Gastroenterology Issues in Schizophrenia: Why the Gut Matters

  • Emily G. Severance
  • Emese Prandovszky
  • James Castiglione
  • Robert H. Yolken
Schizophrenia and Other Psychotic Disorders (SJ Siegel, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Schizophrenia and Other Psychotic Disorders

Abstract

Genetic and environmental studies implicate immune pathologies in schizophrenia. The body’s largest immune organ is the gastrointestinal (GI) tract. Historical associations of GI conditions with mental illnesses predate the introduction of antipsychotics. Current studies of antipsychotic-naïve patients support that gut dysfunction may be inherent to the schizophrenia disease process. Risk factors for schizophrenia (inflammation, food intolerances, Toxoplasma gondii exposure, cellular barrier defects) are part of biological pathways that intersect those operant in the gut. Central to GI function is a homeostatic microbial community, and early reports show that it is disrupted in schizophrenia. Bioactive and toxic products derived from digestion and microbial dysbiosis activate adaptive and innate immunity. Complement C1q, a brain-active systemic immune component, interacts with gut-related schizophrenia risk factors in clinical and experimental animal models. With accumulating evidence supporting newly discovered gut–brain physiological pathways, treatments to ameliorate brain symptoms of schizophrenia should be supplemented with therapies to correct GI dysfunction.

Keywords

Microbiome Autoimmunity Blood–brain barrier Gluten Autism Synapses 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    APA. Diagnostic and Statistical Manual of Mental Disorders, 5th edition: DSM-5. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.Google Scholar
  2. 2.
    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7. doi:10.1038/nature13595.PubMedCentralGoogle Scholar
  3. 3.
    Kavanagh DH, Tansey KE, O’Donovan MC, Owen MJ. Schizophrenia genetics: emerging themes for a complex disorder. Mol Psychiatry. 2014. doi:10.1038/mp.2014.148.PubMedGoogle Scholar
  4. 4.
    Demjaha A, MacCabe JH, Murray RM. How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr Bull. 2012;38(2):209–14. doi:10.1093/schbul/sbr100.PubMedCentralPubMedGoogle Scholar
  5. 5.
    van Os J, Rutten BP, Myin-Germeys I, Delespaul P, Viechtbauer W, van Zelst C, et al. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations. Schizophr Bull. 2014;40(4):729–36. doi:10.1093/schbul/sbu069.PubMedGoogle Scholar
  6. 6.
    Corvin A, Morris DW. Genome-wide association studies: findings at the major histocompatibility complex locus in psychosis. Biol Psychiatry. 2014;75(4):276–83. doi:10.1016/j.biopsych.2013.09.018.PubMedGoogle Scholar
  7. 7.
    Muller N. Immunology of schizophrenia. Neuroimmunomodulation. 2014;21(2–3):109–16. doi:10.1159/000356538.PubMedGoogle Scholar
  8. 8.
    Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? a review of the evidence. Mol Psychiatry. 2008;13(5):470–9. doi:10.1038/mp.2008.5.PubMedGoogle Scholar
  9. 9.
    Benros ME, Eaton WW, Mortensen PB. The epidemiologic evidence linking autoimmune diseases and psychosis. Biol Psychiatry. 2014;75(4):300–6. doi:10.1016/j.biopsych.2013.09.023.PubMedGoogle Scholar
  10. 10.••
    The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci. 2015. doi: 10.1038/nn.3922. These investigators analysed the most currently available genetic data from GWAS studies of schizophrenia in the context of biological pathway interactions and found strong associations of DNA methylation, immune system, and neuronal signalling processes.
  11. 11.
    APA. Diagnostic and Statistical Manual of Mental Disorders (DSM-I). 1st ed. Washington, D.C.: American Psychiatric Association; 1952.Google Scholar
  12. 12.
    WHO. Manual of the international statistical classification of diseases, injuries and causes of death. Geneva: World Health Organization; 1949.Google Scholar
  13. 13.
    Severance EG, Alaedini A, Yang S, Halling M, Gressitt KL, Stallings CR, et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res. 2012;138(1):48–53. doi:10.1016/j.schres.2012.02.025.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Severance EG, Dickerson FB, Halling M, Krivogorsky B, Haile L, Yang S, et al. Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res. 2010;118(1–3):240–7. doi:10.1016/j.schres.2009.12.030.PubMedGoogle Scholar
  15. 15.
