later in life? Am J Obstet Gynecol 208(4):243–246PubMedGoogle Scholar
  33. 33.
    Maynard CL et al (2012) Reciprocal interactions of the intestinal microbiota and immune system. Nature 489(7415):231–241PubMedGoogle Scholar
  34. 34.
    Barrett E et al (2013) The individual-specific and diverse nature of the preterm infant microbiota. Arch Dis Child Fetal Neonatal Ed 98:F334–F340Google Scholar
  35. 35.
    Parfrey LW, Knight R (2012) Spatial and temporal variability of the human microbiota. Clin Microbiol Infect 18(Suppl 4):8–11PubMedGoogle Scholar
  36. 36.
    Turnbaugh PJ et al (2009) A core gut microbiome in obese and lean twins. Nature 457(7228):480–484PubMedCentralPubMedGoogle Scholar
  37. 37.
    Lozupone CA et al (2012) Diversity, stability and resilience of the human gut microbiota. Nature 489(7415):220–230PubMedCentralPubMedGoogle Scholar
  38. 38.
    Foster JA, McVey Neufeld KA (2013) Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36(5):305–312Google Scholar
  39. 39.
    Marques TM et al (2010) Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol 21(2):149–156PubMedGoogle Scholar
  40. 40.
    Johnson CL, Versalovic J (2012) The human microbiome and its potential importance to pediatrics. Pediatrics 129(5):950–960PubMedCentralPubMedGoogle Scholar
  41. 41.
    Clarke G et al (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18(6):666–673PubMedGoogle Scholar
  42. 42.
    Claesson MJ et al (2011) Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A 108(Suppl 1):4586–4591PubMedCentralPubMedGoogle Scholar
  43. 43.
    Biagi E et al (2010) Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 5(5):e10667PubMedCentralPubMedGoogle Scholar
  44. 44.
    Claesson MJ et al (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488(7410):178–184PubMedGoogle Scholar
  45. 45.
    Kinross J, Nicholson JK (2012) Gut microbiota: dietary and social modulation of gut microbiota in the elderly. Nat Rev Gastroenterol Hepatol 9(10):563–564PubMedGoogle Scholar
  46. 46.
    Grenham S et al (2011) Brain-gut-microbe communication in health and disease. Front Physiol 2:94PubMedCentralPubMedGoogle Scholar
  47. 47.
    Cryan JF, O’Mahony SM (2011) The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 23(3):187–192PubMedGoogle Scholar
  48. 48.
    Aziz Q, Thompson DG (1998) Brain-gut axis in health and disease. Gastroenterology 114(3):559–578PubMedGoogle Scholar
  49. 49.
    Mayer EA (2011) Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 12(8):453–466PubMedGoogle Scholar
  50. 50.
    Bonaz BL, Bernstein CN (2013) Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144(1):36–49PubMedGoogle Scholar
  51. 51.
    Davari S et al (2013) Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis. Neuroscience 240:287–296PubMedGoogle Scholar
  52. 52.
    Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6(5):306–314PubMedGoogle Scholar
  53. 53.
    Bercik P (2011) The microbiota-gut-brain axis: learning from intestinal bacteria? Gut 60(3):288–289PubMedGoogle Scholar
  54. 54.
    Dinan TG, Cryan JF (2012) Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 37(9):1369–1378PubMedGoogle Scholar
  55. 55.
    O’Mahony SM et al (2011) Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl) 214(1):71–88Google Scholar
  56. 56.
    Mertz H (2002) Role of the brain and sensory pathways in gastrointestinal sensory disorders in humans. Gut 51(Suppl 1):i29–i33PubMedCentralPubMedGoogle Scholar
  57. 57.
    Kunze WA et al (2009) Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. J Cell Mol Med 13(8B):2261–2270PubMedGoogle Scholar
  58. 58.
    McVey Neufeld KA et al (2013) The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol Motil 25(2):183–e88PubMedGoogle Scholar
  59. 59.
    Browning KN, Mendelowitz D (2003) Musings on the wanderer: what’s new in our understanding of vago-vagal reflexes?: II. Integration of afferent signaling from the viscera by the nodose ganglia. Am J Physiol Gastrointest Liver Physiol 284(1):G8–G14PubMedGoogle Scholar
  60. 60.
