Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia

https://doi.org/10.1016/j.schres.2013.05.018Get rights and content

Abstract

The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of low-grade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n = 141 schizophrenia, n = 75 bipolar disorder, n = 78 controls; (2) n = 78 antipsychotic-naïve first-episode schizophrenia, n = 38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR = 3.09, p < 0.0001) compared to controls. Case–control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R2 = 0.21, p < 0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R2 = 0.26–0.27, p < 0.0001) and elevated in females compared to males (p < 0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R2 = 0.27, p < 0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R2 = 0.37, p < 0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based monocyte activation, autoimmunity and metabolic dysfunction may also contribute to the observed marker profiles.

Introduction

Chronic inflammation is a risk factor intrinsically linked to cardiovascular disease, type 2 diabetes, insulin resistance and obesity (Berg and Scherer, 2005, Hansson, 2005, Hotamisligil, 2006, Gregor and Hotamisligil, 2011). Inflammatory abnormalities in systemic circulation and in the central nervous system are increasingly reported in psychiatric diseases such as schizophrenia and bipolar disorder (Padmos et al., 2009, Drexhage et al., 2010, Miller et al., 2011, Leonard et al., 2012, Miller et al., 2012, Muller et al., 2012a, Severance et al., 2012b, Dickerson et al., 2013, Fillman et al., 2013, Gibney and Drexhage, 2013). The inflammation source is not known but may be inherent to the disease or may result from antipsychotic-related metabolic disturbances (Drexhage et al., 2010, Miller et al., 2011, Leonard et al., 2012, Miller et al., 2012, Muller et al., 2012a, Severance et al., 2012a, Severance et al., 2012b, Steiner et al., 2012). A chronic inflammatory state predisposes the bearer to a heightened risk of comorbidities that compromise general health and quality of life; therefore, it is important to understand the source of abnormal inflammation and implement corrective treatments.

Several risk factors for the development of schizophrenia (inflammation, Toxoplasma gondii exposures, gluten sensitivity) can be linked through a common origin in the gastrointestinal (GI) tract (Dickerson et al., 2010, Samaroo et al., 2010, Severance et al., 2010a, Severance et al., 2010b, Dickerson et al., 2011, Niebuhr et al., 2011, Dickerson et al., 2012, Severance et al., 2012a, Severance et al., 2012c). The innate immune molecule, complement C1q, forms immune complexes with food antigens at increased rates in individuals with schizophrenia (Severance et al., 2012b). Exposure to the gut pathogen, T. gondii, results in elevated antibodies to dietary gluten in both humans and experimentally infected animals (Severance et al., 2012a, Severance et al., 2012c). Food-derived antibodies in schizophrenia coincide with antibody levels to the commensal fungus, Saccharomyces cerevisiae, a marker of microbial translocation and GI inflammation used to help diagnose Crohn's disease (Severance et al., 2012a).

If the GI barrier is differentially compromised in schizophrenia, we would expect that increased levels of gut-dwelling commensal enteric bacteria are exposed to systemic circulation, a process known as bacterial translocation (Brenchley et al., 2006, Sandler and Douek, 2012). Heightened rates of bacterial translocation are reported in individuals with unipolar depression compared to controls (Maes et al., 2008, Maes et al., 2012, Maes et al., 2013). Here, we measured two markers of bacteria translocation, soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), in serum samples from one cohort of individuals with schizophrenia, bipolar disorder and non-psychiatric controls and from a second cohort of individuals with first-episode schizophrenia who were antipsychotic-naïve or who had received antipsychotic medication.

Section snippets

Cohort 1 — Sheppard Pratt Health System, Baltimore, MD, USA

One hundred and forty one individuals with schizophrenia, 75 individuals with bipolar disorder and 78 individuals with no history of psychiatric disorders were recruited. Methods for identifying and characterizing individuals of diagnostic groups according to criteria defined by DSM-IV have been previously described (Severance et al., 2010b, Dickerson et al., 2011, Severance et al., 2012a, Dickerson et al., 2013). Individuals with schizophrenia had a DSM-IV diagnosis (DSM-IV, 1994) of

Results

In multivariate regressions, quantitative levels of sCD14 and LBP were significantly inter-correlated in both cohorts in all diagnostic and treatment groups (Fig. 1; R2 = 0.32–0.67, p < 0.0001–0.02).