    Severance EG, Gressitt KL, Stallings CR, Origoni AE, Khushalani S, Leweke FM, et al. Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res. 2013;148(1–3):130–7. doi:10.1016/j.schres.2013.05.018.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Severance EG, Kannan G, Gressitt KL, Xiao J, Alaedini A, Pletnikov MV, et al. Anti-gluten immune response following Toxoplasma gondii infection in mice. PLoS One. 2012;7(11):e50991. doi:10.1371/journal.pone.0050991.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Severance EG, Yolken RH, Eaton WW. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. 2014. doi:10.1016/j.schres.2014.06.027.Google Scholar
  18. 18.
    Severance EG, Gressitt KL, Alaedini A, Rohleder C, Enning F, Bumb JM, et al. IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia. Brain Behav Immun. 2015;44:148–58. doi:10.1016/j.bbi.2014.09.009.PubMedGoogle Scholar
  19. 19.
    Severance EG, Gressitt KL, Buka SL, Cannon TD, Yolken RH. Maternal complement C1q and increased odds for psychosis in adult offspring. Schizophr Res. 2014;159(1):14–9. doi:10.1016/j.schres.2014.07.053.PubMedGoogle Scholar
  20. 20.
    Severance EG, Gressitt KL, Halling M, Stallings CR, Origoni AE, Vaughan C, et al. Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiol Dis. 2012;48(3):447–53. doi:10.1016/j.nbd.2012.07.005.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Jackson SW. Galen – on mental disorders. J Hist Behav Sci. 1969;5(4):365–84.PubMedGoogle Scholar
  22. 22.
    Jackson SW. Unusual mental states in medieval Europe. I. Medical syndromes of mental disorder: 400–1100 A.D. J Hist Med Allied Sci. 1972;27(3):262–97.PubMedGoogle Scholar
  23. 23.
    APA. The American Journal of Insanity. American Journal of Psychiatry. 1844;1(October):97–192.Google Scholar
  24. 24.
    Earle P, APA. Contributions to the pathology of insanity. Am J Insanity. 1846;3(1):35–40.Google Scholar
  25. 25.
    Allen JR. On the treatment of insanity. Am J Insanity. 1850;6(January):263–83.Google Scholar
  26. 26.
    Woodward SB. Observations on the medical treatment of insanity. Am J Insanity. 1850;7(July):1–29.Google Scholar
  27. 27.
    Bucknill JC. On the pathology of insanity. Am J Insanity. 1857;14(July):29, 172, 254, 348Google Scholar
  28. 28.
    Gray JP. The dependence of insanity on physical disease. Am J Insanity. 1871;27(April):317–408.Google Scholar
  29. 29.
    Workman J. Certain abdominal lesions in the insane. Am J Insanity. 1863;20:44–60.Google Scholar
  30. 30.
    Deecke T. Condition of the brain in insanity. Am J Insanity. 1881;37:361–92.Google Scholar
  31. 31.
    Cowles E. Notes and comments. Am J Insanity. 1903;60Google Scholar
  32. 32.
    Herter, C.A. (1907) The common bacterial infections of the digestive tract and the intoxications arising from them. The Macmillan Company, New York, and LondonGoogle Scholar
  33. 33.
    Schneck JM. Gastro-intestinal symptomatology in schizophrenia. Am J Dig Dis. 1946;13:257–60.PubMedGoogle Scholar
  34. 34.
    Sonnenberg A, Tsou VT, Muller AD. The “institutional colon”: a frequent colonic dysmotility in psychiatric and neurologic disease. Am J Gastroenterol. 1994;89(1):62–6.PubMedGoogle Scholar
  35. 35.
    Sprince H. Biochemical aspects of indole metabolism in normal and schizophrenic subjects. Ann N Y Acad Sci. 1962;96:399–418.PubMedGoogle Scholar
  36. 36.
    Fadgyas-Stanculete M, Buga AM, Popa-Wagner A, Dumitrascu DL. The relationship between irritable bowel syndrome and psychiatric disorders: from molecular changes to clinical manifestations. J Mol Psychiatry. 2014;2(1):4. doi:10.1186/2049-9256-2-4.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Gupta S, Masand PS, Kaplan D, Bhandary A, Hendricks S. The relationship between schizophrenia and irritable bowel syndrome (IBS). Schizophr Res. 1997;23(3):265–8.PubMedGoogle Scholar
  38. 38.
