The Effects And Underlying Mechanism Of Intermittent Fasting On Diabetes-induced Cognitive Impairment

With the development of social economy,more and more people live with unhealthy life styles and dietary patterns causing the risk of metabolic disorders for instance,obesity and diabetes which seriously threatens the human health.Intermittent fasting is a new method of restraining obesity rates,improving insulin sensitivity and blood lipids,and lowering blood pressure in obese individuals.Intermittent fasting also known as the fast diet,refers to a dietary therapy that prevents and treats disease by periodically switching between fasting and free diet.Previous studies demonstrated that intermittent fasting could alleviate chronic metabolic diseases which caused by insulin resistance.However,the effects and mechanisms that intermittent fasting alleviates diabetes induced cognitive impairment still remain uncover.In the present study,we use db/db mice to further investigate the mechanism that intermittent fasting improved diabetes-induced cognitive impairment.The main investigations and results are as follows:(1)db/db type 2 diabetes mice were on a 4-week alternate day fasting.Morris-Water maze tests and Y maze tests showed that intermittent fasting improved spatial memory and cognitive impairment in db/db mice.Proteins in various regions of the brain showed intermittent fasting could improve nerves and synaptic injury of the brain and increase the synaptic associated protein in hippocampus.It could activate signaling pathway,energy metabolism pathway,cognitive related pathway and inhibit the expression of inflammatory signaling.Transcriptome in hippocampus showed that intermittent fasting activated energy metabolism related pathways.(2)16S r DNA Microbiome sequencing showed that intermittent fasting could improve the diversity and richness of intestinal microflora in db/db mice.It could promote relative abundance of probiotics Lactobacillus;inhibit the abundance of harmful microbiota.At the same time,the content of short chain fatty acids which were tested in faeces was significantly reduced in db/db group,while intermittent fasting could increase them.Untargeted metabolomics showed that intermittent fasting could increase microbial metabolites such as5-HT,IPA,TUDCA and improve the normal physiological function.(3)Reverse verification test: db/db type 2 diabetes mice with antibiotic treatment wereon a 4-week alternate day fasting,aimed to determine the function of microbial in the intermittent fasting beneficial effects.Removing gut microbiota with antibiotics partly abolished the neuroprotective effects of intermittent fasting.(4)Forward verification test: Administration of 3-indolepropionic acid,serotonin,short chain fatty acids or tauroursodeoxycholic acid showed a similar effect to intermittent fasting in terms of improving cognitive function.Together,these findings purport the “gut-brain” axis as a mechanism that enables therapeutic strategies against metabolism-implicated cognitive pathophysiologies.The present study reveals that “gut-brain axis”makes great important in the effects of intermittent fasting on alleviating diabetes-induced cognitive impairment,which provides the theoretical basis for the effects of dietary patterns on alleviating metabolic disease.