LEI Senlin, CHEN Xiaoan, PAN Wei, SONG Weizheng, LI Xianhui, YANG Yang
Long-term high-fat diet (HFD) feeding leads to obesity-related cognitive impairment and motor function decline, with the underlying mechanisms involving gut microbiota dysbiosis and activation of the pyroptosis signalling pathway.Curcumin (CUR) has shown potential in treating obesity-related cognitive impairment due to its anti-inflammatory and gut microbiota-modulating effects.This study aimed to investigate the effects of CUR intervention on cognitive function and motor ability in obese mice through modulation of the “microbiota-gut-brain” axis, with a focus on the NLRP3/Caspase-1/GSDMD pyroptosis signalling pathway.Male C57BL/6 mice were randomly divided into a control group (CON) and a model group.After 12 weeks of HFD feeding to induce obesity-related cognitive impairment, the model group was further divided into a high-fat diet group (HFD) and a curcumin group [CUR, 100 mg/(kg·d) by gavage].After 8 weeks of intervention, serum biochemical indicators, cognitive function, motor performance, gut permeability, cecal microbiota composition, and the expression of synaptic plasticity/pyroptosis-related proteins were analyzed.Results showed that compared with the CON group, the HFD group showed significant increases in body weight, liver index, BMI, and Lee’s index, abnormal blood lipid levels (significant increases in low-Density Lipoprotein Cholesterol, total Cholesterol, and triglycerides, and a significant decrease in high-Density Lipoprotein Cholesterol), a significant reduction in the number of neurons in the hippocampus, and significant declines in learning and memory abilities and motor function (P<0.05).Compared with the HFD group, the CUR group exhibited significant improvements in body weight, health indices, and blood lipid levels, an increase in the number of hippocampal neurons, and enhanced learning and memory abilities and motor coordination and endurance (P<0.05).The results of the microbiota analysis showed that at the phylum level, the ratio of Firmicutes and Bacteroidota was significantly higher in the HFD group than in the CON group, while it was significantly lower in the CUR group (P<0.01).At the genus level, the relative abundances of Coriobacteriaceae_UCG-002 and Escherichia-Shigella were significantly higher in the HFD group than in the CON group, but significantly lower in the CUR group (P<0.01).Compared with the CON group, the HFD group exhibited significantly lower expression of ZO-1in the gut, increased gut permeability, and significantly higher levels of LPS in the cecal contents and serum, all of which were significantly reduced by CUR intervention (P<0.05).Compared with the CON group, the HFD group exhibited significantly reduced hippocampal levels of synaptic plasticity-related proteins BDNF, SYP, and SYN1 (P<0.05), and significantly elevated mRNA and protein levels of pyroptosis-related genes NLRP3, GSDMD, and IL-1β, as well as increased mRNA expression of Caspase1 and protein expression of Cleaved-Caspase1.CUR intervention significantly enhanced synaptic plasticity-related protein expression and attenuated pyroptosis-related gene mRNA and protein expression (P<0.05).Correlation analysis indicated that Coriobacteriaceae_UCG-002 and Escherichia-Shigella were significantly negatively correlated with BDNF and SYN1 and positively correlated with GSDMD and NLRP3.The former was positively correlated with the time to fall in the pole test, while the latter was negatively correlated with the fatigue rotarod time and the time to hang (P<0.05).CUR intervention downregulates the NLRP3/Caspase-1/GSDMD pathway via the “microbiota-gut-brain” axis, thereby inhibiting pyroptosis and reducing the expression of the inflammatory factor IL-1β.This leads to increased synaptic plasticity and improved peripheral metabolic disorder levels, ultimately alleviating obesity-related cognitive impairment and motor function decline.
