Microbiota, Immunoregulatory Old Friends and Psychiatric Disorders

  • Graham A. W. Rook
  • Charles L. Raison
  • Christopher A. Lowry
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 817)


Regulation of the immune system is an important function of the gut microbiota. Increasing evidence suggests that modern living conditions cause the gut microbiota to deviate from the form it took during human evolution. Contributing factors include loss of helminth infections, encountering less microbial biodiversity, and modulation of the microbiota composition by diet and antibiotic use. Thus the gut microbiota is a major mediator of the hygiene hypothesis (or as we prefer, “Old Friends” mechanism), which describes the role of organisms with which we co-evolved, and that needed to be tolerated, as crucial inducers of immunoregulation. At least partly as a consequence of reduced exposure to immunoregulatory Old Friends, many but not all of which resided in the gut, high-income countries are undergoing large increases in a wide range of chronic inflammatory disorders including allergies, autoimmunity and inflammatory bowel diseases. Depression, anxiety and reduced stress resilience are comorbid with these conditions, or can occur in individuals with persistently raised circulating levels of biomarkers of inflammation in the absence of clinically apparent peripheral inflammatory disease. Moreover poorly regulated inflammation during pregnancy might contribute to brain developmental abnormalities that underlie some cases of autism spectrum disorders and schizophrenia. In this chapter we explain how the gut microbiota drives immunoregulation, how faulty immunoregulation and inflammation predispose to psychiatric disease, and how psychological stress drives further inflammation via pathways that involve the gut and microbiota. We also outline how this two-way relationship between the brain and inflammation implicates the microbiota, Old Friends and immunoregulation in the control of stress resilience.


Autism Spectrum Disorder Inflammatory Bowel Disease Autism Spectrum Disorder Quinolinic Acid Early Life Stress 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Autism spectrum disorders




Crohn’s disease


Central nervous system


Corticotropin-releasing hormone


C-reactive protein


Dorsal anterior cingulate cortex


Dendritic cells


Regulatory dendritic cells


Functional magnetic resonance imaging


g-Aminobutyric acid


Glucocorticoid resistance


Hypothalamic-pituitary adrenal axis


Inflammatory bowel disease


Irritable bowel syndrome










Monocyte chemoattractant protein-1


Multiple sclerosis


Nitric oxide


Nucleotide-binding oligomerization domain-containing protein-1


Peripheral blood monocyte cells


Positron emission tomography


Short chain fatty acids


Systemic lupus erythematosus


Single nucleotide polymorphisms


Sympathetic nervous system


Selective serotonin reuptake inhibitors


Type 1 diabetes


Tumor necrosis factor


Regulatory T cells


Ulcerative colitis


X-linked autoimmunity-allergic dysregulation syndrome



GAWR is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. CLR receives grant support from the National Center for Complementary and Alternative Medicine (R01AT004698, R01AT004698-01A1S1), the Depressive and Bipolar Disorder Alternative Treatment Foundation and The Brain and Behavior Research Foundation. He reports the following activities for the previous 2 years: advisory board participation and related travel funds for Pamlab, Lilly and North American Center for Continuing Education; development and presentation of disease state slides for Pamlab, Pfizer and Johnson & Johnson, as well as related travel funds for these activities; development of continuing medical education material for North American Center for Continuing Education and for CME Incite. CAL receives grant support from the National Institute of Mental Health (R01MH065702, R01MH086539, R01DA019921, R01MH075968), the National Science Foundation (NSF- IOS 0921969), the Depressive and Bipolar Disorder Alternative Treatment Foundation, and is the recipient of an NSF CAREER Award (NSF-IOS 0845550) and a NARSAD, Brain & Behavior Research Foundation 2010 Young Investigator Award. He reports the following activities for the previous 2 years: consultant for Enlight Biosciences.


