Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis

Genes, Brain and Behavior

Volumn 13, Issue 1, 2014, Pages 69-86

  Stilling, R M ^a   Dinan, T G ^a,b   Cryan, J F ^a,c  

^a UNIVERSITY COLLEGE CORK   (Ireland)

^b Department of Psychiatry ^*  (Ireland)

^c UNIVERSITY COLLEGE CORK   (Ireland)

Author keywords

Anxiety; Cognition; Depression; Epigenetics; Germ free; Gut; HDAC; Histone modification; Hologenome; Learning; Microbiome; Microbiota; Nucleomodulin; Probiotic; Stress

Indexed keywords

3 HYDROXYBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA1; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA2; BRAIN DERIVED NEUROTROPHIC FACTOR; CAFFEIC ACID; CORTICOSTERONE; CORTICOTROPIN; DOPAMINE RECEPTOR; ENTINOSTAT; HISTONE DEACETYLASE 3; HISTONE DEACETYLASE 5; IMIPRAMINE; LACTIC ACID; MOCETINOSTAT; MONOAMINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 1; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 2A; NEUROMODULIN; NEUROTRANSMITTER; NEUROTRANSMITTER RECEPTOR; PARA COUMARIC ACID; PROBIOTIC AGENT; PROTEIN C FOS; PYRUVIC ACID; SEROTONIN; SHORT CHAIN FATTY ACID; TRANSCRIPTOME; TRICHOSTATIN A; TRYPTOPHAN; VORINOSTAT;

ANXIETY; ARTICLE; AUTISM; AUTONOMIC NERVOUS SYSTEM; BACTERIAL COLONIZATION; BEHAVIOR; BIFIDOBACTERIUM; BIFIDOBACTERIUM ANIMALIS; BIFIDOBACTERIUM LONGUM; BIFIDOBACTERIUM LONGUM INFANTIS; BRAIN FUNCTION; CAMPYLOBACTER JEJUNI; CELL COMMUNICATION; CEREBELLUM; CITROBACTER RODENTIUM; COGNITION; DEPRESSION; DEVELOPMENTAL DISORDER; DNA SEQUENCE; DYSBIOSIS; ENZYME INHIBITION; EPIGENETICS; GENE EXPRESSION; GENETIC REGULATION; GENOTYPE ENVIRONMENT INTERACTION; GERMFREE ANIMAL; GNOTOBIOTICS; GROOMING; HIPPOCAMPUS; HISTONE MODIFICATION; HOST PATHOGEN INTERACTION; HUMAN; HYPERALGESIA; HYPOTHALAMUS; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; IMMUNOMODULATION; INTESTINE FLORA; INTESTINE FUNCTION; INTRACELLULAR SIGNALING; IRRITABLE COLON; LACTOBACILLUS; LACTOBACILLUS FERMENTUM; LACTOBACILLUS HELVETICUS; LACTOBACILLUS RHAMNOSUS; LEARNING; MEMORY; MICROBIAL GENE; MICROBIOME; MICROFLORA; NONHUMAN; PRIORITY JOURNAL; SOCIAL INTERACTION; TRICHURIS MURIS; VISCERAL PAIN;

ANXIETY; COGNITION; DEPRESSION; EPIGENETICS; GERM-FREE; GUT; HDAC; HISTONE MODIFICATION; HOLOGENOME; LEARNING; MICROBIOME; MICROBIOTA; NUCLEOMODULIN; PROBIOTIC; STRESS;

ANIMALS; BRAIN; CHROMATIN ASSEMBLY AND DISASSEMBLY; EPIGENESIS, GENETIC; GENE-ENVIRONMENT INTERACTION; GENES, BACTERIAL; HOST-PATHOGEN INTERACTIONS; HUMANS; INTESTINES; MICROBIOTA; STRESS, PSYCHOLOGICAL;

EID: 84891628557     PISSN: 16011848     EISSN: 1601183X     Source Type: Journal    
DOI: 10.1111/gbb.12109     Document Type: Article

References (186)