    Forsythe P et al (2010) Mood and gut feelings. Brain Behav Immun 24(1):9–16PubMedGoogle Scholar
  61. 61.
    Wang X et al (2002) Evidences for vagus nerve in maintenance of immune balance and transmission of immune information from gut to brain in STM-infected rats. World J Gastroenterol 8(3):540–545PubMedGoogle Scholar
  62. 62.
    Borovikova LV et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462PubMedGoogle Scholar
  63. 63.
    Lyte M et al (2006) Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol Behav 89(3):350–357PubMedGoogle Scholar
  64. 64.
    Perez-Burgos A et al (2013) Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents. Am J Physiol Gastrointest Liver Physiol 304(2):G211–G220PubMedGoogle Scholar
  65. 65.
    Bercik P et al (2011) The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 23(12):1132–1139PubMedCentralPubMedGoogle Scholar
  66. 66.
    Bercik P et al (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141(2):599–609, 609. e1–e3Google Scholar
  67. 67.
    Costedio MM, Hyman N, Mawe GM (2007) Serotonin and its role in colonic function and in gastrointestinal disorders. Dis Colon Rectum 50(3):376–388PubMedGoogle Scholar
  68. 68.
    McLean PG, Borman RA, Lee K (2007) 5-HT in the enteric nervous system: gut function and neuropharmacology. Trends Neurosci 30(1):9–13PubMedGoogle Scholar
  69. 69.
    Cryan JF, Leonard BE (2000) 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol 15(2):113–135PubMedGoogle Scholar
  70. 70.
    Folks DG (2004) The interface of psychiatry and irritable bowel syndrome. Curr Psychiatry Rep 6(3):210–215PubMedGoogle Scholar
  71. 71.
    Tack J et al (2006) A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 55(8):1095–1103PubMedCentralPubMedGoogle Scholar
  72. 72.
    Weilburg JB (2004) An overview of SSRI and SNRI therapies for depression. Manag Care 13(6 Suppl Depression):25–33Google Scholar
  73. 73.
    Creed F et al (2003) The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 124(2):303–317PubMedGoogle Scholar
  74. 74.
    Browne CA et al (2012) An effective dietary method for chronic tryptophan depletion in two mouse strains illuminates a role for 5-HT in nesting behavior. Neuropharmacology 62(5–6):1903–1915PubMedGoogle Scholar
  75. 75.
    Moore P et al (2000) Clinical and physiological consequences of rapid tryptophan depletion. Neuropsychopharmacology 23(6):601–622PubMedGoogle Scholar
  76. 76.
    Desbonnet L et al (2008) The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res 43(2):164–174PubMedGoogle Scholar
  77. 77.
    Wikoff WR et al (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 106(10):3698–3703PubMedCentralPubMedGoogle Scholar
  78. 78.
    Schwarcz R et al (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13(7):465–477PubMedCentralPubMedGoogle Scholar
  79. 79.
    Myint AM (2012) Kynurenines: from the perspective of major psychiatric disorders. FEBS J 279(8):1375–1385PubMedGoogle Scholar
  80. 80.
    Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34(2):136–143PubMedGoogle Scholar
  81. 81.
    Ruddick JP et al (2006) Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med 8(20):1–27PubMedGoogle Scholar
  82. 82.
    Clarke G et al (2009) Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterol 9:6PubMedCentralPubMedGoogle Scholar
  83. 83.
    Clarke G et al (2009) Irritable bowel syndrome: towards biomarker identification. Trends Mol Med 15(10):478–489PubMedGoogle Scholar
  84. 84.
    Fitzgerald P et al (2008) Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity. Neurogastroenterol Motil 20(12):1291–1297PubMedGoogle Scholar
  85. 85.
    Bercik P et al (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139(6):2102–2112 e1Google Scholar
  86. 86.
    Li G, Young KD (2013) Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan. Microbiology 159(Pt 2):402–410PubMedGoogle Scholar
  87. 87.
    Cameron J, Doucet E (2007) Getting to the bottom of feeding behavior: who’s on top? Appl Physiol Nutr Metab 32(2):177–189PubMedGoogle Scholar
  88. 88.
    Wren AM, Bloom SR (2007) Gut hormones and appetite control. Gastroenterology 132(6):2116–2130PubMedGoogle Scholar
  89. 89.
