OBJECTIVE  To investigate the effects and underlying mechanisms of caffeoylquinic acid(CQA) combined with Limosilactobacillus reuteri(L. reuteri) on metabolic disorders and cognitive impairment in obese Alzheimer’s disease(AD) mice.

METHODS  5×FAD transgenic AD mouse models were randomly assigned to 4 experimental groups: chow diet control(CD-V), chow diet with CQA+L. reuteri intervention(CD-CQA+L. reuteri), high-fat diet model(HFD-V), and high-fat diet with CQA+L. reuteri intervention(HFD-CQA+L. reuteri). After 8 weeks of treatment, metabolic parameters including body mass, body fat, blood glucose, and lipid profiles were measured. Cognitive function was assessed using the novel object recognition test and Y-maze test. Hippocampal neuronal loss and synaptic protein expression(PSD95) were evaluated. Gut microbiota composition was analyzed via 16S rRNA sequencing, and serum short-chain fatty acid levels were quantified by LC-MS.

RESULTS  The combined intervention of CQA and L. reuteri significantly reduced body fat content, fat/lean ratio, and serum lipid levels in AD mice, while improving glucose metabolism and ameliorating HFD-induced metabolic disorders. Meanwhile, the treatment markedly enhanced recognition index and spontaneous alternation rate, indicating improved exploration behavior and spatial memory. The recognition indices were negatively correlated with blood glucose and lipid levels. The intervention also attenuated astrocyte activation by reducing GFAP levels, while increasing PSD95 expression to alleviating brain tissue damage. Notably, CQA significantly enhanced the growth and probiotic activity of L. reuteri. Additionally, the combination of CQA and L. reuteri restored gut microbiota homeostasis, increased beneficial bacterial abundance, and elevated propionic acid levels.

CONCLUSION  CQA and L. reuteri synergistically ameliorate cognitive dysfunction and neuropathology by improving obesity-related metabolic disorders, reducing hippocampal neuronal loss and synaptic damage, suppressing astrocyte activation, and restoring intestinal microbiota homeostasis.