1. Adamo, S.A. & Webster, J.P. (2013) Neural parasitology: how parasites manipulate host behaviour. J Exp Biol 216, 1-2.
2. Ait-Belgnaoui, A., Durand, H., Cartier, C., Chaumaz, G., Eutamene, H., Ferrier, L., Houdeau, E., Fioramonti, J., Bueno, L. & Theodorou, V. (2012) Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37, 1885-1895.
3. Alenghat, T., Osborne, L.C., Saenz, S.A. et al. (2013) Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504, 153-157.
4. Arumugam, M., Raes, J., Pelletier, E. et al. (2011) Enterotypes of the human gut microbiome. Nature 473, 174-180.
5. Bähr, K.H. (1970) Observations of the behavior of gnotobiotic piglets. Dtsch Tierarztl Wochenschr 77, 138-140.
6. Bailey, M.T. & Coe, C.L. (1999) Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol 35, 146-155.
7. Bailey, M.T., Dowd, S.E., Galley, J.D., Hufnagle, A.R., Allen, R.G. & Lyte, M. (2011) Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 25, 397-407.
8. Bercik, P., Collins, S.M. & Verdu, E.F. (2012) Microbes and the gut-brain axis. Neurogastroenterol Motil 24, 405-413.
9. Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K.D., Verdu, E.F. & Collins, S.M. (2011a) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599-609, 609.e1-3.
10. Bercik, P., Park, A.J., Sinclair, D., Khoshdel, A., Lu, J., Huang, X., Deng, Y., Blennerhassett, P.A., Fahnestock, M., Moine, D., Berger, B., Huizinga, J.D., Kunze, W., McLean, P.G., Bergonzelli, G.E., Collins, S.M. & Verdu, E.F. (2011b) The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 23, 1132-1139.
11. Bercik, P., Verdu, E.F., Foster, J.A., Macri, J., Potter, M., Huang, X., Malinowski, P., Jackson, W., Blennerhassett, P., Neufeld, K.A., Lu, J., Khan, W.I., Corthesy-Theulaz, I., Cherbut, C., Bergonzelli, G.E. & Collins, S.M. (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, 2102-2112.e1.
12. Berdoy, M., Webster, J.P. & Macdonald, D.W. (2000) Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci 267, 1591-1594.
13. Berenreiterová, M., Flegr, J., Kuběna, A.A. & Němec, P. (2011) The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: implications for the behavioral manipulation hypothesis. PLoS ONE 6, e28925.
14. Berer, K. & Krishnamoorthy, G. (2012) Commensal gut flora and brain autoimmunity: a love or hate affair? Acta Neuropathol 123, 639-651.
15. Berrill, J.W., Gallacher, J., Hood, K., Green, J.T., Matthews, S.B., Campbell, A.K. & Smith, A. (2013) An observational study of cognitive function in patients with irritable bowel syndrome and inflammatory bowel disease. Neurogastroenterol Motil 25, 918-e704.
16. Bierne, H. (2013) Nuclear microbiology-bacterial assault on the nucleolus. EMBO Rep 14, 663-664.
17. Bierne, H. & Cossart, P. (2012) When bacteria target the nucleus: the emerging family of nucleomodulins. Cell Microbiol 14, 622-633.
18. Bierne, H., Hamon, M. & Cossart, P. (2012) Epigenetics and bacterial infections. Cold Spring Harb Perspect Med 2, a010272.
19. Bohacek, J., Gapp, K., Saab, B.J. & Mansuy, I.M. (2013) Transgenerational epigenetic effects on brain functions. Biol Psychiatry 73, 313-320.
20. Borody, T.J., Torres, M., Campbell, J., Hills, L. & Ketheeswaran, S. (2000) Clinical vignettes - functional bowel disorders. Am J Gastroenterol 104, S367-S368.
21. Bravo, J.A., Forsythe, P., Chew, M.V., Escaravage, E., Savignac, H.M., Dinan, T.G., Bienenstock, J. & Cryan, J.F. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 108, 16050-16055.
22. Brucker, R.M. & Bordenstein, S.R. (2012) The roles of host evolutionary relationships (genus: Nasonia) and development in structuring microbial communities. Evol Int J Org Evol 66, 349-362.
23. Brucker, R.M. & Bordenstein, S.R. (2013) The capacious hologenome. Zoology (Jena) 116, 260-261.
24. Cahenzli, J., Balmer, M.L. & McCoy, K.D. (2013) Microbial-immune cross-talk and regulation of the immune system. Immunology 138, 12-22.
25. Candido, E.P., Reeves, R. & Davie, J.R. (1978) Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14, 105-113.
26. Cebra, J.J. (1999) Influences of microbiota on intestinal immune system development. Am J Clin Nutr 69, 1046S-1051S.
27. Cézilly, F., Thomas, F., Médoc, V. & Perrot-Minnot, M.-J. (2010) Host-manipulation by parasites with complex life cycles: adaptive or not? Trends Parasitol 26, 311-317.
