Recently, the Jiangsu Key Laboratory of Immunity and Metabolism and Jiangsu International Joint Laboratory of Immunity and Metabolism of our school published an online research paper in Cell Host & Microbe (CAS Zone 1 Top, IF=18.7) titled Gut microbiota-derived ergothioneine alleviates antipsychotic-induced synaptic and cognitive impairments.
Xuzhou Medical University is the first affiliation of the paper. Dr. Zheng Mingxuan (Postdoctoral Fellow), Yan Hanrong and Hao Wenting (PhD Candidates) from the School of Basic Medical Sciences, and Chief Physician An Huimei from Beijing Huilongguan Hospital are the first authors. Prof. Yu Yinghua and Prof. Zheng Kuiyang from Xuzhou Medical University, and Prof. Xu-Feng Huang from the University of Wollongong, Australia, are the corresponding authors.
This research was supported by grants from the National Natural Science Foundation of China, Jiangsu Natural Science Foundation, General Program of Natural Science Research in Jiangsu Universities, Jiangsu Excellent Postdoctoral Program, and “Jiebang Guashuai” Program of Xuzhou Medical University, an open competition to identify the most capable candidates for tackling key technological challenges.
Antipsychotic drugs are first-line medications for schizophrenia and bipolar disorder. While effectively controlling hallucinations and delusions in patients with schizophrenia, they often cause a distressing side effect: cognitive decline. For a long time, academia has attributed these cognitive impairments to disease progression or the direct effects of drugs on neurotransmitters, yet overlooked that these drugs first pass through the gut before crossing the blood–brain barrier. Whether and how gut microbiota play a role in this process has remained unclear. Using multi-omics analyses, this study found that long-term administration of the antipsychotic olanzapine leads to gut dysbiosis and impaired intestinal barrier in mice, and significantly reduces levels of the gut microbiota-derived metabolite ergothioneine in the blood and brain. This depletion is closely associated with the reduction of ergothioneine-producing bacteria (e.g., Cyanobacteria and related taxa).
Furthermore, ergothioneine deficiency triggers oxidative stress in the hippocampus and activates the oxidation-sensitive phosphatase PTP1B (protein tyrosine phosphatase 1B). Specific knockout of PTP1B in hippocampal neurons blocks olanzapine-induced synaptic and cognitive dysfunction. This study reveals the pivotal role of the gut microbiota–ergothioneine–PTP1B axis in the neuropsychiatric side effects of antipsychotics, opening a novel potential intervention strategy for preventing and treating cognitive impairment associated with long-term antipsychotic therapy.
In recent years, the Jiangsu Key Laboratory of Immunity and Metabolism has focused on major national and local needs, emphasized interdisciplinary research, and conducted cutting-edge basic and translational research on major diseases centered on immunity and metabolism, as well as gut microbiota–host interactions. Its research findings have been published in journals including Journal of Clinical Investigation, Microbiome, PNAS, Hepatology, Cancer Research, Advanced Science, and Nature Communications, with more than 10 national invention patents authorized.
Original Link: https://www.cell.com/cell-host-microbe/abstract/S1931-3128(26)00128-9
(First Review: Li Li; Second Review: Wang Wenshi; Third Review: Han Hongliu)
