Objective: A high-fat diet is a risk factor for cognitive impairment， but its underlying biological mechanisms have not been elucidated. Methods: twenty-four male 3-month-old C57BL/6J mice were randomly divided into two groups， and fed with normal chow diet (ND) and high-fat diet (HFD) for 12 weeks. At the end of the experiment， the glucose tolerance test (GTT) was performed. Cognitive function was evaluated with the Morris Water Maze (MWM) test. After overnight fast， the mice were sacrificed and serum and colon contents were collected. Serum insulin levels were detected by ELISA， serum glucose levels were determined by colorimetric method and HOMA-IR was calculated. Liquid chromatography tandem mass spectrometry was used to detect serum BCAA levels. 16S rDNA amplicon sequencing was used to detect gut microbiota alterations， and their correlation with serum BCAAs was performed by Spearman correlation. Results: After 12 weeks feeding， compared with the control mice， the HFD-fed mice showed significant increases in body weight (31.6 g vs 37.5 g， P<0.001)， body fat rate (3.2% vs 5.8%， P<0.001)， area under curve (AUC) of GTT (1 440 mmol/L·min vs 1 841 mmol/L·min， P<0.05)， and fasting serum levels of isoleucine (1.27-fold of the control group， P<0.05) and total BCAAs (1.16-fold of the control group， P<0.05). Additionally， the fluorescence intensity of NeuN-positive immunoreactive regions in the dentate gyrus of the hippocampus was significantly decreased in the HFD group (27 vs 12， P<0.01). HFD-fed mice displayed a decrease in the number of platform and the target quadrant entries during the probe trial compared with the control group， and these indicators were negatively correlated with serum isoleucine and total BCAA levels. In addition， the composition of gut microbiota in HFD group was significantly different from that in the control group. At the genus level， Romboutsia and Blautia are the dominant microbiota in the colon of HFD-fed mice. Bacterial functionality prediction indicated that gut microbiota genes involved in BCAA degradation were significantly reduced in HFD group compared with the control group. The Parvibacter genus is negatively correlated with isoleucine levels (P=0.01)， while the Blautia and Anaerotruncuus genus are positively correlated with isoleucine levels (the P-value were 0.00 and 0.03， respectively). Conclusion: Gut microbiota may be the link between elevated serum BCAA levels and HFD-induced cognitive impairment.

gut microbiota  /  branched-chain amino acids  /  obesity  /  cognitive impairment  /  high-fat diet