biostudies-literatureShi YTop Talent Support Program for young and middle-aged people of Wuxi Health CommitteeMedical Young Talents Program of Jiangsu ProvinceWuxi Taihu Lake Talent Plan, Supports for Leading Talents in Medical and Health Profession196https://www.ebi.ac.uk/biostudies/studies/S-EPMC12372200biostudies-literatureUnknown17(1)Growing evidence has suggested that elevated Trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite, are closely associated with brain aging and cognitive impairment. Glycogen synthase kinase-3 beta (GSK-3β) activity was depicted to be essential in regulating learning and memory. The current study examined the impact of TMAO on cognitive function in mild cognitive impairment (MCI) patients and rat models while exploring the mechanisms regulating the TMAO-induced GSK-3β signaling. This study recruited 115 MCI patients and 128 healthy controls. All participants underwent neuropsychological assessments. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. The study also explored whether the GSK-3β signaling was involved in cognitive and function deficits linked with elevated TMAO in rat models. Our results indicated that TMAO plasma levels were elevated in MCI patients compared to healthy controls, depicting a significant association with potential MCI risk. Furthermore, chronic exposure to choline considerably impacted spatial cognitive performance in the Morris water maze task. This reduced the phosphorylation of Ser9 of GSK-3β and the synaptic plasticity-related proteins within the hippocampus, which could be restored by inhibiting TMAO with ABS. In addition, inhibition of GSK-3β by SB216763 significantly prevented the TMAO-induced synaptic damage while decreasing the membrane level of GluA1 and improving hippocampal learning and memory. These results indicate that TMAO can induce hippocampal-dependent learning and memory ability impairment with deficits in synaptic plasticity by regulating the GSK-3β activity.Alzheimer's research & therapyGut microbial metabolite TMAO impairs cognitive function and induces hippocampal synaptic plasticity decline through modulation of GSK-3β activity.PMC12372200QNRC2016191HB20200162020THRC-DJ-SNWFang XXi GLi YWang PDeng JWang FChen YHan YWang HHui JShi YfalseGut microbial metabolite TMAO impairs cognitive function and induces hippocampal synaptic plasticity decline through modulation of GSK-3β activity.Growing evidence has suggested that elevated Trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite, are closely associated with brain aging and cognitive impairment. Glycogen synthase kinase-3 beta (GSK-3β) activity was depicted to be essential in regulating learning and memory. The current study examined the impact of TMAO on cognitive function in mild cognitive impairment (MCI) patients and rat models while exploring the mechanisms regulating the TMAO-induced GSK-3β signaling. This study recruited 115 MCI patients and 128 healthy controls. All participants underwent neuropsychological assessments. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. The study also explored whether the GSK-3β signaling was involved in cognitive and function deficits linked with elevated TMAO in rat models. Our results indicated that TMAO plasma levels were elevated in MCI patients compared to healthy controls, depicting a significant association with potential MCI risk. Furthermore, chronic exposure to choline considerably impacted spatial cognitive performance in the Morris water maze task. This reduced the phosphorylation of Ser9 of GSK-3β and the synaptic plasticity-related proteins within the hippocampus, which could be restored by inhibiting TMAO with ABS. In addition, inhibition of GSK-3β by SB216763 significantly prevented the TMAO-induced synaptic damage while decreasing the membrane level of GluA1 and improving hippocampal learning and memory. These results indicate that TMAO can induce hippocampal-dependent learning and memory ability impairment with deficits in synaptic plasticity by regulating the GSK-3β activity.2025-01-01T00:00:00Z2025 Aug2026-05-09T10:39:42.63Z2026-04-08T00:48:20.539ZS-EPMC123722004084697910.1186/s13195-025-01846-z