    Vu J, Kushnir V, Cassell B, Gyawali CP, Sayuk GS. The impact of psychiatric and extraintestinal comorbidity on quality of life and bowel symptom burden in functional GI disorders. Neurogastroenterol Motil. 2014;26(9):1323–32. doi:10.1111/nmo.12396.PubMedGoogle Scholar
  39. 39.
    Filipovic BR, Filipovic BF. Psychiatric comorbidity in the treatment of patients with inflammatory bowel disease. World J Gastroenterol. 2014;20(13):3552–63. doi:10.3748/wjg.v20.i13.3552.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Vaknin A, Eliakim R, Ackerman Z, Steiner I. Neurological abnormalities associated with celiac disease. J Neurol. 2004;251(11):1393–7. doi:10.1007/s00415-004-0550-9.PubMedGoogle Scholar
  41. 41.
    Palmer SE, McLean RM, Ellis PM, Harrison-Woolrych M. Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry. 2008;69(5):759–68.PubMedGoogle Scholar
  42. 42.
    Stanniland C, Taylor D. Tolerability of atypical antipsychotics. Drug Saf. 2000;22(3):195–214.PubMedGoogle Scholar
  43. 43.
    De Hert M, Dockx L, Bernagie C, Peuskens B, Sweers K, Leucht S, et al. Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study. BMC Gastroenterol. 2011;11:17. doi:10.1186/1471-230X-11-17.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Hayes G, Gibler B. Clozapine-induced constipation. Am J Psychiatry. 1995;152(2):298.PubMedGoogle Scholar
  45. 45.
    McGrath JJ, Soares KV. Cholinergic medication for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2000;2, CD000207. doi:10.1002/14651858.CD000207.PubMedGoogle Scholar
  46. 46.
    Lechin F, Gomez F, van der Dijs B, Lechin E. Distal colon motility in schizophrenic patients. J Clin Pharmacol. 1980;20(7):459–64.PubMedGoogle Scholar
  47. 47.
    Gray GE, Gray LK. Nutritional aspects of psychiatric disorders. J Am Diet Assoc. 1989;89(10):1492–8.PubMedGoogle Scholar
  48. 48.
    Buscaino V. Patologia extraneurale della schizofrenia. Fegato, tubo digerente, sistema reticolo-endoteliale. Acta neurologica 1953;VIII:1–60.Google Scholar
  49. 49.
    Hemmings G. Schizophrenia. Lancet. 2004;364(9442):1312–3. doi:10.1016/S0140-6736(04)17181-X.
  50. 50.
    Desplat-Jego S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N, et al. 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. 2007;13(16):2312–8.Google Scholar
  51. 51.
    Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. Br Med J. 2004;328(7437):438–9. doi:10.1136/bmj.328.7437.438.Google Scholar
  52. 52.
    Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull. 2011;37(1):94–100. doi:10.1093/schbul/sbp055.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Guandalini S, Assiri A. Celiac disease: a review. JAMA Pediatr. 2014;168(3):272–8. doi:10.1001/jamapediatrics.2013.3858.PubMedGoogle Scholar
  54. 54.
    Dohan FC. Wartime changes in hospital admissions for schizophrenia a comparison of admission for schizophrenia and other psychoses in six countries during World War II. Acta Psychiatr Scand. 1966;42(1):1–23.PubMedGoogle Scholar
  55. 55.
    Dohan FC. Wheat “consumption” and hospital admissions for schizophrenia during World War II. A preliminary report. Am J Clin Nutr. 1966;18(1):7–10.Google Scholar
  56. 56.
    Dohan F. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull. 1988;14(4):489–94.PubMedGoogle Scholar
  57. 57.
    Reichelt KL, Seim AR, Reichelt WH. Could schizophrenia be reasonably explained by Dohan’s hypothesis on genetic interaction with a dietary peptide overload? Prog Neuro-Psychopharmacol Biol Psychiatry. 1996;20(7):1083–114.Google Scholar
  58. 58.
    Lachance LR, McKenzie K. Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis. Schizophr Res. 2014;152(2–3):521–7. doi:10.1016/j.schres.2013.12.001.PubMedGoogle Scholar
  59. 59.
