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

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 (R(2)=0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R(2)=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 (R(2)=0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R(2)=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.

Keywords: BMI; C-reactive protein; CRP; Diet; GI; Gut; LBP; LPS; Macrophage; Mental illness; Metabolic syndrome; Microbiome; Psychosis; body mass index; gastrointestinal; lipopolysaccharide; lipopolysaccharide binding protein; sCD14; soluble CD14; tTG; tissue transglutaminase.

Figure 1

Markers of bacterial translocation, sCD14 and LBP, were inter-correlated. A. sCD14 and LBP marker correlations in cohort 1 based in Baltimore, MD, U.S.A. are shown. Multiple linear regressions included age, gender, race, smoking status, and assay plate designation. B. sCD14 and LBP marker correlations in cohort 2 based in Cologne, Germany, are shown. Multiple linear regressions included age, gender, and assay plate designation. AP refers to antipsychotic. [For color reproduction]

Figure 2

sCD14 and LBP levels in cohort 1 cases compared to controls. A. sCD14 levels were elevated in schizophrenia and bipolar disorder compared to controls. B. LBP levels were not different between cases and controls, but levels in schizophrenia were higher than levels in bipolar disorder. [For color reproduction]

Figure 3

sCD14 and LBP exhibited sex-specific patterns. A. sCD14 levels were elevated in female individuals with schizophrenia compared to males. B. LBP levels were elevated in females compared to males in both the control and schizophrenia groups. [For color reproduction]

Figure 4

Overview of coordinated activation of sCD14 and LBP during bacterial translocation. Following episodes of increased GI permeability, enteric bacteria may be exposed to the immune cells of the lamina propria and to systemic circulation. LBP interacts directly with the LPS endotoxin of Gram-negative bacteria and transports LPS monomers to sCD14 and CD14 bound to macrophage membranes. sCD14 is manufactured by immune cells of the GI mucosa, whereas LBP is synthesized by GI epithelial cells. Both markers are also produced by the liver (Heumann and Roger, 2002; Kitchens and Thompson, 2005; Miyake, 2004; Sandler and Douek, 2012; Stehle et al., 2012). Dietary gluten may impact components of these pathways and based on our study results is included in a hypothetical role in this diagram. [For color reproduction]