Advertisement

pp 1-18 | Cite as

From Infection to the Microbiome: An Evolving Role of Microbes in Schizophrenia

  • Emily G. SeveranceEmail author
  • Robert H. Yolken
Chapter
Part of the Current Topics in Behavioral Neurosciences book series

Abstract

The study of microorganisms such as bacteria, viruses, archaea, fungi, and protozoa in the context of psychiatric disorders may be surprising to some. This intersection of disciplines, however, has a rich history and is currently revitalized by newfound functions of the microbiome and the gut-brain axis in human diseases. Schizophrenia, in particular, fits this model as a disorder with gene and environmental roots that may be anchored in the immune system. In this context, the combination of a precisely timed pathogen exposure in a person with genetically encoded altered immunity may have especially destructive consequences for the central nervous system (CNS). Furthermore, significant components of immunity, such as the development of the immune response and the concept of immune tolerance, are largely dictated by the commensal residents of the microbiome. When this community of microbes is imbalanced, perhaps as the result of a pathogen invasion, stress, or immune gene deficiency, a pathological cycle of localized inflammation, endothelial barrier compromise, translocation of gut-derived products, and systemic inflammation may ensue. If these pathologies enable access of gut and microbial metabolites and immune molecules to the CNS across the blood-brain barrier (BBB), and studies of the gut-brain axis support this hypothesis, a worsening of cognitive deficits and psychiatric symptoms is predicted to occur in susceptible individuals with schizophrenia. In this chapter, we review the role of microbes in various stages of this model and how these organisms may contribute to documented phenotypes of schizophrenia. An increased understanding of the role of pathogens and the microbiome in psychiatric disorders will better guide the development of microbial and immune-based therapeutics for disease prevention and treatment.

Keywords

Gastrointestinal Host-pathogen interactions Microbiota Neuroimmune Psychiatry 

Notes

Acknowledgments

This work was supported by a NIMH P50 Silvio O. Conte Center at Johns Hopkins (grant# MH-94268) and by the Stanley Medical Research Institute.

References

  1. Alam R, Abdolmaleky HM, Zhou JR (2017) Microbiome, inflammation, epigenetic alterations, and mental diseases. Am J Med Genet B Neuropsychiatr Genet 174:651–660Google Scholar
  2. Alander T, Svardsudd K, Johansson SE, Agreus L (2005) Psychological illness is commonly associated with functional gastrointestinal disorders and is important to consider during patient consultation: a population-based study. BMC Med 3:8Google Scholar
  3. Allswede DM, Buka SL, Yolken RH, Torrey EF, Cannon TD (2016) Elevated maternal cytokine levels at birth and risk for psychosis in adult offspring. Schizophr Res 172:41–45Google Scholar
  4. APA (1952) Diagnostic and statistical manual of mental disorders (DSM-I), 1st edn. American Psychiatric Association, WashingtonGoogle Scholar
  5. Arias I, Sorlozano A, Villegas E, de Dios Luna J, McKenney K, Cervilla J et al (2012) Infectious agents associated with schizophrenia: a meta-analysis. Schizophr Res 136:128–136Google Scholar
  6. Ashorn S, Valineva T, Kaukinen K, Ashorn M, Braun J, Raukola H et al (2009) Serological responses to microbial antigens in celiac disease patients during a gluten-free diet. J Clin Immunol 29:190–195Google Scholar
  7. Azami M, Jalilian FA, Khorshidi A, Mohammadi Y, Tardeh Z (2018) The association between Borna disease virus and schizophrenia: a systematic review and meta-analysis. Asian J Psychiatr 34:67–73Google Scholar
  8. Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS (2006) Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry 163:927–929Google Scholar
  9. Bechter K (2013) Updating the mild encephalitis hypothesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:71–91Google Scholar
  10. Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Annu Rev Med 60:355–366Google Scholar
  11. Blomstrom A, Karlsson H, Gardner R, Jorgensen L, Magnusson C, Dalman C (2016) Associations between maternal infection during pregnancy, childhood infections, and the risk of subsequent psychotic disorder – a Swedish cohort study of nearly two million individuals. Schizophr Bull 42:125–133Google Scholar