28. Chen, J., Ghazawi, F.M. & Li, Q. (2010) Interplay of bromodomain and histone acetylation in the regulation of p300-dependent genes. Epigenetics 5, 509-515.
29. Chiu, I.M., Heesters, B.A., Ghasemlou, N., Von Hehn, C.A., Zhao, F., Tran, J., Wainger, B., Strominger, A., Muralidharan, S., Horswill, A.R., Wardenburg, J.B., Hwang, S.W., Carroll, M.C. & Woolf, C.J. (2013) Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52-57.
30. Chung, H., Pamp, S.J., Hill, J.A., Surana, N.K., Edelman, S.M., Troy, E.B., Reading, N.C., Villablanca, E.J., Wang, S., Mora, J.R., Umesaki, Y., Mathis, D., Benoist, C., Relman, D.A. & Kasper, D.L. (2012) Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578-1593.
31. Claesson, M.J., Jeffery, I.B., Conde, S. et al. (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178-184.
32. Clarke, G., Cryan, J.F., Dinan, T.G. & Quigley, E.M. (2012) Review article: probiotics for the treatment of irritable bowel syndrome - focus on lactic acid bacteria. Aliment Pharmacol Ther 35, 403-413.
33. Clarke, G., Grenham, S., Scully, P., Fitzgerald, P., Moloney, R.D., Shanahan, F., Dinan, T.G. & Cryan, J.F. (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18, 666-673.
34. Collins, L.M., Toulouse, A., Connor, T.J. & Nolan, Y.M. (2012a) Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease. Neuropharmacology 62, 2154-2168.
35. Collins, S.M., Kassam, Z. & Bercik, P. (2013) The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. Curr Opin Microbiol 16, 240-245.
36. Collins, S.M., Surette, M. & Bercik, P. (2012b) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10, 735-742.
37. Cowansage, K.K., LeDoux, J.E. & Monfils, M.-H. (2010) Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr Mol Pharmacol 3, 12-29.
38. Critchfield, J.W., van Hemert, S., Ash, M., Mulder, L. & Ashwood, P. (2011) The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterol Res Pract 2011, 161358.
39. Cryan, J.F. & Dinan, T.G. (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13, 701-712.
40. Cryan, J.F. & O'Mahony, S.M. (2011) The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil 23, 187-192.
41. Czirr, E. & Wyss-Coray, T. (2012) The immunology of neurodegeneration. J Clin Invest 122, 1156-1163.
42. Da Silva, W.C., Bonini, J.S., Bevilaqua, L.R.M., Medina, J.H., Izquierdo, I. & Cammarota, M. (2008) Inhibition of mRNA synthesis in the hippocampus impairs consolidation and reconsolidation of spatial memory. Hippocampus 18, 29-39.
43. Das, R. & Kanungo, M.S. (1979) Effects of polyamines on phosphorylation and acetylation of histones of the cerebral cortex of rats of various ages. Biochem Biophys Res Commun 90, 708-714.
44. Davari, S., Talaei, S.A., Alaei, H. & Salami, M. (2013) Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for the microbiome-gut-brain axis. Neuroscience 240, 287-296.
45. Dave, M., Higgins, P.D., Middha, S. & Rioux, K.P. (2012) The human gut microbiome: current knowledge, challenges, and future directions. Transl Res J Lab Clin Med 160, 246-257.
46. Davie, J.R. (2003) Inhibition of histone deacetylase activity by butyrate. J Nutr 133, 2485S-2493S.
47. Day, J.J. & Sweatt, J.D. (2010) DNA methylation and memory formation. Nat Neurosci 13, 1319-1323.
48. Day, J.J. & Sweatt, J.D. (2011a) Epigenetic mechanisms in cognition. Neuron 70, 813-829.
49. Day, J.J. & Sweatt, J.D. (2011b) Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory. Neurobiol Learn Mem 96, 2-12.
50. De Theije, C.G.M., Wu, J., da Silva, S.L., Kamphuis, P.J., Garssen, J., Korte, S.M. & Kraneveld, A.D. (2011) Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol 668 (Suppl 1), S70-S80.
51. Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T.G. & Cryan, J.F. (2013) Microbiota is essential for social development in the mouse. Mol Psychiatry. DOI:10.1038/mp.2013.65.
52. Desbonnet, L., Garrett, L., Clarke, G., Kiely, B., Cryan, J.F. & Dinan, T.G. (2010) Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179-1188.
53. Dinan, T.G., Cryan, J., Shanahan, F., Keeling, P.W.N. & Quigley, E.M.M. (2010) IBS: an epigenetic perspective. Nat Rev Gastroenterol Hepatol 7, 465-471.
