Gut microbiota-derived ergothioneine alleviates antipsychotic-induced synaptic and cognitive impairments.

Chronic olanzapine treatment induces gut microbial dysbiosis, compromises intestinal barrier integrity, and causes cognitive deficits in mice.

• Multi-omics analyses were used to characterize the gut microbiome and metabolome changes following chronic olanzapine treatment.
• Intestinal barrier integrity was found to be compromised alongside the dysbiosis.
• Cognitive deficits were documented as a downstream consequence of chronic olanzapine exposure.

Chronic antipsychotic treatment causes profound depletion of the microbiota-associated metabolite ergothioneine in blood and brain.

• Ergothioneine depletion was detected in both blood and brain tissue of olanzapine-treated mice.
• The finding was validated in blood samples from olanzapine-treated patients.
• Ergothioneine depletion was also observed in risperidone- and clozapine-treated mice, suggesting a class effect across multiple antipsychotics.
• Multi-omics analyses were used to identify the metabolite depletion.

Ergothioneine depletion correlates with a loss of ergothioneine-producing bacteria, specifically Cyanobacteria and subordinate taxa.

• Cyanobacteria and their subordinate taxa were identified as the primary ergothioneine-producing bacteria affected.
• The correlation between specific bacterial taxa loss and metabolite depletion was established through multi-omics analyses.
• This finding links the microbial dysbiosis directly to the metabolic deficit.

Fecal microbiota transplantation (FMT) from olanzapine-treated mice transfers cognitive impairment to recipient mice.

• FMT from olanzapine-treated donor mice was sufficient to confer cognitive impairment in recipient animals.
• This finding demonstrates that the gut microbiome changes are causally involved in cognitive deficits, not merely correlative.
• The result supports the gut-brain axis as a mechanistic pathway for antipsychotic-induced cognitive side effects.

Ergothioneine supplementation mitigates antipsychotic-induced cognitive impairment.

• Direct ergothioneine supplementation was tested as an intervention in olanzapine-treated mice.
• Supplementation was sufficient to reduce cognitive deficits associated with chronic antipsychotic treatment.
• This finding identifies ergothioneine as a candidate therapeutic strategy to mitigate antipsychotic side effects.

Ergothioneine attenuates hippocampal oxidative stress and inhibits the redox-sensitive phosphatase protein tyrosine phosphatase 1B (PTP1B).

• Hippocampal oxidative stress was identified as a mechanistic link between ergothioneine depletion and cognitive impairment.
• PTP1B was identified as a redox-sensitive phosphatase that is inhibited by ergothioneine.
• PTP1B is described as 'redox-sensitive,' suggesting that oxidative stress activates it when ergothioneine is depleted.
• The mechanism connects antipsychotic-induced microbial changes to synaptic dysfunction via an oxidative stress-PTP1B pathway.

Hippocampal neuronal-specific deletion of PTP1B abolishes olanzapine-induced synaptic and cognitive deficits.

• Neuronal-specific (not global) PTP1B knockout was used to establish cell-type specificity of the effect.
• Deletion of PTP1B specifically in hippocampal neurons was sufficient to prevent both synaptic and cognitive impairments induced by olanzapine.
• This genetic evidence confirms PTP1B as a critical mediator in the pathway from ergothioneine depletion to cognitive impairment.
• The finding positions PTP1B as a potential pharmacological target for preventing antipsychotic-induced cognitive side effects.

The study identifies depletion of microbiota-derived ergothioneine as a mechanism underlying antipsychotic-induced cognitive impairment.

• The proposed mechanistic pathway runs from antipsychotic treatment → gut dysbiosis → loss of ergothioneine-producing bacteria → ergothioneine depletion in blood and brain → hippocampal oxidative stress → PTP1B activation → synaptic and cognitive deficits.
• The mechanism was supported by multi-omics analyses, FMT experiments, supplementation studies, and neuronal-specific genetic deletion.
• Clinical validation in antipsychotic-treated patients strengthens translational relevance.
• The authors highlight this as identifying both the mechanism and potential therapeutic strategies to mitigate the side effect.