Role of Gut Microbiome in Schizophrenia

Researchers investigate potential links between schizophrenia, the gut microbiome, the gut-brain axis, and short-chain fatty acids (SCFAs) in a recent review published in Nutrients.

Background

The gut microbiome is critical to human physiology and disease because it stimulates digestive enzyme performance and vitamin synthesis, as well as modulates the immune system. Inflammation and altered neurotransmitter synthesis can be caused by an imbalance between beneficial and pathogenic microbes in the gut, as well as low SCFA levels.

Schizophrenia is a severe psychiatric condition characterized by delusions, hallucinations, cognitive impairment, difficulties with social interaction, anxiety, and depression. Neural connection deficiencies, subcortical dopamine dysfunction, locus coeruleus-norepinephrine dysregulation, and slower autonomic nervous system (ANS) function, as well as higher serotonin and glucocorticoid levels, may be present in affected people.

Toxoplasma gondii infections have been linked to schizophrenia and have affected the gut microbiome in mice. However, research on the links between the gut microbiome, SCFAs, and schizophrenia is scarce. Further research in this area may contribute to the development of tailored medicines to enhance the quality of care for people suffering from schizophrenia.

The gut-brain axis and SCFAs

The vagus nerve, enteric nervous system (ENS), hypothalamic-pituitary-adrenal (HPA) axis, immunological system, metabolic pathways, and neuroendocrine system all have a role in regulating brain activity via the gut-brain axis. The vagus nerve strengthens the intestinal barrier, decreases inflammation, and inhibits pro-inflammatory cytokine upregulation. The hypothalamic-pituitary-adrenal axis secretes glucocorticoids, which have an effect on behavior and brain function.

The gut microbiota can be influenced by stress, which is regulated by the hypothalamic-pituitary-adrenal axis. Gut microorganisms are required for microglia normalization and maturation, and disruptions in the gut microbiota may result in central nervous system (CNS) diseases.

The gut microbiome has been shown in rats to influence brain-derived neurotrophic factor (BDNF) expression via gut hormones and microglial growth. Gut microorganisms regulate the CNS by creating a variety of metabolites such as SCFAs, bile acids, norepinephrine, glutamate, dopamine, gamma-aminobutyric acid (GABA), histamine, and serotonin.

SCFAs including acetate, propionate, and butyrate acids are produced during gut fermentation and can cross the blood-brain barrier (BBB) to interact with microglia. SCFAs also trigger G protein-coupled receptors (GPCRs), which govern immunological responses, anti-inflammatory pathways, cellular communication, and the generation of reactive oxygen species (ROS).

Butyric acid, a SCFA, promotes neurotransmitter production in the CNS by influencing the release of molecules such as BDNF. SCFAs also have an impact on serotonin synthesis in the stomach. SCFAs have also been related to mental illnesses such as neuropathy due to decreased levels of GABA, serotonin, dopamine, acetate, propionate, and butyrate.

Gut microbial imbalance and schizophrenia

In comparison to disease-free persons, schizophrenia patients have aberrant lipid and glucose metabolism, with less numerous SCFA-releasing bacteria in the gut microbiome and an increased number of oral cavity-related and anaerobic bacteria. Transplanting Streptococcus vestibularis into mice produced in schizophrenia-like behavior, with higher levels of many cytokines found in schizophrenia patients compared to healthy people.

Interleukin-1 (IL-1) was considerably higher in schizophrenia patients than in controls, as were IL-4, IL-6, IL-8, tumor necrosis factor-alpha (TNF-), and macrophage inflammatory protein-1 alpha (MIP-1). Other cytokines, such as monocyte chemoattractant protein-1 (MCP-1), Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES), IL-1ra, IL-9, IL-13, interferon-gamma (IFN-), and MIP-1b, were shown to be expressed at lower levels in schizophrenia patients.

Individuals with schizophrenia have a negative link between lower levels of butyrate-producing bacteria such Butyricicoccus, Roseburia, and Faecalibacterium and higher levels of cytokines, whereas positive relationships with cytokines show reduced expression.

In schizophrenic patients, the gut microbiota diversity is similarly reduced. Gut dysbiosis reduces the function of receptor proteins for glial-cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and N-methyl-d-aspartate (NMDA), all of which govern brain plasticity.
In mice exposed to fecal transplants from schizophrenia patients, neurotransmitter expression in hippocampus cells was altered, resulting in lower glutamate levels and higher GABA and glutamine levels.

Valeric acid, one of the SCFAs produced by intestinal microbes, protected the brain from excitotoxins and cellular death, but caproic acid had an effect on cognitive performance. In schizophrenia patients, isovaleric acid levels had a substantial but inverse relationship with lower Repeated Battery for Neuropsychological Status (RBANS) scores in both immediate and delayed memory.

Conclusion

SCFAs, which have the ability to cross the BBB, influence CNS activity via influencing cytokine production and microglial function. However, due to diversity in the composition of the intestinal microbiota and SCFA secretion, research on the processes underpinning the impact of the gut on mental health, particularly in schizophrenia, is limited. As a result, further study is required to clarify the causes and create novel therapeutic techniques for schizophrenia.

For more information: The Gut-Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production. Nutrients.

doi:10.3390/ nu15204391