8.4 GUT DYSBIOSIS AND AUTOIMMUNE FEATURES IN SCHIZOPHRENIA FUEL BROKEN BARRIER HYPOTHESES

Abstract

Background: The blood-gut and blood-brain barriers represent highly regulated and dynamic cellular interfaces that when dysfunctional set into motion neuropathological sequelae relevant to schizophrenia . . The recognition of gastrointestinal (GI) comorbidities has a long history in schizophrenia and predates the advent of currently utilized antipsychotic agents. In particular, inflammatory bowel diseases are over-represented in schizophrenia and may be the combined result of genetic predispositions and environmental insults. Exposure to stress, food-derived antigens and infection all serve to unsettle the balance of a resident community of gut microbes, a collective functional unit that determines the blood-gut barrier integrity and modulates the immune system to minimize autoimmune responses. Here we focus on the blood-gut barrier as the genesis for ensuing systemic processes that ultimately impact the blood-brain barrier and function of the central nervous system. Toward this end, we present translational work regarding the gut microbiome and inflammatory autoimmune phenotypes based on data from clinical studies of schizophrenia and modeling of this pathological process in rodents. Methods: We examined biomarkers of endothelial barrier integrity, microbial translocation, GI inflammation and autoimmunity in biological samples from individuals with schizophrenia and controls. We then evaluated these same markers in an experimental mouse model of inflammatory bowel disease induced by a neurotropic pathogen, Toxoplasma gondii. Analysis of variance and multi-variate regression models were used to detect differences in levels of blood biomarkers amongst experimental groups. Results: In individuals with schizophrenia, the measurement of diverse biomarkers of intestinal dysbiosis demonstrates a pro-inflammatory gut environment that is associated with gut barrier breakdown. In mice, infection with T. gondii, a gut pathogen, resulted in the increased prevalence of markers of a breached blood-gut and blood-brain barrier, compared to uninfected controls. Similarly, in T. gondii-positive individuals with schizophrenia, the same set of markers of barrier compromise were elevated compared to controls. Intriguingly, this loss of blood-gut and blood-brain barrier integrity was accompanied by elevated levels of autoantibodies to the NMDA (NR2) receptor in both humans and mice. Conclusions: Infection and intestinal inflammation lead to an environment that is conducive to the concurrent generation of autoimmune pathologies and endothelial barrier dysfunction. NMDA receptor hypofunction is a leading hypothesis concerning the etiology and pathophysiology of schizophrenia. Of note, the enteric nervous system hosts an array of neurotransmitter receptors and thus may serve as a location where autoantibodies against important brain proteins are formed. Mechanistically, GI inflammation may expose novel immunogenic triggers composed of neurotransmitter receptors in association with other intestinal cellular, dietary or microbial antigens. Breached endothelial barriers would enable the transit of antibodies directed against these novel targets in the gut to reach the brain. The precise timing and interactions of these key elements across the gut-brain axis is complex. As our understanding of the relevant mechanisms progresses, suitable diagnosis and treatment strategies related to the gut-brain axis in psychiatric disorders can be identified and refined.