54. Dinan, T.G., Stanton, C. & Cryan, J.F. (2013) Psychobiotics: a novel class of psychotropic. Biol Psychiatry 74, 720-726.
55. Dominguez-Bello, M.G., Costello, E.K., Contreras, M., Magris, M., Hidalgo, G., Fierer, N. & Knight, R. (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 107, 11971-11975.
56. Douglas-Escobar, M., Elliott, E. & Neu, J. (2013) Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr 167, 374-379.
57. Dulac, C. (2010) Brain function and chromatin plasticity. Nature 465, 728-735.
58. Eisenberg, T., Knauer, H., Schauer, A. et al. (2009) Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11, 1305-1314.
59. Eskandarian, H.A., Impens, F., Nahori, M.-A., Soubigou, G., Coppée, J.-Y., Cossart, P. & Hamon, M.A. (2013) A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection. Science 341, 1238858.
60. Espallergues, J., Teegarden, S.L., Veerakumar, A., Boulden, J., Challis, C., Jochems, J., Chan, M., Petersen, T., Deneris, E., Matthias, P., Hahn, C.-G., Lucki, I., Beck, S.G. & Berton, O. (2012) HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience. J Neurosci 32, 4400-4416.
61. Evans, J.M., Morris, L.S. & Marchesi, J.R. (2013) The gut microbiome: the role of a virtual organ in the endocrinology of the host. J Endocrinol 218, R37-R47.
62. Fischer, A., Sananbenesi, F., Mungenast, A. & Tsai, L.-H. (2010) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31, 605-617.
63. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L.-H. (2007) Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178-182.
64. Flegr, J. (2013) How and why Toxoplasma makes us crazy. Trends Parasitol 29, 156-163.
65. Forsythe, P. & Kunze, W.A. (2013) Voices from within: gut microbes and the CNS. Cell Mol Life Sci 70, 55-69.
66. Foster, J.A. & Neufeld, K.-A.M. (2013) Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36, 305-312.
67. Francis, D.D., Szegda, K., Campbell, G., Martin, W.D. & Insel, T.R. (2003) Epigenetic sources of behavioral differences in mice. Nat Neurosci 6, 445-446.
68. Frank, D.N. & Pace, N.R. (2008) Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol 24, 4-10.
69. Franzenburg, S., Walter, J., Künzel, S., Wang, J., Baines, J.F., Bosch, T.C.G. & Fraune, S. (2013) Distinct antimicrobial peptide expression determines host species-specific bacterial associations. Proc Natl Acad Sci USA 110, E3730-E3738.
70. Fukudo, S. & Kanazawa, M. (2011) Gene, environment, and brain-gut interactions in irritable bowel syndrome. J Gastroenterol Hepatol 26 (Suppl 3), 110-115.
71. Funkhouser, L.J. & Bordenstein, S.R. (2013) Mom knows best: the universality of maternal microbial transmission. PLoS Biol 11, e1001631.
72. Gómez-Díaz, E., Jordà, M., Peinado, M.A. & Rivero, A. (2012) Epigenetics of host-pathogen interactions: the road ahead and the road behind. PLoS Pathog 8, e1003007.
73. Gondalia, S.V., Palombo, E.A., Knowles, S.R., Cox, S.B., Meyer, D. & Austin, D.W. (2012) Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 5, 419-427.
74. Govindarajan, N., Agis-Balboa, R.C., Walter, J., Sananbenesi, F. & Fischer, A. (2011) Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression. J Alzheimers Dis 26, 187-197.
75. Gräff, J. & Tsai, L.-H. (2013a) Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14, 97-111.
76. Gräff, J. & Tsai, L.-H. (2013b) The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol 53, 311-330.
77. Grafodatskaya, D., Chung, B., Szatmari, P. & Weksberg, R. (2010) Autism spectrum disorders and epigenetics. J Am Acad Child Adolesc Psychiatry 49, 794-809.
78. Grenham, S., Clarke, G., Cryan, J.F. & Dinan, T.G. (2011) Brain-gut-microbe communication in health and disease. Front Physiol 2, 94.
79. Gupta, V.K., Scheunemann, L., Eisenberg, T., Mertel, S., Bhukel, A., Koemans, T.S., Kramer, J.M., Liu, K.S.Y., Schroeder, S., Stunnenberg, H.G., Sinner, F., Magnes, C., Pieber, T.R., Dipt, S., Fiala, A., Schenck, A., Schwaerzel, M., Madeo, F. & Sigrist, S.J. (2013) Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci 16, 1453-1460.
80. Hamon, M.A. & Cossart, P. (2008) Histone modifications and chromatin remodeling during bacterial infections. Cell Host Microbe 4, 100-109.
81. Hargreaves, D.C., Horng, T. & Medzhitov, R. (2009) Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129-145.