    Rustay NR et al (2005) Galanin impairs performance on learning and memory tasks: findings from galanin transgenic and GAL-R1 knockout mice. Neuropeptides 39(3):239–243PubMedGoogle Scholar
  90. 90.
    Wrenn CC et al (2004) Learning and memory performance in mice lacking the GAL-R1 subtype of galanin receptor. Eur J Neurosci 19(5):1384–1396PubMedGoogle Scholar
  91. 91.
    Giordano R et al (2006) Neuroregulation of the hypothalamus-pituitary-adrenal (HPA) axis in humans: effects of GABA-, mineralocorticoid-, and GH-Secretagogue-receptor modulation. ScientificWorldJournal 6:1–11PubMedGoogle Scholar
  92. 92.
    Jaszberenyi M et al (2006) Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin. Horm Behav 50(2):266–273PubMedGoogle Scholar
  93. 93.
    Lu XY et al (2006) Leptin: a potential novel antidepressant. Proc Natl Acad Sci U S A 103(5):1593–1598PubMedCentralPubMedGoogle Scholar
  94. 94.
    Finger BC, Dinan TG, Cryan JF (2010) Leptin-deficient mice retain normal appetitive spatial learning yet exhibit marked increases in anxiety-related behaviors. Psychopharmacology (Berl) 210(4):559–568Google Scholar
  95. 95.
    Hirano S, Miyata S, Kamei J (2007) Antidepressant-like effect of leptin in streptozotocin-induced diabetic mice. Pharmacol Biochem Behav 86(1):27–31PubMedGoogle Scholar
  96. 96.
    Lesniewska V et al (2006) Effect on components of the intestinal microflora and plasma neuropeptide levels of feeding Lactobacillus delbrueckii, Bifidobacterium lactis, and inulin to adult and elderly rats. Appl Environ Microbiol 72(10):6533–6538PubMedCentralPubMedGoogle Scholar
  97. 97.
    Di Giancamillo A et al (2008) Effects of orally administered probiotic Pediococcus acidilactici on the small and large intestine of weaning piglets. A qualitative and quantitative micro-anatomical study. Histol Histopathol 23(6):651–664PubMedGoogle Scholar
  98. 98.
    Schele E et al (2013) The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (BDNF) in the central nervous system. Endocrinology 154(10):3643–3651PubMedGoogle Scholar
  99. 99.
    Holzer P, Reichmann F, Farzi A (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46(6):261–274PubMedCentralPubMedGoogle Scholar
  100. 100.
    O’Malley D et al (2014) Differential visceral pain sensitivity and colonic morphology in four common laboratory rat strains. Exp Physiol 99:359–367Google Scholar
  101. 101.
    Macpherson AJ, Uhr T (2004) Compartmentalization of the mucosal immune responses to commensal intestinal bacteria. Ann N Y Acad Sci 1029:36–43PubMedGoogle Scholar
  102. 102.
    Vighi G et al (2008) Allergy and the gastrointestinal system. Clin Exp Immunol 153(Suppl 1):3–6PubMedCentralPubMedGoogle Scholar
  103. 103.
    Bilbo SD, Schwarz JM (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33(3):267–286PubMedCentralPubMedGoogle Scholar
  104. 104.
    Dantzer R (2009) Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am 29(2):247–264PubMedCentralPubMedGoogle Scholar
  105. 105.
    Lotrich FE et al (2011) The role of inflammation in the pathophysiology of depression: different treatments and their effects. J Rheumatol Suppl 88:48–54PubMedGoogle Scholar
  106. 106.
    Ratnayake U et al (2013) Cytokines and the neurodevelopmental basis of mental illness. Front Neurosci 7:180PubMedCentralPubMedGoogle Scholar
  107. 107.
    Dinan TG, Stanton C, Cryan JF (2013) Psychobiotics: a novel class of psychotropic. Biol Psychiatry 74:720–726Google Scholar
  108. 108.
    Konieczna P et al (2012) Portrait of an immunoregulatory Bifidobacterium. Gut Microbes 3(3):261–266PubMedCentralPubMedGoogle Scholar
  109. 109.
    Macpherson AJ, Uhr T (2002) Gut flora–mechanisms of regulation. Eur J Surg Suppl 587:53–57PubMedGoogle Scholar
  110. 110.
