Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder
Corresponding Author
Emily G Severance
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Corresponding author:
Emily G. Severance, Ph.D.
Stanley Division of Developmental Neurovirology
Department of Pediatrics
Johns Hopkins University School of Medicine
600 North Wolfe Street, Blalock 1105
Baltimore, MD 21287-4933
USA
Fax: 410-955-3723
E-mail: [email protected]
Search for more papers by this authorKristin L Gressitt
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Search for more papers by this authorShuojia Yang
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Search for more papers by this authorCassie R Stallings
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorAndrea E Origoni
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorCrystal Vaughan
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorSunil Khushalani
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorArmin Alaedini
Department of Medicine, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorFaith B Dickerson
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorRobert H Yolken
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Search for more papers by this authorCorresponding Author
Emily G Severance
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Corresponding author:
Emily G. Severance, Ph.D.
Stanley Division of Developmental Neurovirology
Department of Pediatrics
Johns Hopkins University School of Medicine
600 North Wolfe Street, Blalock 1105
Baltimore, MD 21287-4933
USA
Fax: 410-955-3723
E-mail: [email protected]
Search for more papers by this authorKristin L Gressitt
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Search for more papers by this authorShuojia Yang
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Search for more papers by this authorCassie R Stallings
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorAndrea E Origoni
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorCrystal Vaughan
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorSunil Khushalani
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorArmin Alaedini
Department of Medicine, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorFaith B Dickerson
Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA
Search for more papers by this authorRobert H Yolken
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Search for more papers by this authorAbstract
Objectives
Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder.
Methods
We measured a marker of GI inflammation, anti-Saccharomyces cerevisiae antibodies (ASCA), in non-psychiatric controls (n = 207), in patients with bipolar disorder without a recent onset of psychosis (n = 226), and in patients with bipolar disorder with a recent onset of psychosis (n = 38). We compared ASCA levels to antibodies against gluten, casein, Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV-1), influenza A, influenza B, measles, and Toxoplasma gondii.
Results
Elevated ASCA conferred a 3.5–4.4-fold increased odds ratio of disease association (age-, race-, and gender-corrected multinomial logistic regressions, p ≤ 0.00001) that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups (R2 = 0.29–0.59, p ≤ 0.0005), and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group (R2 = 0.31–0.36, p ≤ 0.004–0.01).
Conclusions
Elevated seropositivity of a GI-related marker and its association with antibodies to food-derived proteins and self-reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder.
References
- 1Cascella NG, Kryszak D, Bhatti B 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: 94–100.
- 2Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull 2013; 39: 867–871.
- 3Dickerson F, Stallings C, Origoni A et al. Markers of gluten sensitivity and celiac disease in bipolar disorder. Bipolar Disord 2011; 13: 52–58.
- 4Dickerson F, Stallings C, Origoni A et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry 2010; 68: 100–104.
- 5Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Markers of gluten sensitivity in acute mania: a longitudinal study. Psychiatry Res 2012; 196: 68–71.
- 6Severance EG, Alaedini A, Yang S et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res 2012; 138: 48–53.
- 7Severance EG, Dickerson FB, Halling M et al. Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res 2010; 118: 240–247.
- 8Severance EG, Dupont D, Dickerson FB et al. Immune activation by casein dietary antigens in bipolar disorder. Bipolar Disord 2010; 12: 834–842.
- 9Severance EG, Gressitt KL, Halling M et al. Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiol Dis 2012; 48: 447–453.
- 10Karlsson H, Blomstrom A, Wicks S, Yang S, Yolken RH, Dalman C. Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. Am J Psychiatry 2012; 169: 625–632.
- 11Niebuhr DW, Li Y, Cowan DN et al. Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res 2011; 128: 51–55.
- 12Samaroo D, Dickerson F, Kasarda DD et al. Novel immune response to gluten in individuals with schizophrenia. Schizophr Res 2010; 118: 248–255.
- 13Jackson J, Eaton W, Cascella N et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res 2012; 140: 262–263.
- 14Whiteley P, Shattock P, Knivsberg AM et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci 2012; 6: 344.
- 15Dohan FC. Cereals and schizophrenia data and hypothesis. Acta Psychiatr Scand 1966; 42: 125–152.
- 16Dohan FC. Wheat “consumption” and hospital admissions for schizophrenia during World War II. A preliminary report. Am J Clin Nutr 1966; 18: 7–10.
- 17Dohan 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: 1–23.
- 18Dohan FC. Is celiac disease a clue to the pathogenesis of schizophrenia? Ment Hyg 1969; 53: 525–529.
- 19Dohan FC, Grasberger JC, Lowell FM, Johnston HT Jr, Arbegast AW. Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet. Br J Psychiatry 1969; 115: 595–596.
