Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling

Abstract

Autoimmunity, gastrointestinal (GI) disorders and schizophrenia have been associated with one another for a long time. This paper reviews these connections and provides a context by which multiple risk factors for schizophrenia may be related. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease. Exposure to wheat gluten and bovine milk casein also contribute to non-celiac food sensitivities in susceptible individuals. Co-morbid GI inflammation accompanies humoral immunity to food antigens, occurs early during the course of schizophrenia and appears to be independent from antipsychotic-generated motility effects. This inflammation impacts endothelial barrier permeability and can precipitate translocation of gut bacteria into systemic circulation. Infection by the neurotropic gut pathogen, Toxoplasma gondii, will elicit an inflammatory GI environment. Such processes trigger innate immunity, including activation of complement C1q, which also functions at synapses in the brain. The emerging field of microbiome research lies at the center of these interactions with evidence that the abundance and diversity of resident gut microbiota contribute to digestion, inflammation, gut permeability and behavior. Dietary modifications of core bacterial compositions may explain inefficient gluten digestion and how immigrant status in certain situations is a risk factor for schizophrenia. Gut microbiome research in schizophrenia is in its infancy, but data in related fields suggest disease-associated altered phylogenetic compositions. In summary, this review surveys associative and experimental data linking autoimmunity, GI activity and schizophrenia, and proposes that understanding of disrupted biological pathways outside of the brain can lend valuable information regarding pathogeneses of complex, polygenic brain disorders.

Gastroenterology issues in schizophrenia: Why the gut matters

“…Further propagating this connection are the technological advances that have fueled the burgeoning field of microbiome research. In a series of research reports, we have united conceptually and experimentally a number of risk factors for the development of schizophrenia through a common origin in the gut [13][14][15][16][17][18]. The disease-associated interaction of such biological variables as humoral immunity to food antigens, intestinal inflammation, exposure to the parasite Toxoplasma gondii, endothelial barrier defects and microbial dysbiosis is consistent with a physiological model whereby gut-based processes can create a systemic state of immune dysregulation.…”

Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases

“…61 In patients with schizophrenia, there are increased intestinal permeability and change in intestinal function. 62 Emotional stress and depression have been shown to increase prevalence of disorders of the digestive system. 63 …”

“…122 The fundamental cause of this is unknown and could include both the controversial association with gluten sensitivity and celiac disease 123 as well as primary changes in gut microbiota. 62,124 These theories may not be mutually exclusive as it is possible that certain compositions of gut microbiota can lead to changed metabolism of certain food products such as gluten, and subsequent production of neuroactive peptides, increased absorption of these products due to local inflammation, and alteration of dopaminergic and serotonergic pathways in individuals who are genetically susceptible to schizophrenia. 62 Germ-free mice tend to show a schizoid type behavior, not spending more time in a chamber with another mice in it when put in a 3-chamber sociability test.…”

“…62,124 These theories may not be mutually exclusive as it is possible that certain compositions of gut microbiota can lead to changed metabolism of certain food products such as gluten, and subsequent production of neuroactive peptides, increased absorption of these products due to local inflammation, and alteration of dopaminergic and serotonergic pathways in individuals who are genetically susceptible to schizophrenia. 62 Germ-free mice tend to show a schizoid type behavior, not spending more time in a chamber with another mice in it when put in a 3-chamber sociability test. 125 In a mice model that shows behavioral changes that resemble schizophrenia, treatment with Bacteroides fragilis can ameliorate the symptoms.…”

Breastfeeding and the gut-brain axis: is there a role for melatonin?

“…Enhanced levels of gut permeability and associated alterations in gut microbiota are linked to the etiology and/or course of an array of medical conditions, including multiple sclerosis (13), Parkinson's disease (12), dementia (14), schizophrenia (15), bipolar disorder (16), the autistic spectrum (17) and depression (18). As noted above, the high rates of comorbid depression, often prior to symptom exacerbation, in these conditions suggests that gut-brain axis alterations may mediate some of their associations with such an array of medical presentations via raised levels of depression.…”