  1. 1.
    Blackley CH (1873) Experimental researches on the causes and nature of catarrhus aestivus (Hay-fever and Hay-asthma). Baillière Tindall and Cox, LondonGoogle Scholar
  2. 2.
    Radon K, Windstetter D, Poluda AL, Mueller B, von Mutius E, Koletzko S (2007) Contact with farm animals in early life and juvenile inflammatory bowel disease: a case-control study. Pediatrics 120(2):354–361PubMedGoogle Scholar
  3. 3.
    Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S et al (2009) Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 123(4):774–782.e5Google Scholar
  4. 4.
    Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrlander C et al (2011) Exposure to environmental microorganisms and childhood asthma. N Engl J Med 364(8):701–709PubMedGoogle Scholar
  5. 5.
    Stene LC, Nafstad P (2001) Relation between occurrence of type 1 diabetes and asthma. Lancet 357:607PubMedGoogle Scholar
  6. 6.
    Weinstock JV, Elliott DE (2009) Helminths and the IBD hygiene hypothesis. Inflamm Bowel Dis 15(1):128–133PubMedGoogle Scholar
  7. 7.
    Rook GAW (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol 160(1):70–79PubMedCentralPubMedGoogle Scholar
  8. 8.
    von Hertzen L, Hanski I, Haahtela T (2011) Natural immunity. Biodiversity loss and inflammatory diseases are two global megatrends that might be related. EMBO Rep 12(11):1089–1093Google Scholar
  9. 9.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2006) Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence. J Immunol 176(5):3248–3256PubMedGoogle Scholar
  10. 10.
    Wildin RS, Smyk-Pearson S, Filipovich AH (2002) Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39(8):537–545PubMedCentralPubMedGoogle Scholar
  11. 11.
    Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM (2013) Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 38(2):373–383PubMedCentralPubMedGoogle Scholar
  12. 12.
    Gurven M, Kaplan H, Winking J, Finch C, Crimmins EM (2008) Aging and inflammation in two epidemiological worlds. J Gerontol A Biol Sci Med Sci 63(2):196–199PubMedCentralPubMedGoogle Scholar
  13. 13.
    McDade TW, Tallman PS, Madimenos FC, Liebert MA, Cepon TJ, Sugiyama LS et al (2012) Analysis of variability of high sensitivity C-reactive protein in lowland Ecuador reveals no evidence of chronic low-grade inflammation. Am J Hum Biol 24:675–681PubMedGoogle Scholar
  14. 14.
    Rook G, Raison CL, Lowry CA (2013) Childhood microbial experience, immunoregulation, inflammation and adult susceptibility to psychosocial stressors and depression in rich and poor countries. Evol Med Public Health 2013:14–17PubMedGoogle Scholar
  15. 15.
    McDade TW, Rutherford J, Adair L, Kuzawa CW (2010) Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood. Proc Biol Sci 277(1684):1129–1137PubMedCentralPubMedGoogle Scholar
  16. 16.
    Gimeno D, Kivimaki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A et al (2009) Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 39(3):413–423PubMedCentralPubMedGoogle Scholar
  17. 17.
    Rook GAW, Lowry CA (2008) The hygiene hypothesis and psychiatric disorders. Trends Immunol 29:150–158PubMedGoogle Scholar
  18. 18.
    Raison CL, Lowry CA, Rook GAW (2010) Inflammation, sanitation and consternation: loss of contact with co-evolved, tolerogenic micro-organisms and the pathophysiology and treatment of major depression. Arch Gen Psychiatry 67(12):1211–1224PubMedCentralPubMedGoogle Scholar
  19. 19.
    Maes M, Scharpe S, Van Grootel L, Uyttenbroeck W, Cooreman W, Cosyns P et al (1992) Higher alpha 1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: further evidence for the existence of an inflammatory response during that illness. J Affect Disord 24(3):183–192PubMedGoogle Scholar
  20. 20.
    Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65(9):732–741PubMedCentralPubMedGoogle Scholar
  21. 21.
    Chen Y, Jiang T, Chen P, Ouyang J, Xu G, Zeng Z et al (2011) Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res 188(2):224–230PubMedGoogle Scholar
  22. 22.
    Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH et al (2006) Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 163(9):1630–1633PubMedGoogle Scholar
  23. 23.
    Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al (2001) Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 344(13):961–966PubMedGoogle Scholar
  24. 24.
    Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF et al (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31–41PubMedCentralPubMedGoogle Scholar
  25. 25.
    Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27(40):10695–10702PubMedCentralPubMedGoogle Scholar
  26. 26.
    Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR (2008) Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry 64(6):484–490PubMedCentralPubMedGoogle Scholar
  27. 27.
    Braida D, Sacerdote P, Panerai AE, Bianchi M, Aloisi AM, Iosue S et al (2004) Cognitive function in young and adult IL (interleukin)-6 deficient mice. Behav Brain Res 153(2):423–429PubMedGoogle Scholar
  28. 28.
    Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW (2006) Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 26(42):10709–10716PubMedGoogle Scholar
  29. 29.
    McEwen BS, Gianaros PJ (2010) Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann N Y Acad Sci 1186:190–222PubMedCentralPubMedGoogle Scholar
  30. 30.
    O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM 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
  31. 31.
    Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A (2008) Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 65(4):409–415PubMedCentralPubMedGoogle Scholar
  32. 32.
    McDade TW, Hoke M, Borja JB, Adair LS, Kuzawa CW (2013) Do environments in infancy moderate the association between stress and inflammation in adulthood? Preliminary evidence from a birth cohort in the Philippines. Brain Behav Immun 31:23–30Google Scholar
  33. 33.
