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Breakdown of the Paracellular Tight and Adherens Junctions in the Gut and Blood Brain Barrier and Damage to the Vascular Barrier in Patients with Deficit Schizophrenia

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Abstract

Deficit schizophrenia is characterized by leaky intestinal tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular, and vascular barriers in the gut and blood-brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin, and β-catenin (paracellular pathway, PARA); talin, actin, vinculin, and epithelial intermediate filament (transcellular pathway, TRANS); and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin, and β-catenin, the sum of the four PARA proteins, and the ratio PARA/TRANS were significantly higher in deficit schizophrenia patients than in nondeficit schizophrenia patients and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism, and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall, and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs), and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, β-catenin, and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria, and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses, and indices of BBB breakdown.

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Funding

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, VIC, Australia

    Michael Maes

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

    Sunee Sirivichayakul

  5. Immunosciences Lab., Inc, Los Angeles, CA, USA

    Aristo Vodjani

  6. Cyrex Labs, LLC, Phoenix, AZ, USA

    Aristo Vodjani

  7. Department of Preventive Medicine, Loma Linda University, Loma Linda, CA, USA

    Aristo Vodjani

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  1. Michael Maes
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  2. Sunee Sirivichayakul
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  4. Aristo Vodjani
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Contributions

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 AV) contributed to the 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., Sirivichayakul, S., Kanchanatawan, B. et al. Breakdown of the Paracellular Tight and Adherens Junctions in the Gut and Blood Brain Barrier and Damage to the Vascular Barrier in Patients with Deficit Schizophrenia. Neurotox Res 36, 306–322 (2019). https://doi.org/10.1007/s12640-019-00054-6

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