Şizofreni Etyolojisinde Mikrobiyotanın Rolü

Öz

Son yıllarda diğer bozukluklarda olduğu gibi şizofreni etyolojisinde de mikrobiyotanın rolü araştırıl-maktadır. Beyin ve bağırsak mikrobiyotası arasında çift yönlü iletişimin olduğu gittikçe artan bir şekilde kabul edilmektedir. Gastrointestinal sistemdeki yapısal hasarlar, enfektif patojenlere ve gıda antijenlerine karşı artmış bağışıklık tepkileri şizofrenide olası mikrobiyotik değişiklikleri gösteren kanıtlardır. Mikrobiyotadaki değişikliklerin şizofreni hastalarındaki metabolik anormalliklere katkıda bulunabileceği ileri sürülmektedir. Bu yazıda, mikrobiyota ve şizofreni bağlantısını inceleyen güncel araştırmalar gözden geçirilmiştir.

Anahtar Kelimeler

• Mikrobiyota,bağırsak-beyin ekseni,şizofreni

The Role of Microbiota in the Etiology of Schizophrenia

Öz

In recent years, the role of microbiota in the etiology of schizophrenia has been a focus of investigation. It is now increasingly recognized that bidirectional communication exists between brain and gut microbiota. Evidence that indicate possible microbiota alteration in schizophrenia includes structural damage to the gastrointestinal tract, a heightened immune response to infectious pathogens and food antigens. It is proposed that an altered microbiome may contribute to abnormalities in metabolic function in schizophrenia. The aim of this article is to review recent literature on connection of the microbiota and schizophrenia.

Anahtar Kelimeler

• Microbiota,gut-brain axis,schizophrenia

Kaynakça

1. Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism-comparisons to typical children and correlation with autism severity. BMC Gastroenterol, 11:11-22.
2. Ait-Belgnaoui A, Colom A, Braniste V, Ramalho L, Marrot A, Cartier C (2014) Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterol Motil, 26:510–520.
3. Alander T, Svärdsudd K, Johansson SE, Agréus 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, 3:8.
4. Artis D (2008) Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Immunology, 8:411-420.
5. Asano Y, Hiramoto T, Nishino R, Aiba Y, Kimura T, Yoshihara K et al. (2012) Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am J Physiol Gastrointest Liver Physiol, 303:G1288–G1295.
6. Ashdown H, Dumont Y, Ng M, Poole S, Boksa P, Luheshi GN (2006) The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psychiatry, 11:47–55.
7. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A et al. (2007) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A, 101:15718-15723.
8. Barry S, Clarke G, Scully P, Dinan TG (2009) Kynurenine pathway in psychosis: evidence of increased tryptophan degradation. J Psychopharmacol, 23:287-294.