82. Diaz Heijtz, R.D., Wang, S., Anuar, F., Qian, Y., Björkholm, B., Samuelsson, A., Hibberd, M.L., Forssberg, H. & Pettersson, S. (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 108, 3047-3052.
83. Holliday, R. (1987) The inheritance of epigenetic defects. Science 238, 163-170.
84. Hooper, L.V., Littman, D.R. & Macpherson, A.J. (2012) Interactions between the microbiota and the immune system. Science 336, 1268-1273.
85. Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486, 207-214.
86. Igaz, L.M., Bekinschtein, P., Vianna, M.M.R., Izquierdo, I. & Medina, J.H. (2004) Gene expression during memory formation. Neurotox Res 6, 189-204.
87. Igaz, L.M., Vianna, M.R.M., Medina, J.H. & Izquierdo, I. (2002) Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning. J Neurosci 22, 6781-6789.
88. Jaenisch, R. & Bird, A. (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 (Suppl), 245-254.
89. Jeffery, I.B., O'Toole, P.W., Öhman, L., Claesson, M.J., Deane, J., Quigley, E.M.M. & Simrén, M. (2012) An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 61, 997-1006.
90. Jochems, J., Boulden, J., Lee, B.G., Blendy, J.A., Jarpe, M., Mazitschek, R., Van Duzer, J.H., Jones, S. & Berton, O. (2013) Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology. DOI:10.1038/npp.2013.207.
91. Kaas, G.A., Zhong, C., Eason, D.E., Ross, D.L., Vachhani, R.V., Ming, G.-L., King, J.R., Song, H. & Sweatt, J.D. (2013) TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79, 1086-1093.
92. Kennedy, P.J., Clarke, G., O'Neill, A., Groeger, J.A., Quigley, E.M.M., Shanahan, F., Cryan, J.F. & Dinan, T.G. (2013) Cognitive performance in irritable bowel syndrome: evidence of a stress-related impairment in visuospatial memory. Psychol Med, 1-14.
93. Korolev, N., Vorontsova, O.V. & Nordenskiöld, L. (2007) Physicochemical analysis of electrostatic foundation for DNA-protein interactions in chromatin transformations. Prog Biophys Mol Biol 95, 23-49.
94. Kosik, K.S., Rapp, P.R., Raz, N., Small, S.A., Sweatt, J.D. & Tsai, L.-H. (2012) Mechanisms of age-related cognitive change and targets for intervention: epigenetics. J Gerontol A Biol Sci Med Sci 67, 741-746.
95. Kovacs, A., Ben-Jacob, N., Tayem, H., Halperin, E., Iraqi, F.A. & Gophna, U. (2011) Genotype is a stronger determinant than sex of the mouse gut microbiota. Microb Ecol 61, 423-428.
96. Kristensson, K. (2011) Microbes' roadmap to neurons. Nat Rev Neurosci 12, 345-357.
97. Lampron, A., Elali, A. & Rivest, S. (2013) Innate immunity in the CNS: redefining the relationship between the CNS and Its environment. Neuron 78, 214-232.
98. Landry, C.D., Kandel, E.R. & Rajasethupathy, P. (2013) New mechanisms in memory storage: piRNAs and epigenetics. Trends Neurosci 36, 535-542.
99. Latham, T., Mackay, L., Sproul, D., Karim, M., Culley, J., Harrison, D.J., Hayward, L., Langridge-Smith, P., Gilbert, N. & Ramsahoye, B.H. (2012) Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acids Res 40, 4794-4803.
100. Ledford, H. (2008) Language: disputed definitions. Nature 455, 1023-1028.
101. LeRoy, G., Rickards, B. & Flint, S.J. (2008) The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell 30, 51-60.
102. Libersat, F., Delago, A. & Gal, R. (2009) Manipulation of host behavior by parasitic insects and insect parasites. Annu Rev Entomol 54, 189-207.
103. Liévin-Le Moal, V. & Servin, A.L. (2013) Pathogenesis of human enterovirulent bacteria: lessons from cultured, fully differentiated human colon cancer cell lines. Microbiol Mol Biol Rev 77, 380-439.
104. Louis, P. (2012) Does the human gut microbiota contribute to the etiology of autism spectrum disorders? Dig Dis Sci 57, 1987-1989.
105. Luckey, T.D. (1972) Introduction to intestinal microecology. Am J Clin Nutr 25, 1292-1294.
106. Lyte, M. (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. BioEssays News Rev Mol Cell Dev Biol 33, 574-581.
107. Lyte, M. (2013) Microbial endocrinology and nutrition: a perspective on new mechanisms by which diet can influence gut-to-brain communication. PharmaNutrition 1, 35-39.
108. Lyte, M. & Freestone, P.P.E. (2010) Microbial Endocrinology Interkingdom Signaling in Infectious Disease and Health. Springer, New York.
109. Macfabe, D.F. (2012) Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis 23.
