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

Chronic antipsychotic use is associated with neuronal damage and cognitive impairment, with the gut microbiome increasingly implicated. However, the specific microbial metabolites and mechanisms involved remain unknown. Here, we demonstrate that chronic olanzapine treatment induces gut microbial dysbiosis, compromises intestinal barrier integrity, and causes cognitive deficits in mice. Multi-omics analyses reveal profound depletion of the microbiota-associated metabolite ergothioneine in blood and brain, a finding validated in the blood of olanzapine-treated patients and risperidone- and clozapine-treated mice. This deficiency correlates with a loss of ergothioneine-producing bacteria (Cyanobacteria and subordinate taxa). Fecal microbiota transplantation from olanzapine-treated mice confers cognitive impairment, while ergothioneine supplementation mitigates it. Mechanistically, ergothioneine attenuates hippocampal oxidative stress and inhibits the redox-sensitive phosphatase protein tyrosine phosphatase 1B (PTP1B). Furthermore, hippocampal neuronal-specific PTP1B deletion abolishes olanzapine-induced synaptic and cognitive deficits. Our findings identify depletion of microbiota-derived ergothioneine as a mechanism underlying antipsychotic-induced cognitive impairment, highlighting therapeutic strategies to mitigate this side effect.