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In Schizophrenia, Increased Plasma IgM/IgA Responses to Gut Commensal Bacteria Are Associated with Negative Symptoms, Neurocognitive Impairments, and the Deficit Phenotype

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Abstract

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative-specific epitopes (OSEs), which are a first-line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls. Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all five Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the receiver operating characteristic curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the negative subscale score of the Positive and Negative Syndrome Scale was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the five enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini-Mental State Examination, Boston naming test, Verbal Fluency, and Word List Memory test scores. These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.

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Acknowledgements

The study was supported by the Asahi Glass Foundation, Chulalongkorn University Centenary Academic Development Project, and Ratchadapiseksompotch Funds, Faculty of Medicine, Chulalongkorn University, grant numbers RA60/042 (to BK) and RA61/050 (to MM).

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Michael Maes & Buranee Kanchanatawan

  2. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  3. IMPACT Strategic Research Center Barwon Health, Deakin University, Geelong, Australia

    Michael Maes

  4. Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Sunee Sirivichayakul

  5. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    André F. Carvalho

  6. Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada

    André F. Carvalho

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  1. Michael Maes
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All the contributing authors have participated in the manuscript. MM and BK designed the study. BK recruited patients and completed diagnostic interviews and rating scale measurements. MM carried out the statistical analyses. All authors (BK, MM, SS, and AC) contributed to interpretation of the data and writing of the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Michael Maes.

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Maes, M., Kanchanatawan, B., Sirivichayakul, S. et al. In Schizophrenia, Increased Plasma IgM/IgA Responses to Gut Commensal Bacteria Are Associated with Negative Symptoms, Neurocognitive Impairments, and the Deficit Phenotype. Neurotox Res 35, 684–698 (2019). https://doi.org/10.1007/s12640-018-9987-y

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