  12. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M et al (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6:263ra158Google Scholar
  13. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S et al (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371Google Scholar
  14. Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261–280Google Scholar
  15. Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M et al (2004) Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 61:774–780Google Scholar
  16. Buka SL, Cannon TD, Torrey EF, Yolken RH, Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders (2008) Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biol Psychiatry 63:809–815Google Scholar
  17. Buscaino V (1953) Patologia extraneurale della schizofrenia. Fegato, tubo digerente, sistema reticolo-endoteliale. Acta Neurol 8:1–60Google Scholar
  18. Carson CM, Phillip N, Miller BJ (2017) Urinary tract infections in children and adolescents with acute psychosis. Schizophr Res 183:36–40Google Scholar
  19. Caso JR, Balanza-Martinez V, Palomo T, Garcia-Bueno B (2016) The microbiota and gut-brain axis: contributions to the immunopathogenesis of schizophrenia. Curr Pharm Des 22:6122–6133Google Scholar
  20. Castro-Nallar E, Bendall ML, Perez-Losada M, Sabuncyan S, Severance EG, Dickerson FB et al (2015) Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls. PeerJ 3:e1140Google Scholar
  21. Catts VS, Wong J, Fillman SG, Fung SJ, Shannon Weickert C (2014) Increased expression of astrocyte markers in schizophrenia: association with neuroinflammation. Aust N Z J Psychiatry 48:722–734Google Scholar
  22. Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10:735–742Google Scholar
  23. Craven M, Egan CE, Dowd SE, McDonough SP, Dogan B, Denkers EY et al (2012) Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn’s disease. PLoS One 7:e41594Google Scholar
  24. Crow TJ (1978) Viral causes of psychiatric disease. Postgrad Med J 54:763–767Google Scholar
  25. Crow TJ (1983) Is schizophrenia an infectious disease? Lancet 1:173–175Google Scholar
  26. Crow TJ (1984) A re-evaluation of the viral hypothesis: is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br J Psychiatry 145:243–253Google Scholar
  27. Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G et al (2008) Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry 165:59–65Google Scholar
  28. Dean B (2010) Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies. Int J Neuropsychopharmacol 14:997–1012Google Scholar
  29. Debost JP, Larsen JT, Munk-Olsen T, Mortensen PB, Meyer U, Petersen L (2017) Joint effects of exposure to prenatal infection and peripubertal psychological trauma in schizophrenia. Schizophr Bull 43:171–179Google Scholar
  30. Demjaha A, MacCabe JH, Murray RM (2012) How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr Bull 38:209–214Google Scholar
  31. Desplat-Jego S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N et al (2007) Update on anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study. World J Gastroenterol: WJG 13:2312–2318Google Scholar
  32. Diaz Heijtz R, 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 108:3047–3052Google Scholar
  33. Dickerson F, Stallings C, Origoni A, Copp C, Khushalani S, Yolken R (2010a) Antibodies to measles in individuals with recent onset psychosis. Schizophr Res 119:89–94Google Scholar
  34. Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Leister F et al (2010b) Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry 68:100–104Google Scholar
  35. Dickerson FB, Stallings C, Origoni A, Katsafanas E, Savage CL, Schweinfurth LA et al (2014) Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord 16.  https://doi.org/10.4088/PCC.13m01579
  36. Dickerson F, Stallings C, Origoni A, Schroeder J, Katsafanas E, Schweinfurth L et al (2016) Inflammatory markers in recent onset psychosis and chronic schizophrenia. Schizophr Bull 42:134–141Google Scholar
  37. Dickerson F, Severance E, Yolken R (2017a) The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun 62:46–52Google Scholar
  38. Dickerson F, Wilcox HC, Adamos M, Katsafanas E, Khushalani S, Origoni A et al (2017b) Suicide attempts and markers of immune response in individuals with serious mental illness. J Psychiatr Res 87:37–43Google Scholar