    Jackson J, Eaton W, Cascella N, Fasano A, Warfel D, Feldman S, et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res. 2012;140(1–3):262–3. doi:10.1016/j.schres.2012.06.011.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Whiteley P, Shattock P, Knivsberg AM, Seim A, Reichelt KL, Todd L, et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012;6:344. doi:10.3389/fnhum.2012.00344.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Dohan FC, Grasberger JC, Lowell FM, Johnston Jr HT, Arbegast AW. Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet. Br J Psychiatry. 1969;115(522):595–6.PubMedGoogle Scholar
  62. 62.
    Dohan FC, Grasberger JC. Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatr. 1973;130(6):685–8.PubMedGoogle Scholar
  63. 63.
    Kaminski S, Cieslinska A, Kostyra E. Polymorphism of bovine beta-casein and its potential effect on human health. J Appl Genet. 2007;48(3):189–98.PubMedGoogle Scholar
  64. 64.
    Niebuhr DW, Li Y, Cowan DN, Weber NS, Fisher JA, Ford GM, et al. Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res. 2011;128(1–3):51–5. doi:10.1016/j.schres.2011.02.005.PubMedGoogle Scholar
  65. 65.
    Trivedi MS, Shah JS, Al-Mughairy S, Hodgson NW, Simms B, Trooskens GA, et al. Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences. J Nutr Biochem. 2014;25(10):1011–8. doi:10.1016/j.jnutbio.2014.05.004.PubMedGoogle Scholar
  66. 66.•
    Sommer F, Backhed F. The gut microbiota—masters of host development and physiology. Nat Rev Microbiol. 2013;11(4):227–38. doi:10.1038/nrmicro2974. This paper reviews host-gut microbial interactions in terms of immune system maintenance and modulation.PubMedGoogle Scholar
  67. 67.••
    Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451–63. doi:10.1016/j.cell.2013.11.024. This study in mice was among the first contemporary investigations to link maternal immune activation with brain processes in offspring through a gut microbiome mechanism.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Daneman R, Rescigno M. The gut immune barrier and the blood–brain barrier: are they so different? Immunity. 2009;31(5):722–35. doi:10.1016/j.immuni.2009.09.012.PubMedGoogle Scholar
  69. 69.
    Maes M, Delanghe J, Bocchio Chiavetto L, Bignotti S, Tura GB, Pioli R, et al. Haptoglobin polymorphism and schizophrenia: genetic variation on chromosome 16. Psychiatry Res. 2001;104(1):1–9.PubMedGoogle Scholar
  70. 70.
    Burghardt K, Grove T, Ellingrod V. Endothelial nitric oxide synthetase genetic variants, metabolic syndrome and endothelial function in schizophrenia. J Psychopharmacol. 2014;28(4):349–56. doi:10.1177/0269881113516200.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Zhao Z, Xu J, Chen J, Kim S, Reimers M, Bacanu SA, et al. Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder. Mol Psychiatry. 2014. doi:10.1038/mp.2014.82.Google Scholar
  72. 72.
    Sun ZY, Wei J, Xie L, Shen Y, Liu SZ, Ju GZ, et al. The CLDN5 locus may be involved in the vulnerability to schizophrenia. Eur Psychiatry. 2004;19(6):354–7. doi:10.1016/j.eurpsy.2004.06.007.PubMedGoogle Scholar
  73. 73.
    Lambert GP. Stress-induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci. 2009;87(14 Suppl):E101–8. doi:10.2527/jas. 2008-1339.PubMedGoogle Scholar
  74. 74.
    Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009;136(6):2003–14. doi:10.1053/j.gastro.2009.01.075.PubMedGoogle Scholar
  75. 75.
    Soderholm JD, Perdue MH. Stress and gastrointestinal tract II. Stress and intestinal barrier function. Am J Physiol Gastrointest Liver Physiol. 2001;280(1):G7–G13.Google Scholar
  76. 76.
    Correale J, Villa A. The blood–brain-barrier in multiple sclerosis: functional roles and therapeutic targeting. Autoimmunity. 2007;40(2):148–60. doi:10.1080/08916930601183522.PubMedGoogle Scholar
  77. 77.
    Turksen K, Troy TC. Barriers built on claudins. J Cell Sci. 2004;117(Pt 12):2435–47. doi:10.1242/jcs.01235.PubMedGoogle Scholar
  78. 78.