110. MacFabe, D.F., Cain, N.E., Boon, F., Ossenkopp, K.-P. & Cain, D.P. (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, 47-54.
111. Maes, M., Kubera, M., Leunis, J.-C. & Berk, M. (2012) Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 141, 55-62.
112. Mao, Y.-K., Kasper, D.L., Wang, B., Forsythe, P., Bienenstock, J. & Kunze, W.A. (2013) Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat Commun 4, 1465.
113. Marazzi, I., Ho, J.S.Y., Kim, J., Manicassamy, B., Dewell, S., Albrecht, R.A., Seibert, C.W., Schaefer, U., Jeffrey, K.L., Prinjha, R.K., Lee, K., García-Sastre, A., Roeder, R.G. & Tarakhovsky, A. (2012) Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428-433.
114. Marques, T.M., Wall, R., Ross, R.P., Fitzgerald, G.F., Ryan, C.A. & Stanton, C. (2010) Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol 21, 149-156.
115. Mason, M.R., Nagaraja, H.N., Camerlengo, T., Joshi, V. & Kumar, P.S. (2013) Deep sequencing identifies ethnicity-specific bacterial signatures in the oral microbiome. PLoS ONE 8, e77287.
116. Matthews, D.M. & Jenks, S.M. (2013) Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav Processes 96, 27-35.
117. Mayer, E.A. (2011) Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 12, 453-466.
118. Mayer, E.A., Naliboff, B.D. & Chang, L. (2001) Basic pathophysiologic mechanisms in irritable bowel syndrome. Dig Dis (Basel, Switz) 19, 212-218.
119. McKernan, D.P., Fitzgerald, P., Dinan, T.G. & Cryan, J.F. (2010) The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. Neurogastroenterol Motil 22 (1029-1035), e268.
120. McQuown, S.C. & Wood, M.A. (2011) HDAC3 and the molecular brake pad hypothesis. Neurobiol Learn Mem 96, 27-34.
121. McVey Neufeld, K.A., Mao, Y.K., Bienenstock, J., Foster, J.A. & Kunze, W.A. (2013) The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol Motil 25, 183-188.
122. Mellén, M., Ayata, P., Dewell, S., Kriaucionis, S. & Heintz, N. (2012) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417-1430.
123. Minárovits, J. (2009) Microbe-induced epigenetic alterations in host cells: the coming era of patho-epigenetics of microbial infections. A review. Acta Microbiol Immunol Hung 56, 1-19.
124. Ming, X., Stein, T.P., Barnes, V., Rhodes, N. & Guo, L. (2012) Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res 11, 5856-5862.
125. Misra, S. & Medhi, B. (2013) Role of probiotics as memory enhancer. Indian J Pharmacol 45, 311-312.
126. Montiel-Castro, A.J., González-Cervantes, R.M., Bravo-Ruiseco, G. & Pacheco-López, G. (2013) The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 7, 70.
127. Mulle, J.G., Sharp, W.G. & Cubells, J.F. (2013) The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep 15, 337.
128. Neu, J. & Rushing, J. (2011) Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis. Clin Perinatol 38, 321-331.
129. Neufeld, K.M., Kang, N., Bienenstock, J. & Foster, J.A. (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23, 255-264.
130. Ng, S.-Y., Lin, L., Soh, B.S. & Stanton, L.W. (2013) Long noncoding RNAs in development and disease of the central nervous system. Trends Genet 29, 461-468.
131. Nicholson, J.K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W. & Pettersson, S. (2012) Host-gut microbiota metabolic interactions. Science 336, 1262-1267.
132. Noack, J., Dongowski, G., Hartmann, L. & Blaut, M. (2000) The human gut bacteria bacteroides thetaiotaomicron and Fusobacterium varium produce putrescine and spermidine in cecum of pectin-fed gnotobiotic rats. J Nutr 130, 1225-1231.
133. O'Connor, R.M., Dinan, T.G. & Cryan, J.F. (2012) Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression. Mol Psychiatry 17, 359-376.
134. O'Mahony, S.M., Hyland, N.P., Dinan, T.G. & Cryan, J.F. (2011) Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl) 214, 71-88.
135. Ørom, U.A. & Shiekhattar, R. (2013) Long noncoding RNAs usher in a new era in the biology of enhancers. Cell 154, 1190-1193.
136. Parent, A. & Carpenter, M.B. (1996) Carpenter's Human Neuroanatomy. Williams & Wilkins, Baltimore.
137. Park, A.J., Collins, J., Blennerhassett, P.A., Ghia, J.E., Verdu, E.F., Bercik, P. & Collins, S.M. (2013) Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterol Motil 25, 733-e575.