9. Benros ME, Mortensen PB, Eaton WW (2012) Autoimmune diseases and infections as risk factors for schizophrenia. Ann N Y Acad Sci, 1262:56–66.
10. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C et al. (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature, 479:538-541.
11. Bosch TCG, McFall-Ngai MJ (2011) Metaorganisms as the new frontier. Zoology(Jena), 114:185-190.
12. Buscaino VM (1953) Patologia extraneurale della schizofrenia: fegato, tubo digerente, sistema reticolo-endoteliale. Acta Neurol, 8:1-60.
13. Caminero A,Herran A,Nistal E,Perez-Andres J,Vaquero L,Vivas S et al. (2014) Diversity of the cultivable human gut microbiome involved in gluten metabolism: isolation of microorganisms with potential interest for coeliac disease.FEMS Microbiol Ecol, 88:309-319.
14. Carruthers VB, Suzuki Y (2007) Effects of Toxoplasma gondii infection on the brain. Schizophr Bull, 33:745-751.
15. Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP et al. (2011) Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull, 37:94-100.
16. 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. Peer J, 3:e1140.
17. Celik T, Kartalci S, Aytas O, Akarsu GA, Gozukara H, Unal S (2015) Association between latent toxoplasmosis and clinical course of schizophrenia - continuous course of the disease is characteristic for Toxoplasma gondii-infected patients. Folia Parasitol (Praha), 62:pii: 2015.015.
18. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F et al. (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry, 18:666–673.
19. Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Dauge V et al. (2014) Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology, 42:207–217.
20. Cryan JF, Dinan TG (2012) Mindaltering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci, 13:701–712.
21. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF (2014) Microbiota is essential for social development in the mouse. Mol Psychiatry, 19:146–148.
22. Desbonnet L, Clarke G, Traplin A, O’Sullivan O, Crispie F, Moloney RD et al. (2015) Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav Immun, 48:165–173.
23. Diaz Heijtz C, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A, 108:3047-3052.
24. Dickerson F, Kirkpatrick B, Boronow J, Stallings C, Origoni A, Yolken R (2006) Deficit schizophrenia: association with serum antibodies to cytomegalovirus. Schizophr Bull, 32:396–400.
25. Dickerson F, Severance E, Yolken R. (2016) The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun, 62:46-52.
26. Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Leister F (2010) Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry, 68:100-104.
27. Dinan TG, Borre YE, Cryan JF (2014) Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry, 19:1252-1257.
28. Ding M, Song X, Zhao J, Gao J, Li X, Yang G et al. (2014) Activation of Th17 cells in drug naïve, first episode schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 51:78-82.
29. Dohan FC (1966) Cereals and schizophrenia data and hypothesis. Acta Psychiatr Scand, 42:125-152.
30. Dohan FC, Harper EH, Clark MH, Rodrigue RB, Zigas V (1984) Is schizophrenia rare if grain is rare? Biol Psychiatry, 19:385-399.
31. Douglas-Escobar M, Elliot E, Neu J (2013) Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr, 167:374-379.
32. Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Aqerbo E, Mortensen PB (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry, 163:521-528.
33. Elder JH (2008) The gluten-free, casein-free diet in autism: an overview with clinical implications. Nutr Clin Pract, 23:583-588 Estran C, Brenier-Pinchart MP, Pelletier L, Cesbron-Delauw MF, Pelloux H (2006) Toxoplasma gondii in human astrocytes in vitro: interleukin (IL)-12 and IL-10 do not influence cystogenesis. J Parasitol, 92:1108–1110.
34. Evrensel A, Ceylan ME (2015) Bağırsak beyin ekseni: psikiyatrik bozukluklarda bağırsak mikrobiyotasının rolü. Psikiyatride Güncel Yaklaşımlar, 7:461-472.
35. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD et al. (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe, 16:444-453.
36. Foley KA, MacFabe DF, Kavaliers M, Ossenko KP (2015) Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: Relevance to autism spectrum disorders. Behav Brain Res, 278:244–256.
37. Francesconi LP, Cereser KM, Mascarenhas R, Stertz L, Gama CS, Belmonte-de-Abreu P (2011) Increased annexin-V and decreased TNF-alpha serum levels in chronic-medicated patients with schizophrenia.Neurosci Lett, 502:143-146.
38. Gupta S, Masand PS, Kaplan D, Bhandary A, Hendricks S (1997) The relationship between schizophrenia and irritable bowel syndrome (IBS). Schizophr Res, 23:265–268.
39. Hoff AL, DeLisi LE, Yolken RH (2004) Relationship of viral infection to progressive MRI and neuropsychological change in a 10 year follow-up study of first episode schizophrenia (abstract). Neuropsychopharmacology, 29(Suppl 1):S164.
40. Hornig M (2013) The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness Curr Opin Rheumatol, 25:488-795.
41. Ibi D, Nagai T, Nabeshima T, Yamada K (2011) PolyI:C-induced neurodevelopmental animal model for schizophrenia. Nihon Shinkei Seishin Yakurigaku Zasshi, 31:201–207.
42. Karakuła-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, 50:747-760.
43. Kartalci S, Karabulut AB, Erbay LG, Acar C (2016) Effects of electroconvulsive therapy on some inflammatory factors in patients with treatment-resistant schizophrenia. J ECT, 32:174-179.
44. Kunz M, Cereser KM, Goi PD, Fries GR, Teixeira BS, Fernandes BS et al. (2011) Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr, 33:268-274.
45. 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 Psychiatr Clin Neurosci, 254:4–8.
46. Lidar M, Langevitz P, Barzilai O, Ram M, Porat-Katz B, Bizzaro N (2009) Infectious serologies and autoantibodies in ınflammatory bowel disease. Ann N Y Acad Sci, 1173:640-648.
47. Lozupone C, Stombaugh J, Gordon J, Jansson J, Knight R (2012) Diversity, stability and resilience of the human gut microbiata. Nature, 489:220-230.