  39. Dinan TG, Cryan JF (2015) The impact of gut microbiota on brain and behaviour: implications for psychiatry. Curr Opin Clin Nutr Metab Care 18:552–558Google Scholar
  40. Dinan TG, Cryan JF, Stanton C (2018) Gut microbes and brain development have black box connectivity. Biol Psychiatry 83:97–99Google Scholar
  41. D’Mello C, Swain MG (2014) Liver-brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders. Brain Behav Immun 35:9–20Google Scholar
  42. Dohan FC (1970) Coeliac disease and schizophrenia. Lancet 1:897–898Google Scholar
  43. Dome P, Teleki Z, Kotanyi R (2007) Paralytic ileus associated with combined atypical antipsychotic therapy. Prog Neuro-Psychopharmacol Biol Psychiatry 31:557–560Google Scholar
  44. Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H (2004) Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ 328:438–439Google Scholar
  45. El Aidy S, Dinan TG, Cryan JF (2014) Immune modulation of the brain-gut-microbe axis. Front Microbiol 5:146Google Scholar
  46. Ellman LM, Yolken RH, Buka SL, Torrey EF, Cannon TD (2009) Cognitive functioning prior to the onset of psychosis: the role of fetal exposure to serologically determined influenza infection. Biol Psychiatry 65:1040–1047Google Scholar
  47. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E et al (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18:965–977Google Scholar
  48. Esquirol JE (1845) Mental maladies, a treatise on insanity. Lea and Blanchard, PhiladelphiaGoogle Scholar
  49. Esshili A, Thabet S, Jemli A, Trifa F, Mechri A, Zaafrane F et al (2016) Toxoplasma gondii infection in schizophrenia and associated clinical features. Psychiatry Res 245:327–332Google Scholar
  50. Estes ML, McAllister AK (2016) Maternal immune activation: implications for neuropsychiatric disorders. Science 353:772–777Google Scholar
  51. European Network of National Networks studying Gene-Environment Interactions in Schizophrenia (EU-GEI), van Os J, Rutten BP, Myin-Germeys I, Delespaul P, Viechtbauer W et al (2014) Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations. Schizophr Bull 40:729–736Google Scholar
  52. Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T et al (2013) Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 18:206–214Google Scholar
  53. Fillman SG, Sinclair D, Fung SJ, Webster MJ, Shannon Weickert C (2014) Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry 4:e365Google Scholar
  54. Fillman SG, Weickert TW, Lenroot RK, Catts SV, Bruggemann JM, Catts VS et al (2016) Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry 21:1090–1098Google Scholar
  55. Foster JA, McVey Neufeld KA (2013) Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36:305–312Google Scholar
  56. Graham KL, Carson CM, Ezeoke A, Buckley PF, Miller BJ (2014) Urinary tract infections in acute psychosis. J Clin Psychiatry 75:379–385Google Scholar
  57. Grainger JR, Wohlfert EA, Fuss IJ, Bouladoux N, Askenase MH, Legrand F et al (2013) Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat Med 19:713–721Google Scholar
  58. Greene C, Kealy J, Humphries MM, Gong Y, Hou J, Hudson N et al (2017) Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Mol Psychiatry 23:2156–2166Google Scholar
  59. Gupta S, Masand PS, Kaplan D, Bhandary A, Hendricks S (1997) The relationship between schizophrenia and irritable bowel syndrome (IBS). Schizophr Res 23:265–268Google Scholar
  60. Gurassa WP, Fleischhacker HH (1958) An investigation of the Rosenow antibody antigen skin reaction in schizophrenia. J Neurol Neurosurg Psychiatry 21:141–145Google Scholar
  61. Hamdani N, Daban-Huard C, Godin O, Laouamri H, Jamain S, Attiba D et al (2017) Effects of cumulative herpesviridae and Toxoplasma gondii infections on cognitive function in healthy, bipolar, and schizophrenia subjects. J Clin Psychiatry 78:e18–e27Google Scholar
  62. Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagan AJ, Pepper M et al (2012) Acute gastrointestinal infection induces long-lived microbiota-specific t cell responses. Science 337:1553–1556Google Scholar
  63. Heimesaat MM, Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J et al (2006) Gram-negative bacteria aggravate murine small intestinal th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol 177:8785–8795Google Scholar