138. Peleg, S., Sananbenesi, F., Zovoilis, A., Burkhardt, S., Bahari-Javan, S., Agis-Balboa, R.C., Cota, P., Wittnam, J.L., Gogol-Doering, A., Opitz, L., Salinas-Riester, G., Dettenhofer, M., Kang, H., Farinelli, L., Chen, W. & Fischer, A. (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328, 753-756.
139. Pennini, M.E., Perrinet, S., Dautry-Varsat, A. & Subtil, A. (2010) Histone methylation by NUE, a novel nuclear effector of the intracellular pathogen chlamydia trachomatis. PLoS Pathog 6, e1000995.
140. Qin, J., Li, R., Raes, J. et al. (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65.
141. Ravel, J., Gajer, P., Abdo, Z., Schneider, G.M., Koenig, S.S.K., McCulle, S.L., Karlebach, S., Gorle, R., Russell, J., Tacket, C.O., Brotman, R.M., Davis, C.C., Ault, K., Peralta, L. & Forney, L.J. (2011) Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA 108 (Suppl 1), 4680-4687.
142. Renthal, W., Maze, I., Krishnan, V., Covington, H.E. 3rd, Xiao, G., Kumar, A., Russo, S.J., Graham, A., Tsankova, N., Kippin, T.E., Kerstetter, K.A., Neve, R.L., Haggarty, S.J., McKinsey, T.A., Bassel-Duby, R., Olson, E.N. & Nestler, E.J. (2007) Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56, 517-529.
143. Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J.P. & Ricciardi-Castagnoli, P. (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2, 361-367.
144. Reyniers, J.A. (1959) Germfree vertebrates: present status. Ann N Y Acad Sci 78, 3-400.
145. Rhee, S.H., Pothoulakis, C. & Mayer, E.A. (2009) Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6, 306-314.
146. Rolando, M., Sanulli, S., Rusniok, C., Gomez-Valero, L., Bertholet, C., Sahr, T., Margueron, R. & Buchrieser, C. (2013) Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication. Cell Host Microbe 13, 395-405.
147. Rosenberg, E., Koren, O., Reshef, L., Efrony, R. & Zilber-Rosenberg, I. (2007) The role of microorganisms in coral health, disease and evolution. Nat Rev Microbiol 5, 355-362.
148. Rosenberg, E., Sharon, G. & Zilber-Rosenberg, I. (2009) The hologenome theory of evolution contains Lamarckian aspects within a Darwinian framework. Environ Microbiol 11, 2959-2962.
149. Rostène, W., Kitabgi, P. & Parsadaniantz, S.M. (2007) Chemokines: a new class of neuromodulator? Nat Rev Neurosci 8, 895-903.
150. Rudenko, A., Dawlaty, M.M., Seo, J., Cheng, A.W., Meng, J., Le, T., Faull, K.F., Jaenisch, R. & Tsai, L.-H. (2013) Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109-1122.
151. Santos, J., Yang, P.C., Söderholm, J.D., Benjamin, M. & Perdue, M.H. (2001) Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat. Gut 48, 630-636.
152. Schaedler, R.W., Dubs, R. & Costello, R. (1965) Association of germfree mice with bacteria isolated from normal mice. J Exp Med 122, 77-82.
153. Schloissnig, S., Arumugam, M., Sunagawa, S., Mitreva, M., Tap, J., Zhu, A., Waller, A., Mende, D.R., Kultima, J.R., Martin, J., Kota, K., Sunyaev, S.R., Weinstock, G.M. & Bork, P. (2013) Genomic variation landscape of the human gut microbiome. Nature 493, 45-50.
154. Shanahan, F. (2012) The gut microbiota-a clinical perspective on lessons learned. Nat Rev Gastroenterol Hepatol 9, 609-614.
155. Shankar, V., Agans, R., Holmes, B., Raymer, M. & Paliy, O. (2013) Do gut microbial communities differ in pediatric IBS and health? Gut Microbes 4, 347-352.
156. Smits, L.P., Bouter, K.E.C., de Vos, W.M., Borody, T.J. & Nieuwdorp, M. (2013) Therapeutic potential of fecal microbiota transplantation. Gastroenterology 145, 946-953.
157. Söderholm, J.D. & Perdue, M.H. (2001) Stress and gastrointestinal tract. II. Stress and intestinal barrier function. Am J Physiol Gastrointest Liver Physiol 280, G7-G13.
158. Soliman, M.L., Combs, C.K. & Rosenberger, T.A. (2013) Modulation of inflammatory cytokines and mitogen-activated protein kinases by acetate in primary astrocytes. J Neuroimmune Pharmacol 8, 287-300.
159. Sommer, F. & Bäckhed, F. (2013) The gut microbiota - masters of host development and physiology. Nat Rev Microbiol 11, 227-238.
160. Stender, J.D. & Glass, C.K. (2013) Epigenomic control of the innate immune response. Curr Opin Pharmacol 13, 582-587.