    Macfarlane S, Macfarlane GT (2003) Regulation of short-chain fatty acid production. Proc Nutr Soc 62(1):67–72PubMedGoogle Scholar
  111. 111.
    Kimura I et al (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4:1829PubMedCentralPubMedGoogle Scholar
  112. 112.
    Steliou K et al (2012) Butyrate histone deacetylase inhibitors. Biores Open Access 1(4):192–198PubMedCentralPubMedGoogle Scholar
  113. 113.
    Schroeder FA et al (2007) Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol Psychiatry 62(1):55–64PubMedGoogle Scholar
  114. 114.
    MacFabe DF et al (2007) Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 176(1):149–169PubMedGoogle Scholar
  115. 115.
    MacFabe DF et al (2011) Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: relevance to autism spectrum disorder. Behav Brain Res 217(1):47–54PubMedGoogle Scholar
  116. 116.
    Stilling RM, Dinan TG, Cryan JF (2014) Microbial genes, brain & behavior – epigenetic regulation of the gut-brain axis. Genes Brain Behav 13(1):69–86PubMedGoogle Scholar
  117. 117.
    Neufeld KM et al (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23(3):255–264, e119Google Scholar
  118. 118.
    Diaz Heijtz R et al (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108(7):3047–3052PubMedGoogle Scholar
  119. 119.
    Nishino R et al (2013) Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterol Motil 25:521–528PubMedGoogle Scholar
  120. 120.
    Gulati AS et al (2012) Mouse background strain profoundly influences Paneth cell function and intestinal microbial composition. PLoS One 7(2):e32403PubMedCentralPubMedGoogle Scholar
  121. 121.
    Olivares M, Laparra JM, Sanz Y (2013) Host genotype, intestinal microbiota and inflammatory disorders. Br J Nutr 109(Suppl 2):S76–S80PubMedGoogle Scholar
  122. 122.
    Desbonnet L et al (2014) Microbiota is essential for social development in the mouse. Mol Psychiatry 19:146–148Google Scholar
  123. 123.
    Gareau MG et al (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60(3):307–317PubMedGoogle Scholar
  124. 124.
    Sudo N et al (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1):263–275PubMedCentralPubMedGoogle Scholar
  125. 125.
    Lakhan SE, Caro M, Hadzimichalis N (2013) NMDA receptor activity in neuropsychiatric disorders. Front Psychiatry 4:52PubMedCentralPubMedGoogle Scholar
  126. 126.
    Rea MC et al (2011) Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc Natl Acad Sci U S A 108(Suppl 1):4639–4644PubMedCentralPubMedGoogle Scholar
  127. 127.
    Murphy R, Stewart AW, Braithwaite I, Beasley R, Hancox RJ, Mitchell EA; the ISAAC Phase Three Study Group. Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study. Int J Obes (Lond). 2013 Nov 21Google Scholar
  128. 128.
    Verdu EF et al (2006) Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 55(2):182–190PubMedCentralPubMedGoogle Scholar
  129. 129.
    Fouhy F et al (2012) High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother 56(11):5811–5820PubMedCentralPubMedGoogle Scholar
  130. 130.
    Ohland CL et al (2013) Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology 38:1738–1747Google Scholar
  131. 131.
    Matthews DM, Jenks SM (2013) Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav Processes 96:27–35Google Scholar
  132. 132.
    Hsiao EY et al (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–1463Google Scholar
  133. 133.
    Rousseaux C et al (2007) Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 13(1):35–37PubMedGoogle Scholar
  134. 134.
    McKernan DP et al (2010) The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. Neurogastroenterol Motil 22(9):1029–1035, e268Google Scholar
  135. 135.
    Johnson AC, Greenwood-Van Meerveld B, McRorie J (2011) Effects of Bifidobacterium infantis 35624 on post-inflammatory visceral hypersensitivity in the rat. Dig Dis Sci 56(11):3179–3186PubMedGoogle Scholar
  136. 136.
    Benton D, Williams C, Brown A (2007) Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr 61(3):355–361PubMedGoogle Scholar
  137. 137.
    Tillisch K et al (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144:1394–1401Google Scholar
  138. 138.
    Yang J et al (2007) Epigenetic marks in cloned rhesus monkey embryos: comparison with counterparts produced in vitro. Biol Reprod 76(1):36–42PubMedGoogle Scholar
  139. 139.