  64. Hemmings G (2004) Schizophrenia. Lancet 364:1312–1313Google Scholar
  65. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T et al (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–1463Google Scholar
  66. Ismail AS, Hooper LV (2005) Epithelial cells and their neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity. Am J Physiol Gastrointest Liver Physiol 289:G779–G784Google Scholar
  67. Iwata Y, Suzuki K, Nakamura K, Matsuzaki H, Sekine Y, Tsuchiya KJ et al (2007) Increased levels of serum soluble l-selectin in unmedicated patients with schizophrenia. Schizophr Res 89:154–160Google Scholar
  68. Jackson WA (2001) A short guide to humoral medicine. Trends Pharmacol Sci 22:487–489Google Scholar
  69. Kannan G, Gressitt KL, Yang S, Stallings CR, Katsafanas E, Schweinfurth LA et al (2017) Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia. Transl Psychiatry 7:e1186Google Scholar
  70. Karakula-Juchnowicz H, Dzikowski M, Pelczarska A, Dzikowska I, Juchnowicz D (2016) The brain-gut axis dysfunctions and hypersensitivity to food antigens in the etiopathogenesis of schizophrenia. Psychiatr Pol 50:747–760Google Scholar
  71. Karlsson H, Bachmann S, Schroder J, McArthur J, Torrey EF, Yolken RH (2001) Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci U S A 98:4634–4639Google Scholar
  72. Karlsson H, Schroder J, Bachmann S, Bottmer C, Yolken RH (2004) HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder. Mol Psychiatry 9:12–13Google Scholar
  73. Kavanagh DH, Tansey KE, O’Donovan MC, Owen MJ (2015) Schizophrenia genetics: emerging themes for a complex disorder. Mol Psychiatry 20:72–76Google Scholar
  74. Kelly DL, Demyanovich HK, Eaton WW, Cascella N, Jackson J, Fasano A et al (2018) Anti gliadin antibodies (AGA IgG) related to peripheral inflammation in schizophrenia. Brain Behav Immun 69:57–59Google Scholar
  75. Khandaker GM, Dantzer R (2016) Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology 233:1559–1573Google Scholar
  76. Khandaker GM, Zimbron J, Lewis G, Jones PB (2013) Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med 43:239–257Google Scholar
  77. Khandaker GM, Stochl J, Zammit S, Lewis G, Jones PB (2014) Childhood Epstein-Barr virus infection and subsequent risk of psychotic experiences in adolescence: a population-based prospective serological study. Schizophr Res 158:19–24Google Scholar
  78. Kim J, Sudbery P (2011) Candida albicans, a major human fungal pathogen. J Microbiol 49:171–177Google Scholar
  79. Kirch DG (1993) Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull 19:355–370Google Scholar
  80. Kirkpatrick B, Miller BJ (2013) Inflammation and schizophrenia. Schizophr Bull 39:1174–1179Google Scholar
  81. Kohler O, Petersen L, Mors O, Mortensen PB, Yolken RH, Gasse C et al (2017) Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr Scand 135:97–105Google Scholar
  82. Kotze LM, Nisihara RM, Utiyama SR, Kotze PG, Theiss PM, Olandoski M (2010) Antibodies anti-Saccharomyces cerevisiae (ASCA) do not differentiate Crohn’s disease from celiac disease. Arq Gastroenterol 47:242–245Google Scholar
  83. Labouesse MA, Langhans W, Meyer U (2015) Long-term pathological consequences of prenatal infection: beyond brain disorders. Am J Physiol Regul Integr Comp Physiol 309:R1–R12Google Scholar
  84. Lambert GP (2009) Stress-induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci 87:E101–E108Google Scholar
  85. Leweke FM, Gerth CW, Koethe D, Klosterkotter J, Ruslanova I, Krivogorsky B et al (2004) Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 254:4–8Google Scholar
  86. Lindgren M, Torniainen-Holm M, Harkanen T, Dickerson F, Yolken RH, Suvisaari J (2018) The association between Toxoplasma and the psychosis continuum in a general population setting. Schizophr Res 193:329–335Google Scholar
  87. Luczynski P, Whelan SO, O’Sullivan C, Clarke G, Shanahan F, Dinan TG et al (2016) Adult microbiota-deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur J Neurosci 44:2654–2666Google Scholar
  88. Maes M, Kubera M, Leunis JC (2008) The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett 29:117–124Google Scholar
  89. Maes M, Kubera M, Leunis JC, Berk M (2012a) Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 141:55–62Google Scholar
  90. Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E (2012b) In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand 127:344–354Google Scholar