161. Stilling, R.M. & Fischer, A. (2011) The role of histone acetylation in age-associated memory impairment and Alzheimer's disease. Neurobiol Learn Mem 96, 19-26.
162. Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X.-N., Kubo, C. & Koga, Y. (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558, 263-275.
163. Sweatt, J.D. (2013) The emerging field of neuroepigenetics. Neuron 80, 624-632.
164. Szulwach, K.E., Li, X., Li, Y., Song, C.-X., Wu, H., Dai, Q., Irier, H., Upadhyay, A.K., Gearing, M., Levey, A.I., Vasanthakumar, A., Godley, L.A., Chang, Q., Cheng, X., He, C. & Jin, P. (2011) 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 14, 1607-1616.
165. Tapia-Arancibia, L., Aliaga, E., Silhol, M. & Arancibia, S. (2008) New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 59, 201-220.
166. Thangaraju, M., Gopal, E., Martin, P.M., Ananth, S., Smith, S.B., Prasad, P.D., Sterneck, E. & Ganapathy, V. (2006) SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res 66, 11560-11564.
167. Thomas, C.M., Hong, T., van Pijkeren, J.P., Hemarajata, P., Trinh, D.V., Hu, W., Britton, R.A., Kalkum, M. & Versalovic, J. (2012a) Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One 7, e31951.
168. Thomas, F., Poulin, R. & Brodeur, J. (2010) Host manipulation by parasites: a multidimensional phenomenon. Oikos 119, 1217-1223.
169. Thomas, R.H., Meeking, M.M., Mepham, J.R., Tichenoff, L., Possmayer, F., Liu, S. & MacFabe, D.F. (2012b) The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflammation 9, 153.
170. Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., Guyonnet, D., Legrain-Raspaud, S., Trotin, B., Naliboff, B. & Mayer, E.A. (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144, 1394-1401.e4.
171. Tran, L., Chaloner, A., Sawalha, A.H. & Greenwood Van-Meerveld, B. (2013) Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress. Psychoneuroendocrinology 38, 898-906.
172. Tsankova, N.M., Berton, O., Renthal, W., Kumar, A., Neve, R.L. & Nestler, E.J. (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9, 519-525.
173. Turnbaugh, P.J., Ley, R.E., Hamady, M., Fraser-Liggett, C.M., Knight, R. & Gordon, J.I. (2007) The human microbiome project. Nature 449, 804-810.
174. Villeda, S.A., Luo, J., Mosher, K.I. et al. (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90-94.
175. Vyas, A., Kim, S.-K., Giacomini, N., Boothroyd, J.C. & Sapolsky, R.M. (2007) Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc Natl Acad Sci USA 104, 6442-6447.
176. Waddington, C.H. (1953) Epigenetics and Evolution. Symp Soc Exp Biol 7, 186-199.
177. Waldecker, M., Kautenburger, T., Daumann, H., Busch, C. & Schrenk, D. (2008) Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J Nutr Biochem 19, 587-593.
178. Walker, M.P., Laferla, F.M., Oddo, S.S. & Brewer, G.J. (2012) Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. Age (Dordr) 35, 519-531.
179. Wall, R., Cryan, J.F., Ross, R.P., Fitzger, G.F., Dinan, T.G. & Stanton, C. (2014) Bacterial neuroactive compounds produced by psychobiotics. In Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. Springer, Heidelberg.
180. Wang, W., Kwon, E.J. & Tsai, L.-H. (2012) MicroRNAs in learning, memory, and neurological diseases. Learn Mem 19, 359-368.
181. Webster, J.P. (2001) Rats, cats, people and parasites: the impact of latent toxoplasmosis on behaviour. Microbes Infect Institut Pasteur 3, 1037-1045.
182. Webster, J.P., Kaushik, M., Bristow, G.C. & McConkey, G.A. (2013) Toxoplasma gondii infection, from predation to schizophrenia: can animal behaviour help us understand human behaviour? J Exp Biol 216, 99-112.
183. Weng, N., Araki, Y. & Subedi, K. (2012) The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol 12, 306-315.
184. Zareie, M., Johnson-Henry, K., Jury, J., Yang, P.-C., Ngan, B.-Y., McKay, D.M., Soderholm, J.D., Perdue, M.H. & Sherman, P.M. (2006) Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut 55, 1553-1560.
185. Zhu, B., Wang, X. & Li, L. (2010) Human gut microbiome: the second genome of human body. Protein Cell 1, 718-725.
186. Zoetendal, E.G., Akkermans, A.D., Akkermans-van Vliet, W.M., de Visser, J.A.G. & de Vos, W.M. (2001) The host genotype affects the bacterial community in the human gastronintestinal tract. Microb Ecol Health Dis 13, 129-134.