48. Lyte M (2013) Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog, 9:e1003726.
49. MacFabe DF (2015) Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb Ecol Health Dis, 26:28177.
50. 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, 112:221-228.
51. Marcason W (2009) What is the current status of research concerning use of a gluten-free, casein-free diet for children diagnosed with autism? J Am Diet Assoc, 109:572.
52. McGeachy MJ, McSorley SJ (2012) Microbial-induced Th17: superhero or supervillain? J Immunol, 187:3285-3291.
53. Menninger KA (1922) Reversible schizophrenia: a study of the implications of delirium schizophrenoides and other post-influenzal syndromes. Am J Psychiatry, 78:573–588.
54. Moos WH, Faller DV, Harpp DN, Kanara I, Pernokas J, Powers WR et al. (2016) Microbiota and Neurological Disorders: A Gut Feeling. Biores Open Access, 5:137-145.
55. Morozov VM (1954) On the problem of the viral aetiology of schizophrenia. J Neuropathol Psychiatrie Korsakov, 54:732-734.
56. Na KS, Jung HY, Kim YK (2014) The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 48:277-286.
57. Nejad MR, Rostami K, Cheraghipour K, Mojarad EN, Volta U,Al Dulaimi D (2011) Celiac disease increases the risk of Toxoplasma gondii infection in a large cohort of pregnant women. Am J Gastroenterol, 106:548-549.
58. Nemani K, Hosseini Ghomi R, McCormick B, Fan X (2015) Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry, 56:155-160.
59. Neufeld KM, Kang N, Bienenstock J, Foster FA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil, 23:255–264.
60. Niebuhr DW, Li Y, Cowan DN, Weber NS, Fisher JA, Ford GM (2011) Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res, 128:51-55.
61. Noll R (2004) Historical review: autointoxication and focal infection theories of dementia praecox. World J Biol Psychiatry, 5: 66–72.
62. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A et al. (2012) Microbial exposure during early life has persistent effects on natural killer T cell function. Science, 336:489-493.
63. Pedrini M, Massuda R, Fries GR, Pasquali MB, Schnor CE, Moreira JCF et al. (2012) Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity.J Psychiatr Res, 46:819-824.
64. Possemiers S, Bolca S, Verstraete W, Heyerick A (2011) The intestinal microbiome: a separate organ inside the body with the metabolic potential to influence the bioactivity of botanicals. Fitoterapia, 82:53–66.
65. Ribeiro-Santos R, Lucıo Teixeria A,Salgado JV (2014) Evidence for an immune role on cognition in schizophrenia: a systematic review. Curr Neuropharmacol, 12:273-280.
66. Rook GAW (2010) 99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol, 160:70-79 .
67. Rook GAW, Lowry CA, Raison CL (2015) Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res, 1617:47-62.
68. Rothschild DM, O'Grady M, Wecker L (1999) Neonatal cytomegalovirus exposure decreases prepulse inhibition in adult rats: implications for schizophrenia. J Neurosci Res, 57: 429–434.
69. Round JL, O'Connell RM, Mazmanian SK (2010) Coordination of tolerogenic immune responses by the commensal microbiota. J Autoimmun, 34:220-225.
70. Savignac HM, Corona G, Mills H, Chen L, Spencer JP, Tzortzis G et al. (2013) Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem Int, 63:756–764.
71. Severance EG, Alaedini A, Yang S, Halling M, Gressitt KL, Stallings CR (2012) Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res, 138:48-53.
72. Severance EG, Dickerson FB, Halling M, Krivogorsky B, Haile L, Yang S (2010) Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res, 118:240-247.
73. 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, 148:130–137.
74. Severance EG, Kannan G, Gressitt KL, Xiao J, Alaedini A, Pletnikov MV et al. (2012) Anti-gluten immune response following Toxoplasma gondii infection in mice. PLoS One, 7:e50991.
75. Severance EG, Prandovszky E, Castiglione J, Yolken RH (2015) Gastroenterology issues in schizophrenia: why the gut matters.Curr Psychiatry Rep, 17:27.
76. Severance EG, Yolken RH, Eaton WW (2016) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res, 176:23–35.
77. Sherwin E, Rea K, Dinan TG, Cryan JF (2016) A gut (microbiome) feeling about the brain. Curr Opin Gastroenterol, 32:96-102.
78. Singh MM, Kay SR (1976) Wheat gluten as a pathogenic factor in schizophrenia. Science, 191:401-402.
79. Song X, Fan X, Song X, Zhang J, Zhang W, Li X et al. (2013) Elevated levels of adiponectin and other cytokines in drug naïve, first episode schizophrenia patients with normal weight. Schizophr Res, 150:269-273.
80. Strachan DP (1989) Hay fever, hygiene, and household size. BMJ,299:1259–1260.
81. Strous RD, Shoenfeld Y (2006) Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun, 27:71-80.
82. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu X (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol, 558:263–275.
83. Torrey EF (1986) Functional psychoses and viral encephalitis. Integr Psychiatry, 4:224-236.
84. Torrey EF, Bartko JJ, Lun ZR, Yolken RH (2007) Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull, 33:729-736.
85. Torrey EF, Bartko JJ, Yolken RH (2012) Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull, 38:642-647.
86. Torrey EF, Leweke MF, Schwarz MJ, Mueller N, Bachmann S, Schroeder J et al. (2006) Cytomegalovirus and schizophrenia. CNS Drugs, 20:879-885.
87. Torrey EF, Peterson MR (1973) Slow and latent viruses in schizophrenia. Lancet, 302:22–24.
88. Wei Y, Melas PA, Wegener G, Mathe AA, Lavebratt C (2014) Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the BDNF gene. Int J Neuropsychopharmacol, 18:pii: pyu032.
89. Yano JM, Yu K, Donaldson GP, Shastri G, Ann P, Ma L et al. (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 161:264-276.
90. 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, 41:1153-1161.
91. Yolken RH, Torrey EF (1995) Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev, 8:131–145.
92. Yolken RH, Torrey EF (2008) Are some cases of psychosis caused by microbial agents? a review of the evidence. Mol Psychiatry, 13:470-479.