    Petschow B et al (2013) Probiotics, prebiotics, and the host microbiome: the science of translation. Ann N Y Acad Sci 1306(1):1–17PubMedGoogle Scholar
  140. 140.
    Saulnier DM et al (2013) The intestinal microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes 4(1):17–27PubMedCentralPubMedGoogle Scholar
  141. 141.
    Drakoularakou A et al (2010) A double-blind, placebo-controlled, randomized human study assessing the capacity of a novel galacto-oligosaccharide mixture in reducing travellers’ diarrhoea. Eur J Clin Nutr 64(2):146–152PubMedGoogle Scholar
  142. 142.
    van Vlies N et al (2012) Effects of short-chain galacto- and long-chain fructo-oligosaccharides on systemic and local immune status during pregnancy. J Reprod Immunol 94(2):161–168PubMedGoogle Scholar
  143. 143.
    Vulevic J et al (2008) Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. Am J Clin Nutr 88(5):1438–1446PubMedGoogle Scholar
  144. 144.
    Hornig M (2013) The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol 25:488–795Google Scholar
  145. 145.
    McEwen BS (2012) Brain on stress: how the social environment gets under the skin. Proc Natl Acad Sci U S A 109(Suppl 2):17180–17185PubMedCentralPubMedGoogle Scholar
  146. 146.
    Nutt DJ, Malizia AL (2004) Structural and functional brain changes in posttraumatic stress disorder. J Clin Psychiatry 65(Suppl 1):11–17PubMedGoogle Scholar
  147. 147.
    Lupien SJ et al (2009) Effects of stress throughout the lifespan on the brain, behavior and cognition. Nat Rev Neurosci 10(6):434–445PubMedGoogle Scholar
  148. 148.
    Bravo JA et al (2012) Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol 12(6):667–672PubMedGoogle Scholar
  149. 149.
    Bested AC, Logan AC, Selhub EM (2013) Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part I – autointoxication revisited. Gut Pathog 5(1):5PubMedCentralPubMedGoogle Scholar
  150. 150.
    Bested AC, Logan AC, Selhub EM (2013) Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III – convergence toward clinical trials. Gut Pathog 5(1):4PubMedCentralPubMedGoogle Scholar
  151. 151.
    Scott LV, Clarke G, Dinan TG (2013) The brain-gut axis: a target for treating stress-related disorders. In: Halaris A, Leonard BE (eds) Inflammation in Psychiatry, vol 28. Karger, BaselGoogle Scholar
  152. 152.
    Tannock GW, Savage DC (1974) Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract. Infect Immun 9(3):591–598PubMedCentralPubMedGoogle Scholar
  153. 153.
    Timoveyev L et al (2002) Stability to sound stress and changeability in intestinal microflora. Eur Psychiatry 17(Suppl 1):200Google Scholar
  154. 154.
    Suzuki K et al (1983) Effects of crowding and heat stress on intestinal flora, body weight gain, and feed efficiency of growing rats and chicks. Nihon Juigaku Zasshi 45(3):331–338PubMedGoogle Scholar
  155. 155.
    Bailey MT, Coe CL (1999) Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol 35(2):146–155PubMedGoogle Scholar
  156. 156.
    Garcia-Rodenas CL et al (2006) Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J Pediatr Gastroenterol Nutr 43(1):16–24PubMedGoogle Scholar
  157. 157.
    O’Mahony SM et al (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 65(3):263–267PubMedGoogle Scholar
  158. 158.
    Bailey MT et al (2011) Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 25(3):397–407PubMedCentralPubMedGoogle Scholar
  159. 159.
    Collins SM, Bercik P (2013) Gut microbiota: intestinal bacteria influence brain activity in healthy humans. Nat Rev Gastroenterol Hepatol 10:326–327Google Scholar
  160. 160.
    Barrett E et al (2012) Bifidobacterium breve with alpha-linolenic acid and linoleic acid alters fatty acid metabolism in the maternal separation model of irritable bowel syndrome. PLoS One 7(11):e48159PubMedCentralPubMedGoogle Scholar
  161. 161.
    Wall R et al (2010) Impact of administered Bifidobacterium on murine host fatty acid composition. Lipids 45(5):429–436PubMedGoogle Scholar
  162. 162.