    Zeissig S, Burgel N, Gunzel D, Richter J, Mankertz J, Wahnschaffe U, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut. 2007;56(1):61–72. doi:10.1136/gut.2006.094375.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Dash S, Clarke G, Berk M, Jacka FN. The gut microbiome and diet in psychiatry: focus on depression. Curr Opin Psychiatry. 2015;28(1):1–6. doi:10.1097/YCO.0000000000000117.PubMedGoogle Scholar
  80. 80.
    Bechter K. Updating the mild encephalitis hypothesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:71–91. doi:10.1016/j.pnpbp.2012.06.019.Google Scholar
  81. 81.
    Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18(2):206–14. doi:10.1038/mp.2012.110.PubMedGoogle Scholar
  82. 82.
    Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663–71. doi:10.1016/j.biopsych.2011.04.013.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Torrey EF, et al. Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth. Biol Psychiatry. 2007;61(5):688–93. doi:10.1016/j.biopsych.2006.05.024.PubMedGoogle Scholar
  84. 84.
    Torrey EF, Bartko JJ, Yolken RH. Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull. 2012;38(3):642–7. doi:10.1093/schbul/sbs043.PubMedCentralPubMedGoogle Scholar
  85. 85.•
    Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagan AJ, Pepper M, et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science. 2012;337(6101):1553–6. doi:10.1126/science.1220961. Results from this rodent model provided a mechanism by which GI infection causes immune pathologies such as loss of tolerance to commensals and activation of T cells that were specific to microbiota groups. Interestingly, T. gondii was used to induce the GI infection.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Craven M, Egan CE, Dowd SE, McDonough SP, Dogan B, Denkers EY, et al. Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn’s disease. PLoS One. 2012;7(7):e41594. doi:10.1371/journal.pone.0041594.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Grainger JR, Wohlfert EA, Fuss IJ, Bouladoux N, Askenase MH, Legrand F, et al. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat Med. 2013;19(6):713–21. doi:10.1038/nm.3189.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Heimesaat MM, Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J, et al. Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol. 2006;177(12):8785–95.PubMedGoogle Scholar
  89. 89.
    Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321–30. doi:10.1016/j.jpsychires.2009.08.008.PubMedGoogle Scholar
  90. 90.
    Bauer K, Kornhuber J. Blood-cerebrospinal fluid barrier in schizophrenic patients. Eur Arch Psychiatry Neurol Sci. 1987;236(5):257–9.PubMedGoogle Scholar
  91. 91.
    Kirch DG, Alexander RC, Suddath RL, Papadopoulos NM, Kaufmann CA, Daniel DG, et al. Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia. J Neural Transm Gen Sect. 1992;89(3):219–32.PubMedGoogle Scholar
  92. 92.
    Reiber H. Flow rate of cerebrospinal fluid (CSF)—a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci. 1994;122(2):189–203.PubMedGoogle Scholar
  93. 93.
    Ismail AS, Hooper LV. Epithelial cells and their neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity. Am J Physiol Gastrointest Liver Physiol. 2005;289(5):G779–84. doi:10.1152/ajpgi.00203.2005.PubMedGoogle Scholar
  94. 94.
    Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–8.PubMedGoogle Scholar
  95. 95.
    Kelly D, Campbell JI, King TP, Grant G, Jansson EA, Coutts AG, et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol. 2004;5(1):104–12. doi:10.1038/ni1018.PubMedGoogle Scholar
  96. 96.
    Lutgendorff F, Akkermans LM, Soderholm JD. The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr Mol Med. 2008;8(4):282–98.PubMedGoogle Scholar
  97. 97.
    Sindhu KN, Sowmyanarayanan TV, Paul A, Babji S, Ajjampur SS, Priyadarshini S, et al. Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2014;58(8):1107–15. doi:10.1093/cid/ciu065.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmytrash A, Backer J, et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G1025–34. doi:10.1152/ajpgi.90227.2008.PubMedGoogle Scholar
  99. 99.••
    Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, et al. The gut microbiota influences blood–brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158. doi:10.1126/scitranslmed.3009759. This rodent study tests and verifies a mechanistic link between the gut microbiota and integrity of the blood–brain barrier.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Boulanger LM. Immune proteins in brain development and synaptic plasticity. Neuron. 2009;64(1):93–109. doi:10.1016/j.neuron.2009.09.001.PubMedGoogle Scholar
  101. 101.••
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78. doi:10.1016/j.cell.2007.10.036. This important study showed that complement C1q, a well-characterized peripheral immune factor, functions in the CNS to tag unwanted synapses for removal.PubMedGoogle Scholar
  102. 102.••
    Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000;290(5499):2155–9. Classic immune molecules such as MHC function to form and remodel synapses in the developing and mature brain.Google Scholar
  103. 103.