- 20Dohan FC. Coeliac disease and schizophrenia. Lancet 1970; 1: 897–898.
- 21Dohan FC. Schizophrenia and neuroactive peptides from food. Lancet 1979; 1: 1031.
- 22Dohan FC. Schizophrenia, celiac disease, gluten antibodies, and the importance of beta. Biol Psychiatry 1981; 16: 1115–1117.
- 23Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull 1988; 14: 489–494.
- 24Reichelt KL, Reichelt WH, Stensrud M. The role of peptides in schizophrenia. J Neurochem 1995; 65: S43–S45.
- 25Reichelt KL, Seim AR, Reichelt WH. Could schizophrenia be reasonably explained by Dohan's hypothesis on genetic interaction with a dietary peptide overload? Prog Neuropsychopharmacol Biol Psychiatry 1996; 20: 1083–1114.
- 26Reichelt KL, Stensrud M. Increase in urinary peptides prior to the diagnosis of schizophrenia. Schizophr Res 1998; 34: 211–213.
- 27Reichelt KL. Exorphins in schizophrenia and autism. J Neurochem 1994; 63: S86–S88.
- 28Kaminski S, Cieslinska A, Kostyra E. Polymorphism of bovine beta-casein and its potential effect on human health. J Appl Genet 2007; 48: 189–198.
- 29Brietzke E, Stertz L, Fernandes BS et al. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord 2009; 116: 214–217.
- 30Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 2009; 70: 1078–1090.
- 31Hope S, Dieset I, Agartz I et al. Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia. J Psychiatr Res 2011; 45: 1608–1616.
- 32Leboyer M, Soreca I, Scott J et al. Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord 2012; 141: 1–10.
- 33Tsai SY, Chung KH, Wu JY, Kuo CJ, Lee HC, Huang SH. Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord 2012; 136: 110–116.
- 34Padmos RC, Van Baal GC, Vonk R et al. Genetic and environmental influences on pro-inflammatory monocytes in bipolar disorder: a twin study. Arch Gen Psychiatry 2009; 66: 957–965.
- 35Savitz JB, Drevets WC. Neuroreceptor imaging in depression. Neurobiol Dis 2013; 52: 49–65.
- 36Stertz L, Magalhaes PV, Kapczinski F. Is bipolar disorder an inflammatory condition? The relevance of microglial activation. Curr Opin Psychiatry 2013; 26: 19–26.
- 37Drexhage RC, Hoogenboezem TH, Versnel MA, Berghout A, Nolen WA, Drexhage HA. The activation of monocyte and T cell networks in patients with bipolar disorder. Brain Behav Immun 2011; 25: 1206–1213.
- 38Drexhage RC, Weigelt K, van Beveren N et al. Immune and neuroimmune alterations in mood disorders and schizophrenia. Int Rev Neurobiol 2011; 101: 169–201.
- 39Brenchley JM, Price DA, Schacker TW et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12: 1365–1371.
- 40Ashorn S, Valineva T, Kaukinen K et al. Serological responses to microbial antigens in celiac disease patients during a gluten-free diet. J Clin Immunol 2009; 29: 190–195.
- 41Desplat-Jego S, Johanet C, Escande A 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: 2312–2318.
- 42Kotze LM, Nisihara RM, Utiyama SR, Kotze PG, Theiss PM, Olandoski M. Antibodies anti-Saccharomyces cerevisiae (ASCA) do not differentiate Crohn's disease from celiac disease. Arq Gastroenterol 2010; 47: 242–245.
- 43Mallant-Hent R, Mary B, von Blomberg E et al. Disappearance of anti-Saccharomyces cerevisiae antibodies in coeliac disease during a gluten-free diet. Eur J Gastroenterol Hepatol 2006; 18: 75–78.
- 44Oshitani N, Hato F, Matsumoto T et al. Decreased anti-Saccharomyces cerevisiae antibody titer by mesalazine in patients with Crohn's disease. J Gastroenterol Hepatol 2000; 15: 1400–1403.
- 45Suvisaari J, Mantere O. Inflammation theories in psychotic disorders: a critical review. Infect Disord Drug Targets 2013; 13: 59–70.
- 46 DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 4th edn. Washington, DC: American Psychiatric Association, 1994.
- 47First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders – Non-patient Edition (SCID I/NP). New York, NY: Biometrics Research, New York State Psychiatric Institute, 1998.
- 48Randolph C. RBANS Manual–Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, TX: Psychological Corporation, 1998.
- 49Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.
- 50Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278–296.
- 51Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–435.
- 52Menard S, Lebreton C, Schumann M et al. Paracellular versus transcellular intestinal permeability to gliadin peptides in active celiac disease. Am J Pathol 2012; 180: 608–615.
- 53Matysiak-Budnik T, Candalh C, Dugave C et al. Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology 2003; 125: 696–707.
