Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia
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)
- et al.
Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome
Psychoneuroendocrinology
(2012) - et al.
Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia
Biol. Psychiatry
(2010) - et al.
Markers of gluten sensitivity in acute mania: a longitudinal study
Psychiatry Res.
(2012) - et al.
C-reactive protein is elevated in schizophrenia
Schizophr. Res.
(2013) Coeliac disease and schizophrenia
Lancet
(1970)- et al.
Immune and neuroimmune alterations in mood disorders and schizophrenia
Int. Rev. Neurobiol.
(2011) - et al.
Schizophrenia and increased risks of cardiovascular disease
Am. Heart J.
(2005) - et al.
Initial responses to endotoxins and Gram-negative bacteria
Clin. Chim. Acta
(2002) - et al.
A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies
Schizophr. Res.
(2012) - et al.
Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB
FEBS Lett.
(2004)
Excess heart-disease-related mortality in a national study of patients with mental disorders: identifying modifiable risk factors
Gen. Hosp. Psychiatry
Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut
J. Affect. Disord.
Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects
Biol. Psychiatry
Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2
Trends Microbiol.
Inflammation in schizophrenia
Adv. Protein Chem. Struct. Biol.
Impaired monocyte activation in schizophrenia
Psychiatry Res.
Association between bovine casein antibody and new onset schizophrenia among US military personnel
Schizophr. Res.
Different biological significance of sCD14 and LPS in HIV-infection: importance of the immunovirology stage and association with HIV-disease progression markers
J. Infect.
Novel immune response to gluten in individuals with schizophrenia
Schizophr. Res.
Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia
Schizophr. Res.
Gastrointestinal inflammation and associated immune activation in schizophrenia
Schizophr. Res.
Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia
Neurobiol. Dis.
Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression
J. Nutr. Biochem.
Adipose tissue, inflammation, and cardiovascular disease
Circ. Res.
The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes
J. Leukoc. Biol.
Microbial translocation is a cause of systemic immune activation in chronic HIV infection
Nat. Med.
Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population
Schizophr. Bull.
Gliadin peptides activate blood monocytes from patients with celiac disease
J. Clin. Immunol.
Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function
Gut
Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study
Am. J. Psychiatry
Markers of gluten sensitivity and celiac disease in bipolar disorder
Bipolar Disord.
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.
Celiac disease and schizophrenia
N. Engl. J. Med.
The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder
Expert Rev. Neurother.
Cited by (194)
Probiotic, prebiotic, synbiotic and fermented food supplementation in psychiatric disorders: A systematic review of clinical trials
2024, Neuroscience and Biobehavioral ReviewsFrom gut to brain: A network model of intestinal permeability, inflammation, and psychotic symptoms in schizophrenia.
2024, European NeuropsychopharmacologyThe Influence of Gut Microbiota in Psychosis
2024, The Gut-Brain Axis, Second EditionCOVID-19 and mental health risks in children: A role for biomarkers of inflammation, stress and the gut-brain axis
2023, Biomarkers in NeuropsychiatryThe role of infections and inflammation in schizophrenia: review of the evidence
2024, Middle East Current Psychiatry