Gut Microbiota-Mediated Amino Acid Reprogramming in Ketamine-Induced Neurotoxicity: A Novel Microbiota-Amino Acid-Mitochondrial Axis Associated with Cognitive Deficits.
Ying Wei, Xiao-Jing Song, Zhiwei Jia, Xiang Liu, Xiao-Qin Chen, Xinyi Zhan, Xue Mei, Lin-Chuan Liao
Neuropharmacology October 27, 2025 DOI: 10.1016/j.neuropharm.2025.110748 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | C57BL/6N mice |
| Intervention | Ketamine |
| Measures | Y-maze, novel object recognition (NOR) test, transmission electron microscopy (TEM), 16S rRNA sequencing, untargeted and targeted plasma metabolomics, Spearman correlation analysis |
| Topics | Esketamine Ketamine |
| Key findings | Chronic ketamine administration in mice was associated with cognitive impairment, hippocampal mitochondrial damage, gut microbiota dysbiosis, and disrupted plasma amino acid levels. The authors propose that a microbiota-amino-acid-mitochondrial axis drives ketamine-induced neurotoxicity and suggest this axis as a target for microbiome-based interventions. |
Abstract
Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is associated with chronic abuse leading to schizophrenia-like cognitive deficits. The gut-brain axis may play a role in mediating substance-induced neurotoxicity; however, its involvement in ketamine-induced cognitive impairment remains poorly understood. Here, chronic ketamine exposure was administered intraperitoneally to C57BL/6N mice to examine its effects on gut microbiota homeostasis and associated amino acid metabolism. Cognitive deficits were evaluated using the Y-maze and novel object recognition (NOR) tests. Hippocampal ultrastructure was assessed by transmission electron microscopy (TEM). Multi-omics integration included 16S rRNA sequencing, untargeted and targeted plasma metabolomics, and Spearman correlation analysis. The results showed that ketamine-exposed mice exhibited significant cognitive impairments, including impaired spontaneous alternation in the Y-maze (P< 0.05) and a reduced discrimination index in the NOR test (P< 0.01). TEM analysis revealed hippocampal mitochondrial damage, accompanied by chromatin condensation. Gut microbiota analysis indicated dysbiosis, with a notable increase in Lachnospiraceae, Bacteroidaceae, Helicobacteraceae, and Rikenellaceae and a decrease in Verrucomicrobiaceae and Prevotellaceae at the family level. Plasma amino acid levels were also disrupted, with a significant decrease in L-glutamine, L-lysine, L-threonine and an increase in L-cysteic acid. Furthermore, strong correlations were observed between the abundance of Bacteroides, branched-chain amino acids (BCAAs), and cognitive scores (|ρ| > 0.6, P< 0.05). This study identifies the microbiota-amino acid-mitochondrial axis as the underlying mechanism driving ketamine-induced neurotoxicity. It highlights the correlation between gut microbiota-associated amino acid reprogramming and this process, offering potential targets for microbiome-based interventions to combat substance-related cognitive impairments.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 13
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine. Journal of Affective Disorders March 15, 2025
- The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment. Molecular genetics and metabolism November 1, 2024
- Ketamine differentially affects implicit and explicit memory processes in rats. Psychopharmacology June 1, 2025
and 8 more in the library