  91. Makikyro T, Karvonen JT, Hakko H, Nieminen P, Joukamaa M, Isohanni M et al (1998) Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort. Public Health 112:221–228Google Scholar
  92. Mallant-Hent R, Mary B, von Blomberg E, Yuksel Z, Wahab PJ, Gundy C et al (2006) Disappearance of anti-Saccharomyces cerevisiae antibodies in coeliac disease during a gluten-free diet. Eur J Gastroenterol Hepatol 18:75–78Google Scholar
  93. Mayilyan KR, Dodds AW, Boyajyan AS, Soghoyan AF, Sim RB (2008) Complement c4b protein in schizophrenia. World J Biol Psychiatry 9:225–230Google Scholar
  94. McNamara RK, Jandacek R, Rider T, Tso P (2011) Chronic risperidone normalizes elevated pro-inflammatory cytokine and C-reactive protein production in omega-3 fatty acid deficient rats. Eur J Pharmacol 652:152–156Google Scholar
  95. Mednick SA, Machon RA, Huttunen MO, Bonett D (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 45:189–192Google Scholar
  96. Menninger KA (1919) Psychoses associated with influenza. J Am Med Assoc 72:235–241Google Scholar
  97. Menninger KA (1926) Influenza and schizophrenia: an analysis of post-influenza “dementia praecox” as of 1918 and five years later. Am J Psychiatr 5:469–529Google Scholar
  98. Meyer U (2014) Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry 75:307–315Google Scholar
  99. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70:663–671Google Scholar
  100. Miller BJ, Graham KL, Bodenheimer CM, Culpepper NH, Waller JL, Buckley PF (2013) A prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry 74:271–277Google Scholar
  101. Modinos G, Iyegbe C, Prata D, Rivera M, Kempton MJ, Valmaggia LR et al (2013) Molecular genetic gene-environment studies using candidate genes in schizophrenia: a systematic review. Schizophr Res 150:356–365Google Scholar
  102. Monroe JM, Buckley PF, Miller BJ (2015) Meta-analysis of anti-Toxoplasma gondii IgM antibodies in acute psychosis. Schizophr Bull 41:989–998Google Scholar
  103. Mortensen PB, Pedersen CB, Hougaard DM, Norgaard-Petersen B, Mors O, Borglum AD et al (2010) A Danish national birth cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring. Schizophr Res 122:257–263Google Scholar
  104. Muller N (2016) What role does inflammation play in schizophrenia? Expert Rev Neurother 16:1337–1340Google Scholar
  105. Murray RM, Lewis SW (1987) Is schizophrenia a neurodevelopmental disorder? Br Med J (Clin Res Ed) 295:681–682Google Scholar
  106. Nielsen PR, Benros ME, Mortensen PB (2014) Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers. Schizophr Bull 40:1526–1532Google Scholar
  107. Nimgaonkar VL, Yolken RH (2012) Neurotropic infectious agents and cognitive impairment in schizophrenia. Schizophr Bull 38:1135–1136Google Scholar
  108. Nimgaonkar VL, Prasad KM, Chowdari KV, Severance EG, Yolken RH (2017) The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis. Mol Psychiatry 22:1554–1561Google Scholar
  109. Noll R (2004) Historical review: autointoxication and focal infection theories of dementia praecox. World J Biol Psychiatry 5:66–72Google Scholar
  110. Oshitani N, Hato F, Matsumoto T, Jinno Y, Sawa Y, Hara J et al (2000) Decreased anti-Saccharomyces cerevisiae antibody titer by mesalazine in patients with Crohn’s disease. J Gastroenterol Hepatol 15:1400–1403Google Scholar
  111. Parks S, Avramopoulos D, Mulle J, McGrath J, Wang R, Goes FS et al (2018) HLA typing using genome wide data reveals susceptibility types for infections in a psychiatric disease enriched sample. Brain Behav Immun 70:203–213Google Scholar
  112. Perron H, Hamdani N, Faucard R, Lajnef M, Jamain S, Daban-Huard C et al (2012) Molecular characteristics of human endogenous retrovirus type-w in schizophrenia and bipolar disorder. Transl Psychiatry 2:e201Google Scholar
  113. Prasad KM, Shirts BH, Yolken RH, Keshavan MS, Nimgaonkar VL (2007) Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia. Mol Psychiatry 12:105–113, 101Google Scholar
  114. Prasad KM, Eack SM, Goradia D, Pancholi KM, Keshavan MS, Yolken RH et al (2011) Progressive gray matter loss and changes in cognitive functioning associated with exposure to herpes simplex virus 1 in schizophrenia: a longitudinal study. Am J Psychiatry 168:822–830Google Scholar