    Compton WM, Conway KP, Stinson FS, Grant BF (2006) Changes in the prevalence of major depression and comorbid substance use disorders in the United States between 1991–1992 and 2001–2002. Am J Psychiatry 163(12):2141–2147PubMedGoogle Scholar
  34. 34.
    Ustun TB, Ayuso-Mateos JL, Chatterji S, Mathers C, Murray CJ (2004) Global burden of depressive disorders in the year 2000. Br J Psychiatry 184:386–392PubMedGoogle Scholar
  35. 35.
    McDade TW, Borja JB, Adair L, Kuzawa CW (2013) Depressive symptoms are not associated with inflammation in younger and older adults in the Philippines. Evol Med Public Health 2013:18–23Google Scholar
  36. 36.
    Peen J, Schoevers RA, Beekman AT, Dekker J (2010) The current status of urban-rural differences in psychiatric disorders. Acta Psychiatr Scand 121(2):84–93PubMedGoogle Scholar
  37. 37.
    Kovess-Masfety V, Lecoutour X, Delavelle S (2005) Mood disorders and urban/rural settings: comparisons between two French regions. Soc Psychiatry Psychiatr Epidemiol 40(8):613–618PubMedGoogle Scholar
  38. 38.
    McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D (2004) A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2:13PubMedCentralPubMedGoogle Scholar
  39. 39.
    Lauritsen MB, Pedersen CB, Mortensen PB (2005) Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J Child Psychol Psychiatry 46(9):963–971PubMedGoogle Scholar
  40. 40.
    Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser M, Maisch S et al (2001) Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358(9288):1129–1133PubMedGoogle Scholar
  41. 41.
    Ege MJ, Herzum I, Buchele G, Krauss-Etschmann S, Lauener RP, Roponen M et al (2008) Prenatal exposure to a farm environment modifies atopic sensitization at birth. J Allergy Clin Immunol 122(2):407–412, 12 e1–e4Google Scholar
  42. 42.
    Nicolaou N, Siddique N, Custovic A (2005) Allergic disease in urban and rural populations: increasing prevalence with increasing urbanization. Allergy 60(11):1357–1360PubMedGoogle Scholar
  43. 43.
    Hou JK, El-Serag H, Thirumurthi S (2009) Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: a systematic review. Am J Gastroenterol 104(8):2100–2109PubMedGoogle Scholar
  44. 44.
    Beebe GW, Kurtzke JF, Kurland LT, Auth TL, Nagler B (1967) Studies on the natural history of multiple sclerosis. 3. Epidemiologic analysis of the army experience in World War II. Neurology 17(1):1–17PubMedGoogle Scholar
  45. 45.
    Antonovsky A, Leibowitz U, Smith HA, Medalie JM, Balogh M, Kats R et al (1965) Epidemiologic Study of Multiple Sclerosis in Israel. I. An overall review of methods and findings. Arch Neurol 13:183–193PubMedGoogle Scholar
  46. 46.
    Lowis GW (1990) The social epidemiology of multiple sclerosis. Sci Total Environ 90:163–190PubMedGoogle Scholar
  47. 47.
    Rottem M, Szyper-Kravitz M, Shoenfeld Y (2005) Atopy and asthma in migrants. Int Arch Allergy Immunol 136(2):198–204PubMedGoogle Scholar
  48. 48.
    Soderstrom U, Aman J, Hjern A (2012) Being born in Sweden increases the risk for type 1 diabetes – a study of migration of children to Sweden as a natural experiment. Acta Paediatr 101(1):73–77PubMedGoogle Scholar
  49. 49.
    Ahlgren C, Oden A, Lycke J (2012) A nationwide survey of the prevalence of multiple sclerosis in immigrant populations of Sweden. Mult Scler 18:1099–1107Google Scholar
  50. 50.
    Breslau J, Borges G, Tancredi D, Saito N, Kravitz R, Hinton L et al (2011) Migration from Mexico to the United States and subsequent risk for depressive and anxiety disorders: a cross-national study. Arch Gen Psychiatry 68(4):428–433PubMedCentralPubMedGoogle Scholar
  51. 51.
    Dealberto MJ (2010) Ethnic origin and increased risk for schizophrenia in immigrants to countries of recent and longstanding immigration. Acta Psychiatr Scand 121(5):325–339PubMedGoogle Scholar
  52. 52.
    Keen DV, Reid FD, Arnone D (2010) Autism, ethnicity and maternal immigration. Br J Psychiatry 196(4):274–281PubMedGoogle Scholar
  53. 53.
    Breslau J, Borges G, Hagar Y, Tancredi D, Gilman S (2009) Immigration to the USA and risk for mood and anxiety disorders: variation by origin and age at immigration. Psychol Med 39(7):1117–1127PubMedCentralPubMedGoogle Scholar
  54. 54.
    Vega WA, Sribney WM, Aguilar-Gaxiola S, Kolody B (2004) 12-month prevalence of DSM-III-R psychiatric disorders among Mexican Americans: nativity, social assimilation, and age determinants. J Nerv Ment Dis 192(8):532–541PubMedGoogle Scholar
  55. 55.
    Coid JW, Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M et al (2008) Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study. Arch Gen Psychiatry 65(11):1250–1258PubMedGoogle Scholar
  56. 56.
    Veling W, Hoek HW, Selten JP, Susser E (2011) Age at migration and future risk of psychotic disorders among immigrants in the Netherlands: a 7-year incidence study. Am J Psychiatry 168(12):1278–1285PubMedGoogle Scholar
  57. 57.
    Cantor-Graae E, Selten JP (2005) Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 162(1):12–24PubMedGoogle Scholar
  58. 58.
    Milo R, Kahana E (2010) Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev 9(5):A387–A394PubMedGoogle Scholar
  59. 59.
    Gale CR, Martyn CN (1995) Migrant studies in multiple sclerosis. Prog Neurobiol 47(4–5):425–448Google Scholar
  60. 60.
    Cabre P (2009) Environmental changes and epidemiology of multiple sclerosis in the French West Indies. J Neurol Sci 286(1–2):58–61PubMedGoogle Scholar
  61. 61.
    Dean G (1967) Annual incidence, prevalence, and mortality of multiple sclerosis in white South-African-born and in white immigrants to South Africa. Br Med J 2(5554):724–730PubMedCentralPubMedGoogle Scholar
  62. 62.
    Hjern A, Rasmussen F, Hedlin G (1999) Age at adoption, ethnicity and atopic disorder: a study of internationally adopted young men in Sweden. Pediatr Allergy Immunol 10(2):101–106PubMedGoogle Scholar
  63. 63.
