How the gut microbiome contributes to schizophrenia

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Oct 19 2023

In a recent review published in Nutrients, researchers explore potential relationships between schizophrenia, the gut microbiome, the gut-brain axis, and short-chain fatty acids (SCFAs).

Study: The Gut-Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production. Image Credit: Ground Picture / Shutterstock.com

Background

The gut microbiome is crucial to human physiology and disease, as it facilitates gastric mucus formation, promotes digestive enzyme function and vitamin synthesis, and modulates the immune system. An imbalance between beneficial and pathogenic microorganisms in the gut and low SCFA levels can cause inflammation and altered neurotransmitter production.

Schizophrenia is a severe psychiatric disorder that may cause delusions, hallucinations, cognitive impairment, social interaction difficulties, anxiety, and depression. Affected individuals may present with neural connectivity deficits, subcortical dopamine dysfunction, locus coeruleus-norepinephrine dysregulation, and slower autonomic nervous system (ANS) function, as well as elevated serotonin and glucocorticoid levels.

Schizophrenia has been associated with Toxoplasma gondii infections, which have altered the gut microbiome in mice. However, data on the associations between the gut microbiome, SCFAs, and schizophrenia are limited. Further research in this area may aid in developing targeted therapies to improve the standard of care for schizophrenia patients.

The gut-brain axis and SCFAs

The gut microbiome is a vital component in regulating brain activity through the gut-brain axis, which includes the vagus nerve, enteric nervous system (ENS), hypothalamic-pituitary-adrenal (HPA) axis, immune system, metabolic pathways, and neuroendocrine system. The vagus nerve fortifies intestinal barrier integrity, reduces inflammation, and restrains pro-inflammatory cytokine upregulation. The hypothalamic-pituitary-adrenal axis produces glucocorticoids, thereby impacting behavior and brain function.

Stress, which is mediated by the hypothalamic-pituitary-adrenal axis, can influence the gut microbiome and vice versa. Gut microbes are essential for microglia normalization and maturation, with disruption in the gut microbiota potentially leading to central nervous system (CNS) disorders.

In rats, the gut microbiome can impact brain-derived neurotrophic factor (BDNF) expression through gut hormones and microglial development. Gut microbes play a crucial role in CNS regulation by producing several metabolites including SCFAs, bile acids, norepinephrine, glutamate, dopamine, gamma-aminobutyric acid (GABA), histamine, and serotonin.

SCFAs, such as acetate, propionate, and butyrate acids, are released during fermentation in the gut and can traverse the blood-brain barrier (BBB) to interact with microglia. Moreover, SCFAs stimulate G protein-coupled receptors (GPCRs), regulate immunological responses, anti-inflammatory pathways, cellular signaling, and reactive oxygen species (ROS) induction.

Butyric acid, an SCFA, influences the release of factors like BDNF, thereby promoting neurotransmitter synthesis in the CNS. SCFAs also affect serotonin production in the gut. Importantly, SCFAs have also been linked to mental disorders like neuropathy, as they lead to reduced levels of GABA, serotonin, dopamine, acetate, propionate, and butyrate.

Gut microbial imbalance and schizophrenia

Schizophrenia patients exhibit abnormal lipid and glucose metabolism, with less abundant SCFA-releasing bacteria in the intestinal microbiome and an increased abundance of oral cavity-related and anaerobic bacteria as compared to disease-free individuals. Transplanting Streptococcus vestibularis into mice resulted in schizophrenia-like conduct, with increased levels of several cytokines observed in schizophrenia patients as compared to healthy individuals.

Of the investigated cytokines, interleukin1β (IL-1β), IL-4, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and macrophage inflammatory protein-1 alpha (MIP-1α) were significantly elevated among schizophrenia patients as compared to controls. Comparatively, reduced expression of other cytokines like 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-γ), and MIP-1b has been observed among schizophrenia patients.

Individuals with schizophrenia exhibit negative correlations between decreased levels of butyrate-producing bacteria such as Butyricicoccus, Roseburia, and Faecalibacterium and elevated cytokines, whereas positive correlations with cytokines showed reduced expression.

Reduced gut microbiota diversity has also been observed in schizophrenia patients. Gut dysbiosis results in reduced activity of glial-cell-derived neurotrophic factor (GDNF) receptor proteins, brain-derived neurotrophic factor (BDNF), and N-methyl-d-aspartate (NMDA), which control brain plasticity.

Neurotransmitter expressions in hippocampal cells were impacted in mice exposed to fecal transplantations from schizophrenia patients, which led to reduced glutamate levels and increased GABA and glutamine levels.

Among SCFAs produced by intestinal microorganisms, valeric acid protected the brain from excitotoxins and cellular death, whereas caproic acid affected cognitive performance. Isovaleric acid levels showed a strong but inverse association with lower Repeated Battery for Neuropsychological Status (RBANS) scores in regard to immediate and delayed memory among schizophrenia patients.

Conclusions

SCFAs, which can cross the BBB, affect CNS activity by impacting cytokine production and microglial function. However, research on the mechanisms underlying the impact of the gut on mental health, especially in schizophrenia, is limited due to variability in the composition of the intestinal microbiota and SCFA secretion. Thus, further research is needed to elucidate the mechanisms and develop innovative treatment approaches for schizophrenia.