Gastroenterology Issues in Schizophrenia: Why the Gut Matters


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.

This is a preview of subscription content, access via your institution.


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.

  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.

    PubMed Central  Google 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.

    PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  7. 7.

    Muller N. Immunology of schizophrenia. Neuroimmunomodulation. 2014;21(2–3):109–16. doi:10.1159/000356538.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

  12. 12.

    WHO. Manual of the international statistical classification of diseases, injuries and causes of death. Geneva: World Health Organization; 1949.

  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.

    PubMed Central  PubMed  Google 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.

    PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. 21.

    Jackson SW. Galen – on mental disorders. J Hist Behav Sci. 1969;5(4):365–84.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  23. 23.

    APA. The American Journal of Insanity. American Journal of Psychiatry. 1844;1(October):97–192.

  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, 348

  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;60

  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 London

  33. 33.

    Schneck JM. Gastro-intestinal symptomatology in schizophrenia. Am J Dig Dis. 1946;13:257–60.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sprince H. Biochemical aspects of indole metabolism in normal and schizophrenic subjects. Ann N Y Acad Sci. 1962;96:399–418.

    CAS  PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  42. 42.

    Stanniland C, Taylor D. Tolerability of atypical antipsychotics. Drug Saf. 2000;22(3):195–214.

    CAS  PubMed  Google 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.

    PubMed Central  PubMed  Google Scholar 

  44. 44.

    Hayes G, Gibler B. Clozapine-induced constipation. Am J Psychiatry. 1995;152(2):298.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  47. 47.

    Gray GE, Gray LK. Nutritional aspects of psychiatric disorders. J Am Diet Assoc. 1989;89(10):1492–8.

    CAS  PubMed  Google Scholar 

  48. 48.

    Buscaino V. Patologia extraneurale della schizofrenia. Fegato, tubo digerente, sistema reticolo-endoteliale. Acta neurologica 1953;VIII:1–60.

  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.

  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.

    PubMed Central  PubMed  Google Scholar 

  53. 53.

    Guandalini S, Assiri A. Celiac disease: a review. JAMA Pediatr. 2014;168(3):272–8. doi:10.1001/jamapediatrics.2013.3858.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

  56. 56.

    Dohan F. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull. 1988;14(4):489–94.

    CAS  PubMed  Google 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.

    CAS  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.

    PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

  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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed  Google 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.

    CAS  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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  90. 90.

    Bauer K, Kornhuber J. Blood-cerebrospinal fluid barrier in schizophrenic patients. Eur Arch Psychiatry Neurol Sci. 1987;236(5):257–9.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  94. 94.

    Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–8.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

  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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed Central  CAS  PubMed  Google 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.

    PubMed  Google 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.

  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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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

Download references

Compliance with Ethics Guidelines

Conflict of Interest

James Castiglione declares that he has no conflict of interest.

Emily G. Severance reports that this work was supported by a NIMH P50 Silvio O. Conte Center at Johns Hopkins (grant no. MH-94268) and by the Stanley Medical Research Institute. Dr. Severance also has received a grant from the Brain & Behavior Research Foundation (NARSAD) and has received support for travel to meetings from the Stanley Medical Research Institute.

Emese Prandovszky has received a grant and support for travel to meetings from the Stanley Medical Research Institute.

Robert H. Yolken reports that this work was supported by a NIMH P50 Silvio O. Conte Center at Johns Hopkins (grant no. MH-94268) and by the Stanley Medical Research Institute. Dr. Yolken is a board member and has received travel support from the Stanley Medical Research Institute.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information



Corresponding author

Correspondence to Emily G. Severance.

Additional information

This article is part of the Topical Collection on Schizophrenia and Other Psychotic Disorders

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Severance, E.G., Prandovszky, E., Castiglione, J. et al. Gastroenterology Issues in Schizophrenia: Why the Gut Matters. Curr Psychiatry Rep 17, 27 (2015).

Download citation


  • Microbiome
  • Autoimmunity
  • Blood–brain barrier
  • Gluten
  • Autism
  • Synapses