    Eldeirawi K, McConnell R, Furner S, Freels S, Stayner L, Hernandez E et al (2009) Associations of doctor-diagnosed asthma with immigration status, age at immigration, and length of residence in the United States in a sample of Mexican American School Children in Chicago. J Asthma 46(8):796–802PubMedGoogle Scholar
  64. 64.
    Pereg D, Tirosh A, Lishner M, Goldberg A, Shochat T, Confino-Cohen R (2008) Prevalence of asthma in a large group of Israeli adolescents: influence of country of birth and age at migration. Allergy 63(8):1040–1045PubMedGoogle Scholar
  65. 65.
    Li X, Sundquist J, Hemminki K, Sundquist K (2011) Risk of inflammatory bowel disease in first- and second-generation immigrants in Sweden: a nationwide follow-up study. Inflamm Bowel Dis 17(8):1784–1791PubMedGoogle Scholar
  66. 66.
    Carr I, Mayberry JF (1999) The effects of migration on ulcerative colitis: a three-year prospective study among Europeans and first- and second-generation South Asians in Leicester (1991–1994). Am J Gastroenterol 94(10):2918–2922PubMedGoogle Scholar
  67. 67.
    Rook GAW (2009) The broader implications of the hygiene hypothesis. Immunology 126:3–11PubMedCentralPubMedGoogle Scholar
  68. 68.
    Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9(5):313–323PubMedGoogle Scholar
  69. 69.
    Osada Y, Kanazawa T (2010) Parasitic helminths: new weapons against immunological disorders. J Biomed Biotechnol 2010:743–758Google Scholar
  70. 70.
    Karimi K, Inman MD, Bienenstock J, Forsythe P (2009) Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am J Respir Crit Care Med 179(3):186–193PubMedGoogle Scholar
  71. 71.
    Allen RG, Lafuse WP, Galley JD, Ali MM, Ahmer BM, Bailey MT (2012) The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity. Brain Behav Immun 26(3):371–382PubMedCentralPubMedGoogle Scholar
  72. 72.
    Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M (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
  73. 73.
    Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16(2):228–231PubMedGoogle Scholar
  74. 74.
    Kim OY, Monsel A, Bertrand M, Cavaillon JM, Coriat P, Adib-Conquy M (2009) Translocation of bacterial NOD2 agonist and its link with inflammation. Crit Care 13(4):R124PubMedCentralPubMedGoogle Scholar
  75. 75.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969PubMedCentralPubMedGoogle Scholar
  76. 76.
    Loke P, MacDonald AS, Robb A, Maizels RM, Allen JE (2000) Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell to cell contact. Eur J Immunol 30:2669–2678PubMedGoogle Scholar
  77. 77.
    Elliott DE, Weinstock JV (2012) Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci 1247:83–96PubMedCentralPubMedGoogle Scholar
  78. 78.
    Schnoeller C, Rausch S, Pillai S, Avagyan A, Wittig BM, Loddenkemper C et al (2008) A helminth immunomodulator reduces allergic and inflammatory responses by induction of IL-10-producing macrophages. J Immunol 180(6):4265–4272PubMedGoogle Scholar
  79. 79.
    Smith P, Mangan NE, Walsh CM, Fallon RE, McKenzie ANJ, van Rooijen N et al (2007) Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism. J Immunol 178:4557–4566PubMedGoogle Scholar
  80. 80.
    Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG (2004) Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 173(10):6346–6356PubMedGoogle Scholar
  81. 81.
    Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF (2008) Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 118(10):3420–3430PubMedCentralPubMedGoogle Scholar
  82. 82.
    Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF (2008) A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28(5):639–650PubMedGoogle Scholar
  83. 83.
    Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG (2010) Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. J Allergy Clin Immunol 125(5):1114–1124 e8Google Scholar
  84. 84.
    Yanaba K, Bouaziz JD, Matsushita T, Magro CM, St Clair EW, Tedder TF (2008) B-lymphocyte contributions to human autoimmune disease. Immunol Rev 223:284–299PubMedGoogle Scholar
  85. 85.
    Correale J, Farez M, Razzitte G (2008) Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol 64(2):187–199PubMedGoogle Scholar
  86. 86.
    Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M (2005) Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J Immunol 174(6):3237–3246PubMedGoogle Scholar
  87. 87.
    Hart AL, Lammers K, Brigidi P, Vitali B, Rizzello F, Gionchetti P et al (2004) Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53(11):1602–1609PubMedCentralPubMedGoogle Scholar
  88. 88.
    Braat H, van den Brande J, van Tol E, Hommes D, Peppelenbosch M, van Deventer S (2004) Lactobacillus rhamnosus induces peripheral hyporesponsiveness in stimulated CD4+ T cells via modulation of dendritic cell function. Am J Clin Nutr 80(6):1618–1625PubMedGoogle Scholar
  89. 89.
    Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TM et al (2005) Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol 115(6):1260–1267PubMedGoogle Scholar
  90. 90.
    Le Bert N, Chain BM, Rook G, Noursadeghi M (2011) DC priming by M. vaccae inhibits Th2 responses in contrast to specific TLR2 priming and is associated with selective activation of the CREB pathway. PLoS One 6(4):e18346PubMedCentralPubMedGoogle Scholar
  91. 91.
    Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL et al (2008) Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med 205(9):2139–2149PubMedCentralPubMedGoogle Scholar
  92. 92.
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR et al (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204(8):1775–1785PubMedCentralPubMedGoogle Scholar
  93. 93.
    Mann ER, Landy JD, Bernardo D, Peake ST, Hart AL, Al-Hassi HO et al (2013) Intestinal dendritic cells: their role in intestinal inflammation, manipulation by the gut microbiota and differences between mice and men. Immunol Lett 150(1–2):30–40PubMedGoogle Scholar
  94. 94.
