From Infection to the Microbiome: An Evolving Role of Microbes in Schizophrenia

Abstract

The study of microorganisms such as bacteria, viruses, archaea, fungi, and protozoa in the context of psychiatric disorders may be surprising to some. This intersection of disciplines, however, has a rich history and is currently revitalized by newfound functions of the microbiome and the gut-brain axis in human diseases. Schizophrenia, in particular, fits this model as a disorder with gene and environmental roots that may be anchored in the immune system. In this context, the combination of a precisely timed pathogen exposure in a person with genetically encoded altered immunity may have especially destructive consequences for the central nervous system (CNS). Furthermore, significant components of immunity, such as the development of the immune response and the concept of immune tolerance, are largely dictated by the commensal residents of the microbiome. When this community of microbes is imbalanced, perhaps as the result of a pathogen invasion, stress, or immune gene deficiency, a pathological cycle of localized inflammation, endothelial barrier compromise, translocation of gut-derived products, and systemic inflammation may ensue. If these pathologies enable access of gut and microbial metabolites and immune molecules to the CNS across the blood-brain barrier (BBB), and studies of the gut-brain axis support this hypothesis, a worsening of cognitive deficits and psychiatric symptoms is predicted to occur in susceptible individuals with schizophrenia. In this chapter, we review the role of microbes in various stages of this model and how these organisms may contribute to documented phenotypes of schizophrenia. An increased understanding of the role of pathogens and the microbiome in psychiatric disorders will better guide the development of microbial and immune-based therapeutics for disease prevention and treatment.

Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

“…Thus these changes may reflect shared molecular pathology and aetiological mechanisms between these clinical phenotypes ( Druart and Le Magueresse, 2019 ). The possible primary and perpetuating causes of complement dysregulation and inflammation in schizophrenia and other mental disorders are unclear, but maternal immune activation ( Conway and Brown, 2019 ), exposure to infections ( Kneeland and Fatemi, 2013 ), the microbiome ( Severance and Yolken, 2019 ) and other environmental factors such as childhood adversity ( Danese and J Lewis, 2017 ) and substance use ( Miller et al, 2018 ) are potential contributing factors. Drugs targeting the complement system are available and others in active development ( Carpanini et al, 2019 ; Druart and Le Magueresse, 2019 ; Ricklin et al, 2018 ; Zelek et al, 2019 ), but whether they may prove useful in the treatment or prevention of psychotic disorders will require extensive preclinical testing before human trials.…”

Complex Gastrointestinal and Endocrine Sources of Inflammation in Schizophrenia

“…In schizophrenia, casecontrol differences in the blood biomarkers examined here suggest that a low-grade peripheral inflammation is related to the translocation of gut-based microbes and metabolic products across compromised gut-associated vascular barriers into systemic circulation. This low-grade systemic inflammation, in turn, is thought to produce similar permeability at the bloodbrain barrier, thus providing a mechanism by which gut-based products might enter the central nervous system and alter brain functioning (4,37,38).…”

“…A susceptibility locus for schizophrenia, complement C4, is of interest since it is a component of the immune system and is also involved in synaptic pruning in the brain (2,3). Environmental and epidemiological studies indicate that people with schizophrenia have increased rates of exposure to pathogens and other antigens (4,5). A reported phenotype in these individuals is a pervasive low level inflammation of unknown origin (6,7).…”

COVID-19: Considering the prevalence of schizophrenia in the coming decades

“…In some studies, schizophrenia has been described as a pathogenic autoimmune disease that is caused by the interaction of viruses, pathogens, and the immune system (Carter, 2011). Also there are some reports about the coexistence of a genetically modified im-mune system with the activity of microorganisms such as viruses that have deleterious consequences for the central nervous system (Severance and Yolken, 2019).…”