    Boyajyan A, Khoyetsyan A, Tsakanova G, Sim RB. Cryoglobulins as indicators of upregulated immune response in schizophrenia. Clin Biochem. 2008;41(6):355–60. doi:10.1016/j.clinbiochem.2007.11.014.PubMedGoogle Scholar
  104. 104.
    Havik B, Le Hellard S, Rietschel M, Lybaek H, Djurovic S, Mattheisen M, et al. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry. 2011;70(1):35–42. doi:10.1016/j.biopsych.2011.01.030.PubMedGoogle Scholar
  105. 105.
    Zakharyan R, Khoyetsyan A, Arakelyan A, Boyajyan A, Gevorgyan A, Stahelova A, et al. Association of C1QB gene polymorphism with schizophrenia in Armenian population. BMC Med Genet. 2011;12:126. doi:10.1186/1471-2350-12-126.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121:91–119. doi:10.1016/B978-0-12-800100-4.00003-9.PubMedGoogle Scholar
  107. 107.
    Kim CH, Park J, Kim M. Gut microbiota-derived short-chain fatty acids, T cells, and inflammation. Immune Netw. 2014;14(6):277–88. doi:10.4110/in.2014.14.6.277.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Smith PM, Garrett WS. The gut microbiota and mucosal T cells. Front Microbiol. 2011;2:111. doi:10.3389/fmicb.2011.00111.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332(6032):974–7. doi:10.1126/science.1206095.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Karimi K, Inman MD, Bienenstock J, Forsythe P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am J Respir Crit Care Med. 2009;179(3):186–93. doi:10.1164/rccm.200806-951OC.PubMedGoogle Scholar
  111. 111.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331(6015):337–41. doi:10.1126/science.1198469.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY, et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nat Immunol. 2007;8(9):931–41. doi:10.1038/ni1504.PubMedGoogle Scholar
  113. 113.
    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. doi:10.1016/j.cell.2009.09.033.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull. 2014;40(6):1412–21. doi:10.1093/schbul/sbu049.PubMedGoogle Scholar
  115. 115.••
    Yolken RH, Severance EG, Sabunciyan S, Gressitt KL, Chen O, Stallings C et al. Metagenomic sequencing indicates that the oropharyngeal phageome of individuals with schizophrenia differs from that of controls. Schizophrenia Bulletin. 2015, In Press. This study of humans is one of the first to show that individuals with schizophrenia have an altered microbiome compared to controls.Google Scholar
  116. 116.
    Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–12. doi:10.1016/j.tins.2013.01.005.PubMedGoogle Scholar
  117. 117.
    Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10(11):735–42. doi:10.1038/nrmicro2876.PubMedGoogle Scholar
  118. 118.
    Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour—epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014;13(1):69–86. doi:10.1111/gbb.12109.PubMedGoogle Scholar
  119. 119.
    Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047–52. doi:10.1073/pnas.1010529108.PubMedGoogle Scholar
  120. 120.
    Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X, et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology. 2010;139(6):2102–12 e1. doi:10.1053/j.gastro.2010.06.063.PubMedGoogle Scholar
  121. 121.
    Vitetta L, Bambling M, Alford H. The gastrointestinal tract microbiome, probiotics, and mood. Inflammopharmacology. 2014;22(6):333–9. doi:10.1007/s10787-014-0216-x.PubMedGoogle Scholar
  122. 122.
    Dickerson FB, Stallings C, Origoni A, Katsafanas E, Savage CL, Schweinfurth LA et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16(1). doi: 10.4088/PCC.13m01579

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Emily G. Severance
    • 1
  • Emese Prandovszky
    • 1
  • James Castiglione
    • 2
  • Robert H. Yolken
    • 1
  1. 1.Stanley Division of Developmental Neurovirology, Department of PediatricsJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Brooklyn CollegeThe City University of New YorkBrooklynUSA

Personalised recommendations