- 54Heyman M, Abed J, Lebreton C, Cerf-Bensussan N. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut 2012; 61: 1355–1364.
- 55Lammers KM, Lu R, Brownley J et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008; 135: 194–204. e3.
- 56Tripathi A, Lammers KM, Goldblum S et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci USA 2009; 106: 16799–16804.
- 57Drago S, El Asmar R, Di Pierro M et al. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 2006; 41: 408–419.
- 58Sander GR, Cummins AG, Henshall T, Powell BC. Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett 2005; 579: 4851–4855.
- 59Rallabhandi P. Gluten and celiac disease–an immunological perspective. J AOAC Int 2012; 95: 349–355.
- 60Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bosmans E. 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 2013; 127: 344–354.
- 61Maes M, Kubera M, Leunis JC, Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 2012; 141: 55–62.
- 62Maes M, Kubera M, Leunis JC. 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 2008; 29: 117–124.
- 63Severance EG, Gressitt KL, Stallings CR et al. Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res 2013; 148: 130–137.
- 64Sidhom O, Laadhar L, Zitouni M et al. Spectrum of autoantibodies in Tunisian psychiatric inpatients. Immunol Invest 2012; 41: 538–549.
- 65Eaton WW, Pedersen MG, Nielsen PR, Mortensen PB. Autoimmune diseases, bipolar disorder, and non-affective psychosis. Bipolar Disord 2010; 12: 638–646.
- 66Vonk R, van der Schot AC, Kahn RS, Nolen WA, Drexhage HA. Is autoimmune thyroiditis part of the genetic vulnerability (or an endophenotype) for bipolar disorder? Biol Psychiatry 2007; 62: 135–140.
- 67Padmos RC, Bekris L, Knijff EM et al. A high prevalence of organ-specific autoimmunity in patients with bipolar disorder. Biol Psychiatry 2004; 56: 476–482.
- 68Ben-Ami Shor D, Orbach H, Boaz M et al. Gastrointestinal-associated autoantibodies in different autoimmune diseases. Am J Clin Exp Immunol 2012; 1: 49–55.
- 69Hamdani N, Daban-Huard C, Lajnef M et al. Relationship between Toxoplasma gondii infection and bipolar disorder in a French sample. J Affect Disord 2013; 148: 444–448.
- 70Bereswill S, Munoz M, Fischer A et al. Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS ONE 2010; 5: e15099.
- 71Bernstein CN, Rawsthorne P, Blanchard JF. Population-based case-control study of measles, mumps, and rubella and inflammatory bowel disease. Inflamm Bowel Dis 2007; 13: 759–762.
- 72D'Souza Y, Dionne S, Seidman EG, Bitton A, Ward BJ. No evidence of persisting measles virus in the intestinal tissues of patients with inflammatory bowel disease. Gut 2007; 56: 886–888.
- 73Dickerson F, Stallings C, Origoni A, Copp C, Khushalani S, Yolken R. Antibodies to measles in individuals with recent onset psychosis. Schizophr Res 2010; 119: 89–94.
- 74Craven M, Egan CE, Dowd SE et al. Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease. PLoS ONE 2012; 7: e41594.
- 75Erridge C, Duncan SH, Bereswill S, Heimesaat MM. The induction of colitis and ileitis in mice is associated with marked increases in intestinal concentrations of stimulants of TLRs 2, 4, and 5. PLoS ONE 2010; 5: e9125.
- 76Hansen TS, Jess T, Vind I et al. Environmental factors in inflammatory bowel disease: a case-control study based on a Danish inception cohort. J Crohns Colitis 2011; 5: 577–584.
- 77Lidar M, Langevitz P, Shoenfeld Y. The role of infection in inflammatory bowel disease: initiation, exacerbation and protection. Isr Med Assoc J 2009; 11: 558–563.
- 78Liesenfeld O. Immune responses to Toxoplasma gondii in the gut. Immunobiology 1999; 201: 229–239.
- 79Munoz M, Heimesaat MM, Danker K et al. Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17. J Exp Med 2009; 206: 3047–3059.
- 80Schreiner M, Liesenfeld O. Small intestinal inflammation following oral infection with Toxoplasma gondii does not occur exclusively in C57BL/6 mice: review of 70 reports from the literature. Mem Inst Oswaldo Cruz 2009; 104: 221–233.
- 81Wakefield AJ, Pittilo RM, Sim R et al. Evidence of persistent measles virus infection in Crohn's disease. J Med Virol 1993; 39: 345–353.
- 82Carter CJ. Toxoplasmosis and polygenic disease susceptibility genes: extensive Toxoplasma gondii host/pathogen interactome enrichment in nine psychiatric or neurological disorders. J Pathog 2013; 2013: 965046.