In comparison between diagnostic groups in cohort 1, sCD14 levels were significantly greater in schizophrenia and bipolar disorder compared to controls (Fig. 2; ANOVA, F = 7.36, p < 0.0008; Sidak post-hoc, schizophrenia p < 0.001, bipolar disorder p < 0.02). sCD14 seropositivity was associated with a

Discussion

We found that the relationship between the bacterial translocation markers used in this study was complex. sCD14 and LBP levels were significantly inter-correlated, as consistent with their coordinated roles in activating the innate immune system (Fig. 4). These markers were also both significantly correlated with CRP in individuals with schizophrenia, suggesting a common pathway of associated inflammation. In spite of these markers' congruencies, a main outcome of our study was the detection

Role of funding source

This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) where Dr. Severance is a Scott-Gentle Foundation Young Investigator; by a NIMH P50 Silvio O. Conte Center at Johns Hopkins (grant# MH-94268); and by the Stanley Medical Research Institute. These funding sources had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Contributors

Drs. Severance and Yolken designed the study with input from Drs. Dickerson, and Leweke. All authors collected and/or analyzed data. Dr. Severance wrote the first draft of the manuscript. All authors approved the final manuscript.

Conflict of interest

Robert Yolken is a member of the Stanley Medical Research Institute Board of Directors and Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. None of the other authors report any potential conflicts of interest.

Acknowledgments

We thank Ruby Pittman for technical assistance and Ann Cusic for administrative support.

References (69)

  • A.M. Kilbourne et al.

    Excess heart-disease-related mortality in a national study of patients with mental disorders: identifying modifiable risk factors

    Gen. Hosp. Psychiatry

    (2009)
  • M. Maes et al.

    Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut

    J. Affect. Disord.

    (2012)
  • B.J. Miller et al.

    Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects

    Biol. Psychiatry

    (2011)
  • K. Miyake

    Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2

    Trends Microbiol.

    (2004)
  • N. Muller et al.

    Inflammation in schizophrenia

    Adv. Protein Chem. Struct. Biol.

    (2012)
  • N. Muller et al.

    Impaired monocyte activation in schizophrenia

    Psychiatry Res.

    (2012)
  • D.W. Niebuhr et al.

    Association between bovine casein antibody and new onset schizophrenia among US military personnel

    Schizophr. Res.

    (2011)
  • M. Romero-Sanchez et al.

    Different biological significance of sCD14 and LPS in HIV-infection: importance of the immunovirology stage and association with HIV-disease progression markers

    J. Infect.

    (2012)
  • D. Samaroo et al.

    Novel immune response to gluten in individuals with schizophrenia

    Schizophr. Res.

    (2010)
  • E.G. Severance et al.

    Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia

    Schizophr. Res.

    (2010)
  • E.G. Severance et al.

    Gastrointestinal inflammation and associated immune activation in schizophrenia

    Schizophr. Res.

    (2012)
  • E.G. Severance et al.

    Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia

    Neurobiol. Dis.

    (2012)
  • F.L. Soares et al.

    Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression

    J. Nutr. Biochem.

    (2013)
  • A.H. Berg et al.

    Adipose tissue, inflammation, and cardiovascular disease

    Circ. Res.

    (2005)
  • W. Beumer et al.

    The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes

    J. Leukoc. Biol.

    (2012)
  • J.M. Brenchley et al.

    Microbial translocation is a cause of systemic immune activation in chronic HIV infection

    Nat. Med.

    (2006)
  • N.G. Cascella et al.

    Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population

    Schizophr. Bull.

    (2011)
  • J. Cinova et al.

    Gliadin peptides activate blood monocytes from patients with celiac disease

    J. Clin. Immunol.

    (2007)
  • M.G. Clemente et al.

    Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function

    Gut

    (2003)
  • C. Crump et al.

    Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study

    Am. J. Psychiatry

    (2013)
  • F. Dickerson et al.

    Markers of gluten sensitivity and celiac disease in bipolar disorder

    Bipolar Disord.

    (2011)
  • F.C. Dohan

    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)
  • F.C. Dohan

    Celiac disease and schizophrenia

    N. Engl. J. Med.

    (1980)
  • R.C. Drexhage et al.

    The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder

    Expert Rev. Neurother.

    (2010)
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