    Wall R et al (2012) Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota. Am J Clin Nutr 95(5):1278–1287PubMedGoogle Scholar
  163. 163.
    Mocking RJ et al (2013) Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression. Psychoneuroendocrinology 38:1607–1617Google Scholar
  164. 164.
    Maes M (2008) The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 29(3):287–291PubMedGoogle Scholar
  165. 165.
    Gareau MG, Silva MA, Perdue MH (2008) Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med 8(4):274–281PubMedGoogle Scholar
  166. 166.
    Ait-Belgnaoui A et al (2012) Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37(11):1885–1895PubMedGoogle Scholar
  167. 167.
    Kendler KS, Thornton LM, Gardner CO (2000) Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry 157(8):1243–1251PubMedGoogle Scholar
  168. 168.
    Caspi A et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–389PubMedGoogle Scholar
  169. 169.
    Krogius-Kurikka L et al (2009) Microbial community analysis reveals high level phylogenetic alterations in the overall gastrointestinal microbiota of diarrhoea-predominant irritable bowel syndrome sufferers. BMC Gastroenterol 9:95PubMedCentralPubMedGoogle Scholar
  170. 170.
    Tana C et al (2010) Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol Motil 22(5):512–519, e114-5PubMedGoogle Scholar
  171. 171.
    Jeffery IB et al (2012) An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 61(7):997–1006PubMedGoogle Scholar
  172. 172.
    Gareau MG et al (2007) Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 56(11):1522–1528PubMedCentralPubMedGoogle Scholar
  173. 173.
    Craft N, Li H (2013) Response to the commentaries on the paper: Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 133:2295–2297Google Scholar
  174. 174.
    Myint AM et al (2013) Tryptophan metabolism and immunogenetics in major depression: a role for interferon-gamma gene. Brain Behav Immun 31:128–133PubMedGoogle Scholar
  175. 175.
    Tillisch K, Mayer EA (2005) Pain perception in irritable bowel syndrome. CNS Spectr 10(11):877–882PubMedGoogle Scholar
  176. 176.
    Davis KD et al (2008) Cortical thinning in IBS: implications for homeostatic, attention, and pain processing. Neurology 70(2):153–154PubMedGoogle Scholar
  177. 177.
    Ellingson BM et al (2013) Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome. Pain 154(9):1528–1541PubMedGoogle Scholar
  178. 178.
    Zucchelli M et al (2011) Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut 60(12):1671–1677PubMedCentralPubMedGoogle Scholar
  179. 179.
    Salonen A, de Vos WM, Palva A (2010) Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. Microbiology 156(Pt 11):3205–3215PubMedGoogle Scholar
  180. 180.
    Rajilic-Stojanovic M, Smidt H, de Vos WM (2007) Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol 9(9):2125–2136PubMedGoogle Scholar
  181. 181.
    Codling C et al (2010) A molecular analysis of fecal and mucosal bacterial communities in irritable bowel syndrome. Dig Dis Sci 55(2):392–397PubMedGoogle Scholar
  182. 182.
    Clarke G et al (2012) Review article: probiotics for the treatment of irritable bowel syndrome–focus on lactic acid bacteria. Aliment Pharmacol Ther 35(4):403–413PubMedGoogle Scholar
  183. 183.
    Moayyedi P et al (2010) The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 59(3):325–332PubMedGoogle Scholar
  184. 184.
    Parkes GC, Sanderson JD, Whelan K (2010) Treating irritable bowel syndrome with probiotics: the evidence. Proc Nutr Soc 69(2):187–194PubMedGoogle Scholar
  185. 185.
    Pimentel M, Lezcano S (2007) Irritable bowel syndrome: bacterial overgrowth—what’s known and what to do. Curr Treat Options Gastroenterol 10(4):328–337PubMedGoogle Scholar
  186. 186.
    Happe F et al (2006) Executive function deficits in autism spectrum disorders and attention-deficit/hyperactivity disorder: examining profiles across domains and ages. Brain Cogn 61(1):25–39PubMedGoogle Scholar
  187. 187.
    Grabrucker AM (2012) Environmental factors in autism. Front Psychiatry 3:118PubMedCentralPubMedGoogle Scholar
  188. 188.