  115. Prasad KM, Watson AM, Dickerson FB, Yolken RH, Nimgaonkar VL (2012) Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr Bull 38:1137–1148Google Scholar
  116. Presumey J, Bialas AR, Carroll MC (2017) Complement system in neural synapse elimination in development and disease. Adv Immunol 135:53–79Google Scholar
  117. Prichard JC (1837) A treatise on insanity and other disorders affecting the mind. E.L. Carey & A. Hart, PhiladelphiaGoogle Scholar
  118. Reiter P (1926) Extrapyramidal motor disturbances in dementia praecox. Acta Psychiatr Neurol 1:287–304Google Scholar
  119. Rosenow EC (1948) Bacteriologic, etiologic, and serologic studies in epilepsy and schizophrenia; cutaneous reactions to intradermal injection of streptococcal antibody and antigen. Postgrad Med 3:367–376Google Scholar
  120. Round JL, O’Connell RM, Mazmanian SK (2010) Coordination of tolerogenic immune responses by the commensal microbiota. J Autoimmun 34:J220–J225Google Scholar
  121. Sampson TR, Mazmanian SK (2015) Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 17:565–576Google Scholar
  122. Sandhya P, Danda D, Sharma D, Scaria V (2016) Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. Int J Rheum Dis 19:8–20Google Scholar
  123. Sandler NG, Douek DC (2012) Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol 10:655–666Google Scholar
  124. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427Google Scholar
  125. Schneck JM (1946) Gastro-intestinal symptomatology in schizophrenia. Am J Dig Dis 13:257–260Google Scholar
  126. Schretlen DJ, Vannorsdall TD, Winicki JM, Mushtaq Y, Hikida T, Sawa A et al (2010) Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia. Schizophr Res 118:224–231Google Scholar
  127. Schwarz E, Maukonen J, Hyytiainen T, Kieseppa T, Oresic M, Sabunciyan S et al (2018) Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res 192:398–403Google Scholar
  128. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N et al (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530:177–183Google Scholar
  129. Severance EG, Dickerson FB, Halling M, Krivogorsky B, Haile L, Yang S et al (2010) Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res 118:240–247Google Scholar
  130. Severance EG, Dickerson FB, Viscidi RP, Bossis I, Stallings CR, Origoni AE et al (2011) Coronavirus immunoreactivity in individuals with a recent onset of psychotic symptoms. Schizophr Bull 37:101–107Google Scholar
  131. Severance EG, Alaedini A, Yang S, Halling M, Gressitt KL, Stallings CR et al (2012) Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res 138:48–53Google Scholar
  132. Severance EG, Gressitt KL, Stallings CR, Origoni AE, Khushalani S, Leweke FM et al (2013) Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res 148:130–137Google Scholar
  133. Severance EG, Gressitt KL, Buka SL, Cannon TD, Yolken RH (2014) Maternal complement c1q and increased odds for psychosis in adult offspring. Schizophr Res 159:14–19Google Scholar
  134. Severance EG, Gressitt KL, Alaedini A, Rohleder C, Enning F, Bumb JM et al (2015a) Igg dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia. Brain Behav Immun 44:148–158Google Scholar
  135. Severance EG, Prandovszky E, Castiglione J, Yolken RH (2015b) Gastroenterology issues in schizophrenia: why the gut matters. Curr Psychiatry Rep 17:27Google Scholar
  136. Severance EG, Gressitt KL, Stallings CR, Katsafanas E, Schweinfurth LA, Savage CL et al (2016a) Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. NPJ Schizophr 2:16018Google Scholar
  137. Severance EG, Xiao J, Jones-Brando L, Sabunciyan S, Li Y, Pletnikov M et al (2016b) Toxoplasma gondii – a gastrointestinal pathogen associated with human brain diseases. Int Rev Neurobiol 131:143–163Google Scholar
  138. Severance EG, Yolken RH, Eaton WW (2016c) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res 176:23–35Google Scholar
  139. Severance EG, Gressitt KL, Stallings CR, Katsafanas E, Schweinfurth LA, Savage CLG et al (2017) Probiotic normalization of Candida albicans in schizophrenia: a randomized, placebo-controlled, longitudinal pilot study. Brain Behav Immun 62:41–45Google Scholar
  140. Shen Y, Xu J, Li Z, Huang Y, Yuan Y, Wang J et al (2018) Analysis of gut microbiota diversity and auxiliary diagnosis as a biomarker in patients with schizophrenia: a cross-sectional study. Schizophr Res.  https://doi.org/10.1016/j.schres.2018.01.002Google Scholar
