Trimethylamine‐N‐Oxide regulates cognitive function in Alzheimer’s Disease patients and mice model through brain‐gut‐microbiota axis

Abstract

Background: The regulatory role of Trimethylamine‐N‐oxide (TMAO) for cognition from the perspective of microbiota‐gut‐brain (MGB) axis in AD remains unclear. Method: In clinical cohort study for effects of 24‐week computerized cognitive training (CCT), registered on clinicaltrials.gov (NCT06094452), plasma TMAO levels were quantified using ELISA in MCI (n=39) and mild AD patients (n=35). Correlation analyses were conducted to assess the relationship between changes in TMAO levels and cognitive function (ADAS‐cog score) and gut microbiota indices. In animal model experiments, C57/BL6 aged mice and APP/PS1 transgenic mice were administrated by water feeding with 1.2% TMAO for 16 weeks and 1.0% of its inhibitor 3,3‐Dimethyl‐1‐butanol (DMB) for 8 weeks. TMAO levels in plasma and cerebrospinal fluid (CSF) were measured by ELISA. Cerebral blood flow (CBF) activation was detected by a laser speckle imaging system. Cognitive behavior was evaluated using Morris Water Maze test. The expressions