    Smelt MJ, de Haan BJ, Bron PA, van Swam I, Meijerink M, Wells JM et al (2012) L. plantarum, L. salivarius, and L. lactis attenuate Th2 responses and increase Treg frequencies in healthy mice in a strain dependent manner. PLoS One 7(10):e47244PubMedCentralPubMedGoogle Scholar
  95. 95.
    Correale J, Farez M (2007) Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol 61(2):97–108PubMedGoogle Scholar
  96. 96.
    Correale J, Farez MF (2011) The impact of parasite infections on the course of multiple sclerosis. J Neuroimmunol 233:6–11PubMedGoogle Scholar
  97. 97.
    Fleming J, Isaak A, Lee J, Luzzio C, Carrithers M, Cook T et al (2011) Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study. Mult Scler 17(6):743–754PubMedCentralPubMedGoogle Scholar
  98. 98.
    Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA et al (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332(6032):974–977PubMedCentralPubMedGoogle Scholar
  99. 99.
    Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ et al (2010) Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J Exp Med 207(11):2331–2341PubMedCentralPubMedGoogle Scholar
  100. 100.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y et al (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–341PubMedCentralPubMedGoogle Scholar
  101. 101.
    Meadow JF, Bateman AC, Herkert KM, O’Connor TK, Green JL (2013) Significant changes in the skin microbiome mediated by the sport of roller derby. Peer J. Doi: 10.7717/peerj.53.
  102. 102.
    Song SJ, Lauber C, Costello EK, Lozupone CA, Humphrey G, Berg-Lyons D et al (2013) Cohabiting family members share microbiota with one another and with their dogs. Elife 2:e00458PubMedCentralPubMedGoogle Scholar
  103. 103.
    Maslowski KM, Mackay CR (2011) Diet, gut microbiota and immune responses. Nat Immunol 12(1):5–9PubMedGoogle Scholar
  104. 104.
    De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S 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
  105. 105.
    Dethlefsen L, Huse S, Sogin ML, Relman DA (2008) The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6(11):e280PubMedCentralPubMedGoogle Scholar
  106. 106.
    Cani PD, Delzenne NM (2011) The gut microbiome as therapeutic target. Pharmacol Ther 130(2):202–212PubMedGoogle Scholar
  107. 107.
    Hildebrand F, Nguyen TL, Brinkman B, Yunta RG, Cauwe B, Vandenabeele P et al (2013) Inflammation-associated enterotypes, host genotype, cage and inter-individual effects drive gut microbiota variation in common laboratory mice. Genome Biol 14(1):R4PubMedCentralPubMedGoogle Scholar
  108. 108.
    Abrahamsson TR, Jakobsson HE, Andersson AF, Bjorksten B, Engstrand L, Jenmalm MC (2012) Low diversity of the gut microbiota in infants with atopic eczema. J Allergy Clin Immunol 129(2):434–440, 40 e1–e2Google Scholar
  109. 109.
    Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L et al (2006) Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55(2):205–211PubMedCentralPubMedGoogle Scholar
  110. 110.
    Nemoto H, Kataoka K, Ishikawa H, Ikata K, Arimochi H, Iwasaki T et al (2012) Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis. Dig Dis Sci 57(11):2955–2964PubMedGoogle Scholar
  111. 111.
    Rehman A, Lepage P, Nolte A, Hellmig S, Schreiber S, Ott SJ (2010) Transcriptional activity of the dominant gut mucosal microbiota in chronic inflammatory bowel disease patients. J Med Microbiol 59(Pt 9):1114–1122PubMedGoogle Scholar
  112. 112.
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE et al (2009) A core gut microbiome in obese and lean twins. Nature 457(7228):480–484PubMedCentralPubMedGoogle Scholar
  113. 113.
    Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S et al (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488(7410):178–184PubMedGoogle Scholar
  114. 114.
    Aichbhaumik N, Zoratti EM, Strickler R, Wegienka G, Ownby DR, Havstad S et al (2008) Prenatal exposure to household pets influences fetal immunoglobulin E production. Clin Exp Allergy 38(11):1787–1794PubMedCentralPubMedGoogle Scholar
  115. 115.
    Ege MJ, Mayer M, Schwaiger K, Mattes J, Pershagen G, van Hage M et al (2012) Environmental bacteria and childhood asthma. Allergy 67:1565–1571Google Scholar
  116. 116.
    Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K, Laatikainen T et al (2012) Environmental biodiversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci U S A 109(21):8334–8339PubMedCentralPubMedGoogle Scholar
  117. 117.
    Korhonen L, Kondrashova A, Tauriainen S, Haapala AM, Huhtala H, Ilonen J et al (2013) Enterovirus infections in early childhood and the risk of atopic disease – a nested case-control study. Clin Exp Allergy 43(6):625–632PubMedGoogle Scholar
  118. 118.
    Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Rapicetta M et al (2000) Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma; epidemiological study. BMJ 320:412–417PubMedCentralPubMedGoogle Scholar
  119. 119.
    Hesselmar B, Sjoberg F, Saalman R, Aberg N, Adlerberth I, Wold AE (2013) Pacifier cleaning practices and risk of allergy development. Pediatrics 131:e1829–e1837Google Scholar
  120. 120.
    Magnus MC, Haberg SE, Stigum H, Nafstad P, London SJ, Vangen S et al (2011) Delivery by Cesarean section and early childhood respiratory symptoms and disorders: the Norwegian mother and child cohort study. Am J Epidemiol 174(11):1275–1285PubMedCentralPubMedGoogle Scholar
  121. 121.
    Guibas GV et al (2013) Conception via in vitro fertilization and delivery by cesarean section are associated with pediatric asthma incidence. Clin Exp Allergy 43:1058–1066Google Scholar
  122. 122.
    Stensballe LG, Simonsen J, Jensen SM, Bonnelykke K, Bisgaard H (2013) Use of antibiotics during pregnancy increases the risk of asthma in early childhood. J Pediatr 162(4):832–838 e3Google Scholar
  123. 123.
    Russell G, Helms PJ (1997) Trend in occurrence of asthma among children and young adults. Reporting of common respiratory and atopic symptoms has increased. BMJ 315(7114):1014–1015PubMedCentralPubMedGoogle Scholar
  124. 124.
