Implications of Gut Microbiota-Derived Metabolites in Neurological Disorders

Oct 30, 2025ACS chemical neuroscience

How Chemicals Made by Gut Bacteria Are Linked to Brain Disorders

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Abstract

Key metabolites from gut bacteria, such as trimethylamine-oxide (TMAO), are linked to the progression of neurological disorders.

Gut microbiota-derived metabolites may influence neuroinflammation, oxidative stress, and cognitive decline.
TMAO is associated with disrupted blood-brain barrier integrity and activation of microglial cells, leading to neuronal apoptosis.
Para-cresol sulfate (pCS) correlates with increased oxidative stress and cognitive impairments in neurodegenerative conditions like Parkinson's and Alzheimer's diseases.
Elevated levels of 4-ethylphenyl sulfate (4-EPS) are linked to anxiety-like behavior and blood-brain barrier disruption in autism spectrum disorder.
Gut-derived metabolites could play a role in psychiatric changes and behavioral disorders.
Interventions targeting gut microbiota through dietary precursors and metabolites may be critical for neurological health.

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Neurological disorders (NDs) represent a significant global health challenges, with neurodegeneration being a common pathological feature. Recent investigations indicate the involvement of gut microbiota-derived metabolites in these disorders, such as neuroinflammation, oxidative stress, and cognitive decline. The gut-brain axis, a communication network between the gut and the central nervous system (CNS), is influenced by microbial metabolites, which can cross the blood-brain barrier and impact brain function. Key metabolites such as trimethylamine-oxide (TMAO), para-cresol sulfate (pCS), 4-ethylphenyl sulfate (4-EPS), and indoxyl sulfate (IS) have been linked with the progression of neurological disorders. TMAO disrupts blood-brain barrier integrity, promotes oxidative stress, and activates microglial cells, which lead to the apoptosis of neurons, resulting in neuroinflammation. This could also result in psychiatric changes and behavioral disorders. pCS produced from gut bacteria metabolizing dietary proteins is correlated with amplified oxidative stress, neuroinflammation, and cognitive impairments in disorders like Parkinson's disease and Alzheimer's disease. Similarly, elevated 4-EPS levels are linked to autism spectrum disorder, contributing to anxiety-like behavior and blood-brain barrier disruption. Understanding the mechanisms by which gut-derived metabolites affect neurological health could lead to novel therapeutic strategies that can target gut microbiota for the medication and treatment of neurological disorders. Dietary precursors and gut microbiota metabolites, modulated by probiotics, prebiotics, postbiotics, and synbiotics, play a critical role in maintaining microbiota homeostasis and influencing neurological health, needing sophisticated biosensors to enable real-time monitoring and early intervention in disorders linked to gut metabolite imbalances. N

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Implications of Gut Microbiota-Derived Metabolites in Neurological Disorders

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