Emerging evidence positions the bidirectional microbiome-brain communication network as a tractable intervention point in neurodegeneration. Yet whether dietary flavonoids can leverage this axis to counteract cognitive decline remains incompletely characterized. Three cohorts of male APP/PS1 mice underwent daily oral administration of quercetin (100mg/kg body weight) or saline vehicle over a 6-month intervention period. Spatial learning and memory were evaluated through Morris Water Maze paradigms. Multi-omics profiling encompassed fecal microbiome characterization (16S rRNA gene amplicon sequencing), serum metabolomic analysis (liquid chromatography-tandem mass spectrometry), and hippocampal transcriptome mapping (RNA sequencing). Relative to vehicle-treated APP/PS1 controls, quercetin intervention elicited marked improvements across multiple spatial memory indices. Specifically, treated animals demonstrated enhanced target quadrant exploration (swimming distance: 11±2m versus 9±2.5m in controls; P<0.001) and prolonged occupancy within the goal zone (12.3±2.2s compared to 7.5±2.2s; P<0.001). Platform crossing frequency nearly doubled following quercetin administration (4.4±0.6 versus 2.1±0.6 crossings; P<0.01), while acquisition-phase escape latency on day 5 decreased by 23% (30s versus 39s in untreated mice). These behavioral improvements coincided with substantial gut microbiome restructuring, characterized by a 3.6-fold reduction in pathogenic Escherichia-Shigella abundance (log₂fold-change = -1.83; P<0.001). Concurrently, circulating tryptophan concentrations rose by 26% (from 380±86 to 480±88ng/mL; P<0.01), while its microbial-derived metabolite indole-3-propionic acid exhibited an 89% increase (579±99ng/mL in controls versus 1098±83ng/mL post-treatment; P<0.001). Transcriptomic interrogation of brain tissue identified significant enrichment of aryl hydrocarbon receptor signaling. Our findings demonstrate that quercetin counteracts Alzheimer's-associated cognitive impairment via coordinated restoration of intestinal microbial ecology and tryptophan catabolic pathways, with aryl hydrocarbon receptor activation potentially serving as a downstream neuroprotective effector mechanism.

To Cite This Article: Feng Y, Shi YH, Wang T, Han JY, Li D, Zhang XT, Xu Q, Liu F, Wei J and Yu X, 2025. Quercetin ameliorates cognitive impairment in app/ps1 mice via gut microbiota modulation and tryptophan metabolism restoration. Pak Vet J, 45(4): 1698-1709. http://dx.doi.org/10.29261/pakvetj/2025.xxx