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Gut Microbiota–Derived Ergothioneine Alleviates Antipsychotic-Induced Synaptic and Cognitive Impairments

ABSTRACT:

Background: Chronic use of antipsychotic drugs is associated with neuronal damage and cognitive impairment, potentially mediated by alterations in gut microbiota metabolites, although the specific metabolite involved remains unknown.

Objective: To identify the key metabolite responsible for antipsychotic-induced synaptic and cognitive impairment and assess the potential for its reversal through targeted supplementation.

Design: Mice were chronically treated (8 weeks) with olanzapine, risperidone, or clozapine. In the olanzapine model, gut microbiota (16S rRNA and shotgun metagenomic sequencing) and metabolites (untargeted metabolomics) were analyzed, identifying ergothioneine depletion, validated in olanzapine-treated patients. Causality was tested via fecal microbiota transplantation (FMT) and ergothioneine supplementation. Neuronal-specific PTP1B knockout mice elucidated mechanistic pathways.

Results: Chronic olanzapine treatment caused gut microbial dysbiosis, disrupted intestinal barrier integrity, and impaired cognitive function in mice. A key finding was the depletion of ergothioneine, the gut microbiota-derived metabolite, in both the blood and brain of mice, and in the blood of patients receiving olanzapine. This depletion was associated with a loss of ergothioneine-producing Cyanobacteria and subordinate taxa. Similar ergothioneine depletion and cognitive impairments were observed in risperidone- and clozapine-treated mice. Ergothioneine supplementation or FMT effectively prevented olanzapine-induced cognitive and synaptic impairments. Mechanistically, ergothioneine attenuated olanzapine-induced hippocampal oxidative stress and inhibited the redox-sensitive phosphatase PTP1B. Furthermore, neuronal- or hippocampal neuronal-specific deletion of PTP1B abolished olanzapine-induced synaptic and cognitive impairments.

Conclusions: The significant reduction of ergothioneine induced by antipsychotic treatment leads to cognitive impairment, highlighting gut microbiota-derived metabolites as potential therapeutic targets for improving cognitive function in patients undergoing antipsychotic therapy.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12751 | MetaboLights | 2026-04-08

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12751_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12751_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12751_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12751_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Gut Microbiota–Derived Ergothioneine Alleviates Antipsychotic-Induced Synaptic and Cognitive Impairments

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