    Coury DL et al (2012) Use of psychotropic medication in children and adolescents with autism spectrum disorders. Pediatrics 130(Suppl 2):S69–S76PubMedGoogle Scholar
  189. 189.
    Buie T et al (2010) Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics 125(Suppl 1):S19–S29PubMedGoogle Scholar
  190. 190.
    de Theije CG et al (2014) Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun 37:197–206Google Scholar
  191. 191.
    Mulle JG, Sharp WG, Cubells JF (2013) The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep 15(2):337PubMedCentralPubMedGoogle Scholar
  192. 192.
    Macfabe DF (2012) Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis 23Google Scholar
  193. 193.
    Kandel E (2012) The biological mind and art. A conversation with Eric Kandel, MD. Interview by Sue Pondrom. Ann Neurol 72(5):A7–A8PubMedGoogle Scholar
  194. 194.
    Squire LR, Wixted JT (2011) The cognitive neuroscience of human memory since H.M. Annu Rev Neurosci 34:259–288PubMedCentralPubMedGoogle Scholar
  195. 195.
    Hedges DW, Woon FL (2011) Early-life stress and cognitive outcome. Psychopharmacology (Berl) 214(1):121–130Google Scholar
  196. 196.
    Kennedy PJ et al (2012) Gut memories: towards a cognitive neurobiology of irritable bowel syndrome. Neurosci Biobehav Rev 36(1):310–340PubMedGoogle Scholar
  197. 197.
    Kennedy PJ et al (2013) Cognitive performance in irritable bowel syndrome: evidence of a stress-related impairment in visuospatial memory. Psychol Med 1–14Google Scholar
  198. 198.
    Fombonne E (2005) Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry 66(Suppl 10):3–8PubMedGoogle Scholar
  199. 199.
    Nolen-Hoeksema S, Larson J, Grayson C (1999) Explaining the gender difference in depressive symptoms. J Pers Soc Psychol 77(5):1061–1072PubMedGoogle Scholar
  200. 200.
    Bethea TC, Sikich L (2007) Early pharmacological treatment of autism: a rationale for developmental treatment. Biol Psychiatry 61(4):521–537PubMedCentralPubMedGoogle Scholar
  201. 201.
    Borody TJ, Khoruts A (2012) Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 9(2):88–96Google Scholar
  202. 202.
    Damman CJ et al (2012) The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol 107(10):1452–1459PubMedGoogle Scholar
  203. 203.
    van Nood E et al (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368(5):407–415PubMedGoogle Scholar
  204. 204.
    Goehler LE, Park SM, Opitz N, Lyte M, Gaykema RP (2008) Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun 22(3):354–366PubMedCentralPubMedGoogle Scholar
  205. 205.
    Lyte M, Varcoe JJ, Bailey MT (1998) Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol Behav 65(1):63–68PubMedGoogle Scholar
  206. 206.
    Arseneault-Bréard J, Rondeau I, Gilbert K, Girard SA, Tompkins TA, Godbout R, Rousseau G (2012) Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model. Br J Nutr 107(12):1793–1799PubMedGoogle Scholar
  207. 207.
    Gilbert K, Arseneault-Bréard J, Flores Monaco F, Beaudoin A, Bah TM, Tompkins TA, Godbout R, Rousseau G (2013) Attenuation of post-myocardial infarction depression in rats by n-3 fatty acids or probiotics starting after the onset of reperfusion. Br J Nutr 109(1):50–56PubMedGoogle Scholar
  208. 208.
    Li W, Dowd SE, Scurlock B, Acosta-Martinez V, Lyte M (2009) Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria. Physiol Behav 96(4–5):557–567PubMedGoogle Scholar

Copyright information

© Springer New York 2014

Authors and Affiliations

  • Yuliya E. Borre
    • 1
  • Rachel D. Moloney
    • 1
    • 2
  • Gerard Clarke
    • 3
  • Timothy G. Dinan
    • 2
  • John F. Cryan
    • 4
  1. 1.Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic CentreUniversity College CorkCorkIreland
  2. 2.Department of PsychiatryUniversity College CorkCorkIreland
  3. 3.Department of Psychiatry and Laboratory of NeuroGastroenterology Alimentary Pharmabiotic CentreUniversity College CorkCorkIreland
  4. 4.Department of Anatomy and NeuroscienceUniversity College CorkCorkIreland

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