Gastrointestinal inflammation and associated immune activation in schizophrenia

Abstract

Immune factors are implicated in normal brain development and in brain disorder pathogenesis. Pathogen infection and food antigen penetration across gastrointestinal barriers are means by which environmental factors might affect immune-related neurodevelopment. Here, we test if gastrointestinal inflammation is associated with schizophrenia and therefore, might contribute to bloodstream entry of potentially neurotropic milk and gluten exorphins and/or immune activation by food antigens. IgG antibodies to Saccharomyces cerevisiae (ASCA, a marker of intestinal inflammation), bovine milk casein, wheat-derived gluten, and 6 infectious agents were assayed. Cohort 1 included 193 with non-recent onset schizophrenia, 67 with recent onset schizophrenia and 207 non-psychiatric controls. Cohort 2 included 103 with first episode schizophrenia, 40 of whom were antipsychotic-naïve. ASCA markers were significantly elevated and correlated with food antigen antibodies in recent onset and non-recent onset schizophrenia compared to controls (p≤0.00001-0.004) and in unmedicated individuals with first episode schizophrenia compared to those receiving antipsychotics (p≤0.05-0.01). Elevated ASCA levels were especially evident in non-recent onset females (p≤0.009), recent onset males (p≤0.01) and in antipsychotic-naïve males (p≤0.03). Anti-food antigen antibodies were correlated to antibodies against Toxoplasma gondii, an intestinally-infectious pathogen, particularly in males with recent onset schizophrenia (p≤0.002). In conclusion, gastrointestinal inflammation is a relevant pathology in schizophrenia, appears to occur in the absence of but may be modified by antipsychotics, and may link food antigen sensitivity and microbial infection as sources of immune activation in mental illness.

Figure 1

Quantitative ASCA IgG levels in individuals with schizophrenia compared to controls. CO refers to controls, Non-RO to non-recent onset, RO to recent onset and SZ to schizophrenia. P-values refer to the level of statistical significance following a two-tailed t-test. Panel A: Elevated ASCA IgG levels were found in individuals with Non-RO SZ and RO SZ compared to controls. Panel B: ASCA IgG levels were significantly elevated in females with Non-RO SZ compared to female controls and in males with RO SZ compared to male controls.

Figure 2

ASCA IgG levels in individuals with schizophrenia according to medication status. SZ-unmed refers to antipsychotic naïve schizophrenia, and SZ-med refers to antipsychotic-positive schizophrenia. P-values refer to the level of statistical significance following a two-tailed t-test. Panel A: ASCA IgG levels were elevated in individuals who are antipsychotic naïve compared to those who received these medications. Panel B: ASCA IgG levels were significantly elevated in males who were antipsychotic naïve compared to males who were antipsychotic-positive.

Figure 3

Correlations of GI inflammation, food antigen IgG and IgG to infectious disease agents in the diagnostic groups. Anti-casein IgG, anti-gluten IgG and ASCA antibody levels were compared to each other as well as to IgG of the infectious disease antigens. Anti-casein IgG used as the Y-axis component is shown as a representative chart and refers to antibody levels following mean-normalized absorbance. P-values refer to the level of statistical significance following a multiple linear regression that was corrected for age, sex and race.