The Alterations Of Gut Microbiota Structure And Plasma Metabolite Profile Through A High-sugar Dietary Intervention In AD Model Mice

Alzheimer's disease(AD)is a progressive neurodegenerative disorder characterized by deterioration of memory and other cognitions.A growing body of investigation has shown the connection between AD and type 2 diabetes,sharing the common pathogenic mechanisms including chronic inflammation,insulin resistance and mitochondrial dysregulation.On the other hand,gut microbiota are able to regulate the host's nutrition,metabolism,immunity and even distal central nervous system.And the high-fat and high-sugar “western” diet can induce the imbalance of gut microbiota,causing several metabolic disorders.Thus,the present study aims at investigating the effect of high-sugar diet on AD onset and development,the intestinal microbiota structure as well as plasma metabolite profile,and finally discussing the possible connections behind them.Firstly,the wild-type and APP/PS1 mice in our study were separately provided with 10% high-sugar water(high-sugar groups),or normal chow and water(normal groups)for 6 months.High-sugar intake promoted spatial learning and memory decline when compared with normal groups in Morris water maze test.Immunohistochemical and immunoblot analysis found the soluble A? concentration and deposit increased in the brain of high-sugar APP/PS1 mice.And further experiments found high-sugar groups showed insulin resistance,increased proinflammatory factors(TNF-? and IL-6)and lipopolysaccharide binding protein in blood,indicating that high-sugar intake could induce endotoxemia and chronic inflammation.In addition,the mRNA transcriptional level of two tight junction proteins(claudin-5 and occludin)were reduced in the colon of high-sugar groups detected by RT-qPCR.These results indicate excess sugar intake might increase intestinal permeability,induce endotoxemia and subsequently trigger chronic inflammation and insulin resistance.These changes are also associated with the imbalance of gut microbiota according to previous literature.Then,the 16 S rRNA gene sequencing of cecum microbiota and operational taxonomic unit(OTU)clustering of valid sequences were conducted.PCA and PLS-DA models,based on the OTUs of each sample,showed that high-sugar intake apparently shifted the whole structure of microbiota community.The results of species annotation of OTUs revealed that the ratio of Firmicutes/Bacteroidetes and the relative abundance of Verrucomicrobia were higher in the gut of high-sugar groups,but Proteobacteria reduced;in genus level,the amount of several beneficial bacteria including Allobaculum,Akkermansia and Lactobacillus were significantly lower in the gut of high-sugar groups,but Bacteroides,Helicobacter,Alloprevotella and Alistipes accumulated when taking sugar.According to previous studies,these changes of microbiota composition are possibly related to disruptive production of short chain fatty acids,impairment of intestinal barrier function,dysregulation of energy metabolism,chronic inflammation,insulin resistance and aging.In addition,we investigated the effect of high-sugar diet on the plasma metabolite profile through UPLC-Q-TOF-MS platform.PLS-DA scores plot showed significant differences in the metabolic profile between high-sugar groups and normal diet groups.The identified differential metabolites including several phospholipids and essential polyunsaturated fatty acids were decreased in APP/PS1 high-sugar groups,but several acylcarnitines and bile acids increased.Besides,two gut microbiota related metabolites,p-cresol sulfate and p-cresol glucuronide which are protein-bound uremic toxins,were elevated in high-sugar groups.These biomarkers indicate dyslipidemia,cell membrane disruption,and toxins produced by gut microorganisms might be implicated in the exacerbation of AD induced by excess sugar intake.In conclusion,the present study has demonstrated that long-term excess sugar intake could promote deficits of spatial learning and memory and amyloidosis in brain of AD model mice.The related underlying mechanisms might include impairment of intestinal barrier,chronic inflammation,insulin resistance and abnormal plasma metabolite profile induced by high-sugar diet.And these changes might be associated with structural imbalance of gut microbiota but it needs further investigations.Our study might provide new insight into the pathogenesis of AD,as well as novel avenues for preventing and treating it.