Exploring the Role of Gut Microbiome in Schizophrenia


A recent review published in Nutrients delves into the potential connections between schizophrenia, the gut microbiome, the gut-brain axis, and short-chain fatty acids (SCFAs). The gut microbiome is an essential component in human physiology and disease, contributing to gastric mucus formation, digestion, vitamin synthesis, and immune system regulation. Imbalances in the gut microbiome and low SCFA levels can lead to inflammation and altered neurotransmitter production.

Schizophrenia is a severe psychiatric disorder characterized by symptoms such as delusions, hallucinations, cognitive impairment, social difficulties, anxiety, and depression. Individuals with schizophrenia often exhibit neural connectivity deficits, dysfunction in subcortical dopamine pathways, dysregulation of the locus coeruleus-norepinephrine system, slower autonomic nervous system function, and elevated serotonin and glucocorticoid levels.

Studies have shown a potential link between schizophrenia and Toxoplasma gondii infections, which have been found to alter the gut microbiome in mice. However, there is limited data on the relationship between the gut microbiome, SCFAs, and schizophrenia. Further research in this area could help improve the standard of care for individuals with schizophrenia through the development of targeted therapies.

The Gut-Brain Axis and SCFAs

The gut microbiome plays a crucial role in regulating brain activity through the gut-brain axis, which includes the vagus nerve, enteric nervous system, hypothalamic-pituitary-adrenal axis, immune system, metabolic pathways, and neuroendocrine system. The vagus nerve helps maintain intestinal barrier integrity, reduces inflammation, and modulates pro-inflammatory cytokine levels. The hypothalamic-pituitary-adrenal axis produces glucocorticoids, which can impact behavior and brain function.

Stress, mediated by the hypothalamic-pituitary-adrenal axis, can influence the composition of the gut microbiome, and in turn, the gut microbiome can impact brain function and behavior. Disruption in the gut microbiota has been associated with central nervous system disorders.

Studies in rats have shown that the gut microbiome can affect the expression of brain-derived neurotrophic factor (BDNF) through gut hormones and microglial development. The gut microbiome plays a crucial role in regulating the central nervous system by producing various metabolites, including SCFAs, bile acids, neurotransmitters like norepinephrine, glutamate, dopamine, gamma-aminobutyric acid (GABA), histamine, and serotonin.

SCFAs, such as acetate, propionate, and butyrate, are produced during gut fermentation and can cross the blood-brain barrier to interact with microglia. SCFAs also stimulate G protein-coupled receptors, regulate immune responses, anti-inflammatory pathways, cellular signaling, and oxidative stress.

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

Gut Microbial Imbalance and Schizophrenia

Individuals with schizophrenia often exhibit abnormal lipid and glucose metabolism, a less diverse gut microbiome with lower levels of SCFA-producing bacteria, and an increased abundance of oral cavity-related and anaerobic bacteria compared to healthy individuals. Transplanting Streptococcus vestibularis into mice has resulted in schizophrenia-like behavior, with increased levels of several cytokines observed in individuals with schizophrenia compared to controls.

Among the investigated cytokines, interleukin-1β (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 in individuals with schizophrenia. On the other hand, 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 in individuals with schizophrenia.

Individuals with schizophrenia also exhibit negative correlations between decreased levels of SCFA-producing bacteria and elevated cytokines, indicating a potential link between gut microbiome imbalances and inflammation. Reduced gut microbiota diversity has also been observed in individuals with schizophrenia, which affects the activity of neurotrophic factor receptor proteins and brain plasticity.

Studies in mice exposed to fecal transplantations from individuals with schizophrenia have shown that neurotransmitter expressions in hippocampal cells were affected, resulting in reduced glutamate levels and increased GABA and glutamine levels.

Among the SCFAs produced by intestinal microorganisms, valeric acid has been found to protect the brain from excitotoxins and cellular death, while caproic acid affects cognitive performance. Isovaleric acid levels have shown a strong but inverse association with lower scores on tests assessing immediate and delayed memory in individuals with schizophrenia.


SCFAs play a significant role in influencing central nervous system activity by modulating cytokine production and microglial function. However, more research is needed to understand the mechanisms underlying the impact of the gut microbiome on mental health, particularly in schizophrenia, due to variability in the composition of the gut microbiota and SCFA secretion. Further investigations will contribute to the development of innovative treatment approaches for schizophrenia.


  1. Source: Coherent Market Insights, Public sources, Desk research
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