    Metsala J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM (2013) Mother’s and offspring’s use of antibiotics and infant allergy to cow’s milk. Epidemiology 24(2):303–309PubMedGoogle Scholar
  125. 125.
    Hviid A, Svanstrom H, Frisch M (2011) Antibiotic use and inflammatory bowel diseases in childhood. Gut 60(1):49–54PubMedGoogle Scholar
  126. 126.
    Shaw SY, Blanchard JF, Bernstein CN (2010) Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol 105(12):2687–2692PubMedGoogle Scholar
  127. 127.
    Mulder IE, Schmidt B, Stokes CR, Lewis M, Bailey M, Aminov RI et al (2009) Environmentally-acquired bacteria influence microbial diversity and natural innate immune responses at gut surfaces. BMC Biol 7:79PubMedCentralPubMedGoogle Scholar
  128. 128.
    Hemarajata P, Versalovic J (2013) Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol 6(1):39–51PubMedCentralPubMedGoogle Scholar
  129. 129.
    Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC et al (2008) Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455(7216):1109–1113PubMedCentralPubMedGoogle Scholar
  130. 130.
    Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ et al (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145(5):745–757PubMedCentralPubMedGoogle Scholar
  131. 131.
    Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S et al (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328(5975):228–231PubMedGoogle Scholar
  132. 132.
    Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T et al (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482(7384):179–185PubMedCentralPubMedGoogle Scholar
  133. 133.
    Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S et al (2007) Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131(1):33–45PubMedCentralPubMedGoogle Scholar
  134. 134.
    Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W et al (2012) Compartmentalized control of skin immunity by resident commensals. Science 337(6098):1115–1119PubMedCentralPubMedGoogle Scholar
  135. 135.
    Nakatsuji T, Chiang HI, Jiang SB, Nagarajan H, Zengler K, Gallo RL (2013) The microbiome extends to subepidermal compartments of normal skin. Nat Commun 4:1431PubMedCentralPubMedGoogle Scholar
  136. 136.
    Bailey MT, Engler H, Sheridan JF (2006) Stress induces the translocation of cutaneous and gastrointestinal microflora to secondary lymphoid organs of C57BL/6 mice. J Neuroimmunol 171(1–2):29–37PubMedGoogle Scholar
  137. 137.
    Friberg IM, Bradley JE, Jackson JA (2010) Macroparasites, innate immunity and immunoregulation: developing natural models. Trends Parasitol 26:540–549Google Scholar
  138. 138.
    Jackson JA, Friberg IM, Bolch L, Lowe A, Ralli C, Harris PD et al (2009) Immunomodulatory parasites and toll-like receptor-mediated tumour necrosis factor alpha responsiveness in wild mammals. BMC Biol 7:16PubMedCentralPubMedGoogle Scholar
  139. 139.
    Harnett MM, Melendez AJ, Harnett W (2010) The therapeutic potential of the filarial nematode-derived immunodulator, ES-62 in inflammatory disease. Clin Exp Immunol 159(3):256–267PubMedCentralPubMedGoogle Scholar
  140. 140.
    Kron MA, Metwali A, Vodanovic-Jankovic S, Elliott D (2013) Nematode AsnRS resolves intestinal inflammation in murine T-cell transfer colitis. Clin Vaccine Immunol 20:276–281Google Scholar
  141. 141.
    Liu W, Li Y, Learn GH, Rudicell RS, Robertson JD, Keele BF et al (2010) Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 467(7314):420–425PubMedCentralPubMedGoogle Scholar
  142. 142.
    Sotgiu S, Angius A, Embry A, Rosati G, Musumeci S (2008) Hygiene hypothesis: innate immunity, malaria and multiple sclerosis. Med Hypotheses 70(4):819–825PubMedGoogle Scholar
  143. 143.
    Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M et al (2009) Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 206(6):1395–1408PubMedCentralPubMedGoogle Scholar
  144. 144.
    Barnes KC, Grant AV, Gao P (2005) A review of the genetic epidemiology of resistance to parasitic disease and atopic asthma: common variants for common phenotypes? Curr Opin Allergy Clin Immunol 5(5):379–385PubMedGoogle Scholar
  145. 145.
    Moller M, Gravenor MB, Roberts SE, Sun D, Gao P, Hopkin JM (2007) Genetic haplotypes of Th-2 immune signalling link allergy to enhanced protection to parasitic worms. Hum Mol Genet 16(15):1828–1836PubMedGoogle Scholar
  146. 146.
    Fredericks CA, Drabant EM, Edge MD, Tillie JM, Hallmayer J, Ramel W et al (2010) Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions. Brain Behav Immun 24:350–357PubMedCentralPubMedGoogle Scholar
  147. 147.
    Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW et al (2009) Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease. J Exp Med 206(9):1883–1897PubMedCentralPubMedGoogle Scholar
  148. 148.
    Pace TW, Hu F, Miller AH (2007) Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 21(1):9–19PubMedCentralPubMedGoogle Scholar
  149. 149.
    Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS et al (2012) Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A 109:5995–5999PubMedCentralPubMedGoogle Scholar
  150. 150.
    Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D et al (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A 100(4):1920–1925PubMedCentralPubMedGoogle Scholar
  151. 151.
    Hanke ML, Powell ND, Stiner LM, Bailey MT, Sheridan JF (2012) Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress. Brain Behav Immun 26(7):1150–1159PubMedCentralPubMedGoogle Scholar
  152. 152.
    Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO et al (2004) Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 24(6):1478–1485PubMedGoogle Scholar
  153. 153.
    Lee R, Geracioti TD Jr, Kasckow JW, Coccaro EF (2005) Childhood trauma and personality disorder: positive correlation with adult CSF corticotropin-releasing factor concentrations. Am J Psychiatry 162(5):995–997PubMedGoogle Scholar
  154. 154.
    Gareau MG, Silva MA, Perdue MH (2008) Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med 8(4):274–281PubMedGoogle Scholar