  141. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I et al (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753–757Google Scholar
  142. Shirts BH, Prasad KM, Pogue-Geile MF, Dickerson F, Yolken RH, Nimgaonkar VL (2008) Antibodies to cytomegalovirus and herpes simplex virus 1 associated with cognitive function in schizophrenia. Schizophr Res 106:268–274Google Scholar
  143. Smith PM, Garrett WS (2011) The gut microbiota and mucosal t cells. Front Microbiol 2:111Google Scholar
  144. Sommer F, Backhed F (2013) The gut microbiota – masters of host development and physiology. Nat Rev Microbiol 11:227–238Google Scholar
  145. Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA (2009) Association between prenatal exposure to bacterial infection and risk of schizophrenia. Schizophr Bull 35:631–637Google Scholar
  146. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al (2009) Common variants conferring risk of schizophrenia. Nature 460:744–747Google Scholar
  147. Stilling RM, Dinan TG, Cryan JF (2014) Microbial genes, brain & behaviour – epigenetic regulation of the gut-brain axis. Genes Brain Behav 13:69–86Google Scholar
  148. Suvisaari J, Haukka J, Tanskanen A, Hovi T, Lonnqvist J (1999) Association between prenatal exposure to poliovirus infection and adult schizophrenia. Am J Psychiatry 156:1100–1102Google Scholar
  149. Tomasik J, Yolken RH, Bahn S, Dickerson FB (2015) Immunomodulatory effects of probiotic supplementation in schizophrenia patients: a randomized, placebo-controlled trial. Biomark Insights 10:47–54Google Scholar
  150. Tomasik J, Smits SL, Leweke FM, Eljasz P, Pas S, Kahn RS et al (2018) Virus discovery analyses on post-mortem brain tissue and cerebrospinal fluid of schizophrenia patients. Schizophr Res.  https://doi.org/10.1016/j.schres.2018.02.012Google Scholar
  151. Torrey EF, Peterson MR (1973) Slow and latent viruses in schizophrenia. Lancet 2:22–24Google Scholar
  152. Torrey EF, Peterson MR (1976) The viral hypothesis of schizophrenia. Schizophr Bull 2:136–146Google Scholar
  153. Torrey EF, Bartko JJ, Lun ZR, Yolken RH (2007) Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull 33:729–736Google Scholar
  154. Torrey EF, Bartko JJ, Yolken RH (2012) Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull 38:642–647Google Scholar
  155. Tsuang M (2000) Schizophrenia: genes and environment. Biol Psychiatry 47:210–220Google Scholar
  156. Watanabe Y, Someya T, Nawa H (2010) Cytokine hypothesis of schizophrenia pathogenesis: evidence from human studies and animal models. Psychiatry Clin Neurosci 64:217–230Google Scholar
  157. Watson AM, Prasad KM, Klei L, Wood JA, Yolken RH, Gur RC et al (2013) Persistent infection with neurotropic herpes viruses and cognitive impairment. Psychol Med 43:1023–1031Google Scholar
  158. Weber NS, Gressitt KL, Cowan DN, Niebuhr DW, Yolken RH, Severance EG (2018) Monocyte activation detected prior to a diagnosis of schizophrenia in the US Military New Onset Psychosis Project (MNOPP). Schizophr Res.  https://doi.org/10.1016/j.schres.2017.12.016Google Scholar
  159. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669Google Scholar
  160. WHO (1949) Manual of the international statistical classification of diseases, injuries and causes of death. World Health Organization, GenevaGoogle Scholar
  161. Xiao J, Buka SL, Cannon TD, Suzuki Y, Viscidi RP, Torrey EF et al (2009) Serological pattern consistent with infection with type i Toxoplasma gondii in mothers and risk of psychosis among adult offspring. Microbes Infect 11:1011–1018Google Scholar
  162. Yolken RH, Torrey EF (2008) Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry 13:470–479Google Scholar
  163. Yolken RH, Torrey EF, Lieberman JA, Yang S, Dickerson FB (2011) Serological evidence of exposure to Herpes Simplex Virus type 1 is associated with cognitive deficits in the CATIE schizophrenia sample. Schizophr Res 128:61–65Google Scholar
  164. Yolken RH, Severance EG, Sabunciyan S, Gressitt KL, Chen O, Stallings C et al (2015) Metagenomic sequencing indicates that the oropharyngeal phageome of individuals with schizophrenia differs from that of controls. Schizophr Bull 41:1153–1161Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Stanley Division of Developmental Neurovirology, Department of PediatricsJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations