The Correlation Between Gut Microbiome And Alzheimer’s Disease Cognitive Impairment And The Effect Of Probiotics Supplement On Mild Cognitive Impairment In The Elderly

Part 1:Systematic review the correlation between gut microbiome and Alzheimer’s disease cognitive impairmentObjective:To systematically review the clinical literatures on the correlation and effect of gut microbiome and Alzheimer’s disease cognitive impairment,to explore the changes of gut microbiome in patients with AD cognitive impairment and the clinical effect of gut microbiome modification on cognitive impairment and provide a novel approach for the diagnosis and treatment of AD cognitive impairment.Methods:Chinese databases including CBM,CNKI,VIP,Wan Fang and English databases including PubMed,Embase and Cochrane were searched with time range from 1September 1996 to June 30,2019.The types of literatures retrieved were observational research and interventional research.Two researchers screened the literatures independently.Data extraction and collation were carried out according to the study types with one researcher extracting and inputting independently,and the other one checking.The literatures’evaluation was completed by two researchers independently,and the quality of the included observational analysis and interventional studies was evaluated using the NOS scale and the modified Jadad scale respectively.The included studies were comprehensively analyzed.Firstly,the qualities were analyzed.Secondly,the bias of the comprehensive results was evaluated.The heterogeneity of literatures suitable for quantitative analysis was evaluated and the effect indexes were explained.If quantitative analysis is not applicable for the studies,the rationality of data selection,the assessment of confounding factors,and the interpretation of the difference of results should be explained in the qualitative analysis.Results:A total of 7 literatures were included in the systematic review,including 4observational studies and 3 interventional studies.All the observational studies’NOS scores were no less than 7 points.As for the time of publication,all 4 studies were published in the past 5 years,and the earliest one was published in 2017.With the research areas,three studies were conducted in China,which were distributed in three provinces/municipals in east China and southwest China.From the analysis of grouping,two studies analyzed AD and health controls,and the other two included MCI population for comparison.According to the sample size analysis,the total sample size of each study was less than 100 cases,and the sample number of Vogt et al wass only 50 cases.On case diagnosis perspective,three Chinese studies all adopted MMSE scale,while American scholars adopted CDR scale.The sequencing information was not complete.The amplification area used in the three Chinese studies was the same as the sequencing platform,but the primers were different.The results of the four studies were as follows:（1）Liu,2019 suggested that gut microbiome diversity in AD group decreased compared with that in the healthy control group,with the proportion decreased for firmicutes and increased for proteobacteria and enterobacteria,showing the same change in family and genus classification.The change trend of the MCI group was similar with that of AD.There was a significant correlation between the clinical severity score and the altered flora abundance in patients with AD.（2）Li,2019 found that AD and MCI had no significant difference in genus level.The proportion of enterobacteria and firmicutes increased,and the proportion of bacteroidetes decreased.（3）Zhuang,2018 found that the proportion of bacteroidetes decreased in the AD group,while that of enterococcaceae and lactobacillus increased.（4）Vogt,2017 also confirmed that the gut microbiome diversity of AD group decreased,the proportion of firmicutes and bifidobacteria decreased,and the bacteroidetes increased.The scores of the interventional studies’modified Jadad scale were all no less than 5 points.From the perspective of study types,three studies were randomized double-blind controlled clinical trials,with a high level of evidence.In terms of subjects,two studies by Iranian scholars were AD,and the other one was MCI.Lactobacillus and bifidobacterium were selected as probiotics in the three studies,and the study period was 12 weeks.However,the outcome evaluation indexes of the three studies were different,so the quantitative analysis could not be carried out.The results of 3 studies were as follows:（1）Hwang,2019 found that compared with placebo group,after plant-based 12 weeks’lactobacillus supplement,MCI patients had a significant improvement in their comprehensive cognitive state（z=2.36,Interaction P=0.02）,which was associated with increased serum levels of brain-derived neurotrophic factor（t=2.83,P=0.007）.（2）Agahi,2018 took moderate to severe AD as the subjects,of which 83.5%were severe AD.There was no difference in the cognitive test scores between the control group and the probiotic group(F_（3,114）=0.29,P=0.82).（3）Akabri et al.found that after 12 weeks’probiotic intervention,the MMSE score of patients with AD was significantly improved compared with the control group（P<0.001）,which was related to the level of serum inflammatory indicators such as hypersensitive C-reactive protein（P<0.001）.Conclusions:1.Compared with healthy people,there were significant changes in gut microbiome and decreased diversity in patients with AD cognitive impairment,but the changes of specific bacterial species were inconsistent.2.In patients with MCI or mild to moderate AD,it has not been confirmed that 12-week’s probiotics supplement therapy has a positive effect on improving cognitive level,and the cognitive improvement effect in patients with moderate to severe AD is not ideal.It is suggested that probiotics treatment of AD cognitive impairment should focus on the early stage or extend the intervention period.Part 2:Effects and influence factors of probiotics supplement on mild cognitive impairment in the elderlyObjective:To explore the effects of commonly used clinical probiotics on cognitive level,living ability and sleep status of elderly patients with mild cognitive impairment and the effect of gender and APOE genotype on probiotics supplement,and provide novel ideas for strengthening the application of probiotics in patients with cognitive impairment.Methods:Sixty elderly patients with MCI were divided into control group and experiment group randomly with 30 patients in each group.Venous blood was collected for thyroid function,preoperative infection（Syphilis,HIV）,cerebral infarction index（HCY,Folic acid,Vitamin B12）,APOE genotype,liver function tests,brain MRI check and Mo CA,MMSE,ADL,PSQI scale assessment,and then patients in the experiment group were given butyric acid clostridium enterococcus sanlian living bacterium（every 200mg contains Streptococcus faecalis 2mg,Clostridium butyricum 10mg,Bacillus mesentericus 10mg）,400 mg per time,3 times/day,with 12 weeks’follow-up.During follow-up period,telephone communications were conducted to strengthen the adherence and acquire the possible adverse reactions,etc.At the end of follow-up,the Mo CA,MMSE and ADL,PSQI scales were evaluated again,and the differences in scale scores before and after the study between the two groups were compared,and then stratified by gender and APOEε4 status.Results:At the end of study,26 and 27 subjects in the control group and the experimental group completed the follow-up respectively,and the difference of scale scores between the two groups before and after intervention was statistically analyzed with repeated measurement ANOVA on per protocol set.Statistical analysis of changes in overall subjects outcome indicators showed no statistical differen ce in 4 scales’scores before and after intervention between the control group and the experimental group.We did subgroup analyses by gender.The results indicated that there was no statistical difference in 4 scales’scores between female and male subjects in the control group and the experimental group before and after intervention.As to APOE genotype,the results showed that Mo CA score changes before and after intervention（post-intervention score-pre-intervention score,mean±SD）in subjects carrying no APOEε4 gene（ε2/ε2、ε2/ε3、ε3/ε3）.The control group was0.150±0.671,and the experiment group was 0.684±0.820.repeated measurement ANOVA was used to compare the difference,with F_（1,37）=2.232,95%confidence interval（CI）,95%CI:0.049～1.019,Interaction P=0.032.No statistical difference was found in MMSE,ADL and PSQI scores.The results of the analysis of the changes in the outcome indicators of the subjects carrying APOEε4 gene（ε2/ε4、ε3/ε4、ε4/ε4）indicated that there was no statistical difference in 4 scales’scores between the control group and the experimental group before and after intervention.Conclusions:1.In elderly MCI patients without APOEε4 gene,Mo CA scale scores improved after 12 weeks of probiotic supplement,suggesting that the regulation of gut microbiota in elderly MCI patients without APOEε4 gene might have a possibly positive effect on the prevention of MCI progression.In the overall population,the outcome is not statistically different.The reasons may be related to sample size,research cycle,choice of subjects and so on.Further clinical research should expand the sample size,choose suitable research period,match subjects and grouping factors.2.It is particularly noteworthy that the APOEε4 gene may be one of the most likely influencing factor for probiotics to improve the cognitive level of MCI in the elderly and has an important clinical value.For elderly MCI patients with APOEε4 gene,a new approach is needed to find a more powerful and accurate therapeutic target to avoid unnecessary medical consumption and disease progression caused by blind probiotics supplement.