Upregulation of the Intestinal Paracellular Pathway with Breakdown of Tight and Adherens Junctions in Deficit Schizophrenia

Abstract

In 2001, the first author of this paper reported that schizophrenia is associated with an increased frequency of the haptoglobin (Hp)-2 gene. The precursor of Hp-2 is zonulin, a molecule that affects intercellular tight junction integrity. Recently, we reported increased plasma IgA/IgM responses to Gram-negative bacteria in deficit schizophrenia indicating leaky gut and gut dysbiosis. The current study was performed to examine the integrity of the paracellular (tight and adherens junctions) and transcellular (cytoskeletal proteins) pathways in deficit versus non-deficit schizophrenia. We measured IgM responses to zonulin, occludin, E-cadherin, talin, actin and vinculin in association with IgA responses to Gram-negative bacteria, CCL-11, IgA responses to tryptophan catabolites (TRYCATs), immune activation and IgM to malondialdehyde (MDA) and NO-cysteinyl in 78 schizophrenia patients and 40 controls. We found that the ratio of IgM to zonulin + occudin / talin + actin + viculin (PARA/TRANS) was significantly greater in deficit than in non-deficit schizophrenia and higher in schizophrenia than controls and was significantly associated with increased IgA responses to Gram-negative bacteria. IgM responses to zonulin were positively associated with schizophrenia (versus controls), while IgM to occludin was significantly associated with deficit schizophrenia (versus non-deficit schizophrenia and controls). A large part of the variance (90.8%) in negative and PHEM (psychosis, hostility, excitation and mannerism) symptoms was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, IgM to E-cadherin and malondialdehyde (MDA) and memory dysfunctions, while 53.3% of the variance in the latter was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, CCL-11, TRYCATs and immune activation. The results show an upregulated paracellular pathway with breakdown of the tight and ahherens junctions and increased bacterial translocation in deficit schizophrenia. These dysfunctions in the intestinal paracellular route together with lowered natural IgM, immune activation and production of CCL-11 and TRYCATs contribute to the phenomenology of deficit schizophrenia.

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<strong></strong>

“…E-Cadherin (epithelial cadherin) is a key component of intestinal adherens junctions, which provide stability and cell-cell adhesion among epithelial cells of the paracellular pathway, modulate intracellular signaling and regulate turnover of the actin cytoskeleton through binding with β-catenin (van Roy and Berx, 2008;Gomez et al, 2015;Bruser and Bogdan, 2017;Hartsock and Nelson, 2008). Interestingly, in our study (Maes et al, 2019) only very modest changes in IgM responses to cytoskeletal proteins, including talin, actin and vinculin were detected in schizophrenia, while the ratio of IgM responses to paracellular versus transcellular proteins was significantly increased in deficit schizophrenia as compared with nondeficit schizophrenia and controls. Actin microfilaments, a major component of the cytoskeleton, maintain the shape and structure of the cell and regulate transcription (Dominguez and Holmes, 2011).…”

“…Importantly, we reported that the upregulated paracellular leak pathway and increased bacterial translocation coupled with other biomarkers of schizophrenia significantly predicted PHEMN (psychosis, hostility, excitation, mannerism and negative) symptoms, psychomotor retardation, formal thought disorders and neurocognitive impairments, including semantic and episodic memory (Maes et al, 2019). Those biomarkers include: lowered natural IgM to malondialdehyde (MDA), increased levels of CCL-11 or eotaxin, an endogenous cognition deteriorating chemokine (ECDC), increased IgA responses to neurotoxic and excitotoxic tryptophan catabolites (TRYCATs) versus more protective TRYCATs and an index of immune activation based on assays of IL-10, soluble IL-1 receptor antagonist (sIL-1RA) and macrophage inflammatory protein (MIP)-1 (Maes et al, 2019). Based on those results we suggested that breakdown of TJs and AJs and the consequent translocation of Gram-negative bacteria may have induced the above mentioned neuro-immune pathways which all together may cause neuroprogression, namely dysfunctions in synaptic sampling, synaptic plasticity, synaptogenesis, neurogenesis, neuroprotection, etc.…”

“…Aberrations in the paracellular pathway may be caused by trigger factors that are relevant to (deficit) schizophrenia, including immune activation, gut dysbiosis, gliadin hypersensitivity and increased zonulin production (Maes et al, 2019). (a) Pro-inflammatory cytokines such as interleukin (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α, which are all increased in schizophrenia (Roomruangwong et al, 2018b), may disassemble TJs and AJs and consequently upregulate the paracellular pathway (Al-Sadi et al, 2009;Utech et al, 2010;Bruewer et al, 2006).…”

“…(c) Schizophrenia is also accompanied by increased IgM responses to zonulin and a higher frequency of the haptoglobin (Hp)-2 phenotype (zonulin is pre-Hp-2) suggesting that increased levels of zonulin may have displaced proteins of the zona occludens with consequent upregulation of the paracellular pathway . A leaky or (upregulated) paracellular pathway is the doorway to increased bacterial translocation, activated immune-inflammatory pathways and autoimmunity explaining that this phenomenon is involved in immune and autoimmune disorders, including diabetes type I, celiac disease, inflammatory bowel disease and schizophrenia Edelblum and Turner, 2009;Maes et al, 2019).…”

“…Based on those results we suggested that breakdown of TJs and AJs and the consequent translocation of Gram-negative bacteria may have induced the above mentioned neuro-immune pathways which all together may cause neuroprogression, namely dysfunctions in synaptic sampling, synaptic plasticity, synaptogenesis, neurogenesis, neuroprotection, etc. (Maes et al, 2019).…”