  155. 155.
    Teitelbaum AA, Gareau MG, Jury J, Yang PC, Perdue MH (2008) Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress. Am J Physiol 295(3):G452–G459Google Scholar
  156. 156.
    Wallon C, Yang PC, Keita AV, Ericson AC, McKay DM, Sherman PM et al (2008) Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro. Gut 57(1):50–58PubMedGoogle Scholar
  157. 157.
    Calcagni E, Elenkov I (2006) Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. Ann N Y Acad Sci 1069:62–76PubMedGoogle Scholar
  158. 158.
    Zbytek B, Slominski AT (2007) CRH mediates inflammation induced by lipopolysaccharide in human adult epidermal keratinocytes. J Invest Dermatol 127(3):730–732PubMedCentralPubMedGoogle Scholar
  159. 159.
    Broadhurst MJ, Ardeshir A, Kanwar B, Mirpuri J, Gundra UM, Leung JM et al (2012) Therapeutic helminth infection of macaques with idiopathic chronic diarrhea alters the inflammatory signature and mucosal microbiota of the colon. PLoS Pathog 8(11):e1003000PubMedCentralPubMedGoogle Scholar
  160. 160.
    Hayakawa M, Asahara T, Henzan N, Murakami H, Yamamoto H, Mukai N et al (2011) Dramatic changes of the gut flora immediately after severe and sudden insults. Dig Dis Sci 56(8):2361–2365PubMedGoogle Scholar
  161. 161.
    Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA et al (2012) Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med 209:903–911PubMedCentralPubMedGoogle Scholar
  162. 162.
    Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L 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
  163. 163.
    Bailey MT, Lubach GR, Coe CL (2004) Prenatal stress alters bacterial colonization of the gut in infant monkeys. J Pediatr Gastroenterol Nutr 38(4):414–421PubMedGoogle Scholar
  164. 164.
    Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN 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
  165. 165.
    Heijtz RD, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A et al (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108(7):3047–3052PubMedCentralGoogle Scholar
  166. 166.
    Miller AH, Haroon E, Raison CL, Felger JC (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30(4):297–306PubMedGoogle Scholar
  167. 167.
    Raison CL, Miller AH (2013) The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry 18:15–37Google Scholar
  168. 168.
    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56PubMedCentralPubMedGoogle Scholar
  169. 169.
    Rook GAW, Lowry CA, Raison CL (2013) Microbial old friends, immunoregulation and stress resilience. Evol Med Pubic Health 2013(1):46–64. Doi:  10.1093/emph/eot004
  170. 170.
    McDade TW (2012) Early environments and the ecology of inflammation. Proc Natl Acad Sci U S A 109(Suppl 2):17281–17288PubMedCentralPubMedGoogle Scholar
  171. 171.
    Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG (2009) Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biol Psychiatry 65(4):344–348PubMedCentralPubMedGoogle Scholar
  172. 172.
    Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ et al (2009) Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry 65(4):296–303PubMedCentralPubMedGoogle Scholar
  173. 173.
    Hagberg H, Gressens P, Mallard C (2012) Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 71(4):444–457PubMedGoogle Scholar
  174. 174.
    D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor alpha signaling during peripheral organ inflammation. J Neurosci 29(7):2089–2102PubMedGoogle Scholar
  175. 175.
    Kivisakk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM et al (2009) Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 65(4):457–469PubMedCentralPubMedGoogle Scholar
  176. 176.
    Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31(4):497–511PubMedGoogle Scholar
  177. 177.
    Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13(7):465–477PubMedCentralPubMedGoogle Scholar
  178. 178.
    Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303(1):1–10PubMedGoogle Scholar
  179. 179.
    O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N et al (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14(5):511–522PubMedCentralPubMedGoogle Scholar
  180. 180.
    Kita T, Morrison PF, Heyes MP, Markey SP (2002) Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. J Neurochem 82(2):258–268PubMedGoogle Scholar
  181. 181.
    Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G et al (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15(4):393–403PubMedCentralPubMedGoogle Scholar
  182. 182.
    Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA (2010) Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35(13):2510–2520PubMedCentralPubMedGoogle Scholar
  183. 183.
    Capuron L, Pagnoni G, Drake DF, Woolwine BJ, Spivey JR, Crowe RJ et al (2012) Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry 69(10):1044–1053PubMedCentralPubMedGoogle Scholar
  184. 184.
    Felger JC, Li L, Marvar PJ, Woolwine BJ, Harrison DG, Raison CL et al (2013) Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations. Brain Behav Immun 31:153–160Google Scholar
  185. 185.
    Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M, Ochani K et al (2009) Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 23(1):41–45PubMedGoogle Scholar
  186. 186.
    Lee M, Schwab C, McGeer PL (2011) Astrocytes are GABAergic cells that modulate microglial activity. Glia 59(1):152–165PubMedGoogle Scholar
  187. 187.
    Hertz-Picciotto I, Delwiche L (2009) The rise in autism and the role of age at diagnosis. Epidemiology 20(1):84–90PubMedGoogle Scholar
  188. 188.
    Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T et al (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68(11):1095–1102PubMedGoogle Scholar
  189. 189.
    Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S et al (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474(7351):380–384PubMedCentralPubMedGoogle Scholar
  190. 190.
    Ziats MN, Rennert OM (2011) Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways. PLoS One 6(9):e24691PubMedCentralPubMedGoogle Scholar
  191. 191.
    Saresella M, Marventano I, Guerini FR, Mancuso R, Ceresa L, Zanzottera M et al (2009) An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children. Biol Psychiatry 66(10):978–984PubMedGoogle Scholar
  192. 192.
    Desmond MM, Montgomery JR, Melnick JL, Cochran GG, Verniaud W (1969) Congenital rubella encephalitis. Effects on growth and early development. Am J Dis Child 118(1):30–31PubMedGoogle Scholar
  193. 193.
    Atladottir HO, Thorsen P, Schendel DE, Ostergaard L, Lemcke S, Parner ET (2010) Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Arch Pediatr Adolesc Med 164(5):470–477PubMedGoogle Scholar
  194. 194.
    Brown AS, Sourander A, Hinkka-Yli-Salomaki S, McKeague IW, Sundvall J, Surcel HM (2014) Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry 19:259–264Google Scholar
  195. 195.
    Howerton CL, Bale TL (2012) Prenatal programing: at the intersection of maternal stress and immune activation. Horm Behav 62:237–242PubMedCentralPubMedGoogle Scholar
  196. 196.
    Dahlgren J, Samuelsson AM, Jansson T, Holmang A (2006) Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. Pediatr Res 60(2):147–151PubMedGoogle Scholar
  197. 197.
    Willette AA, Lubach GR, Knickmeyer RC, Short SJ, Styner M, Gilmore JH et al (2011) Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia. Behav Brain Res 219(1):108–115PubMedCentralPubMedGoogle Scholar
  198. 198.
    Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A 109(31):12776–12781PubMedCentralPubMedGoogle Scholar
  199. 199.
    Meyer U, Feldon J, Dammann O (2011) Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatr Res 69(5 Pt 2):26R–33RPubMedCentralPubMedGoogle Scholar
  200. 200.
    Onore C, Careaga M, Ashwood P (2012) The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 26:383–392PubMedCentralPubMedGoogle Scholar
  201. 201.
    Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57(1):67–81PubMedGoogle Scholar
  202. 202.
    Pardo CA, Vargas DL, Zimmerman AW (2005) Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 17(6):485–495PubMedGoogle Scholar
  203. 203.
    Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM et al (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207(1–2):111–116PubMedCentralPubMedGoogle Scholar
  204. 204.
    Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB et al (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90(21):10061–10065PubMedCentralPubMedGoogle Scholar
  205. 205.
    Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT et al (2011) IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation 8:52PubMedCentralPubMedGoogle Scholar
  206. 206.
    Nordahl CW, Braunschweig D, Iosif AM, Lee A, Rogers S, Ashwood P et al (2013) Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav Immun 30:61–65PubMedCentralPubMedGoogle Scholar
  207. 207.
    Margutti P, Delunardo F, Ortona E (2006) Autoantibodies associated with psychiatric disorders. Curr Neurovasc Res 3(2):149–157PubMedGoogle Scholar
  208. 208.
    Lee JY, Huerta PT, Zhang J, Kowal C, Bertini E, Volpe BT et al (2009) Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat Med 15(1):91–96PubMedCentralPubMedGoogle Scholar
  209. 209.
    Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J et al (2013) Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry 12:1–9Google Scholar
  210. 210.
    Nikolov RN, Bearss KE, Lettinga J, Erickson C, Rodowski M, Aman MG et al (2009) Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. J Autism Dev Disord 39(3):405–413PubMedGoogle Scholar
  211. 211.
    Critchfield JW, 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 2011:161358PubMedCentralPubMedGoogle Scholar
  212. 212.
    Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F et al (2010) Low-grade endotoxemia in patients with severe autism. Neurosci Lett 471(3):162–165PubMedGoogle Scholar
  213. 213.
    Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD et al (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16(4):444–453PubMedGoogle Scholar
  214. 214.
    Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11:22PubMedCentralPubMedGoogle Scholar
  215. 215.
    Williams BL, Hornig M, Parekh T, Lipkin WI (2012) Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio 3(1)Google Scholar
  216. 216.
    Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S et al (2012) 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 9:153PubMedCentralPubMedGoogle Scholar
  217. 217.
    Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35(3):528–548PubMedCentralPubMedGoogle Scholar
  218. 218.
    Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH (2001) Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav Immun 15(4):411–420PubMedGoogle Scholar
  219. 219.
    Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V et al (2004) Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry 161(5):889–895PubMedGoogle Scholar
  220. 220.
    Crespi B, Badcock C (2008) Psychosis and autism as diametrical disorders of the social brain. Behav Brain Sci 31(3):241–261, discussion 61–320PubMedGoogle Scholar
  221. 221.
    Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, Williams TA et al (2009) HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Arch Pediatr Adolesc Med 163(6):542–546PubMedGoogle Scholar

Copyright information

© Springer New York 2014

Authors and Affiliations

  • Graham A. W. Rook
    • 1
  • Charles L. Raison
    • 2
  • Christopher A. Lowry
    • 3
  1. 1.Centre for Clinical MicrobiologyUCL (University College London)LondonUK
  2. 2.Department of Psychiatry, College of Medicine and Norton School of Family and Consumer Sciences, College of Agriculture and Life SciencesUniversity of ArizonaTucsonUSA
  3. 3.Department of Integrative Physiology and Center for NeuroscienceUniversity of Colorado BoulderBoulderUSA

Personalised recommendations