| As the number of fertile age obese women increases worldwide,maternal obesity induces a range of developmental-related dysfunctions in the offspring that have become a non-negligible problem.Epidemiological and genetic evidence suggests that maternal obesity may lead to disturbances in the maternal gut microbiota,which in turn induces a synchronous imbalance in the offspring’s gut microbiota during the longitudinal transmission from mother to offspring.Imbalances in the gut microbiota directly affect the normal cognitive and social functioning of the offspring through alterations in their metabolites during the critical "1000 days" of early development.Therefore,Nutritional research using dietary patterns and discovery of nutritional factors to intervene in maternal obesity-induced neurodevelopmental disorders in offspring has become a hot topic of research within the field of food science.Dietary fiber inulin is a complex carbohydrate made up of fructose molecules with high content in the composite family and platycodontidae family.It has biological activities such as improving intestinal microbiota disorders,reducing insulin sensitivity and decreasing the incidence of colitis.However,there are few reports about its protective effect of improving maternal obesity-induced cognitive impairment in the offspring.This thesis analyses the effects of inulin on intestinal microbiota and on neurodevelopment of the brain in the offspring,and investigates the neuroprotective effects of inulin and mechanisms by co-housing experiment.The main research contents and results of this project are as following:(1)To investigate the effects of dietary fiber inulin on the cognitive function and social impairment of offspring,C57BL/6J mice offspring were used as the research object.A maternal obese animal model was constructed by a 12-week high-fat diet(60% energy from fat),the sire was fed a control diet,and the offspring mice were born and weaned on a diet supplemented with dietary fiber inulin(37 g/1000 kcal)for 5 weeks.The results of behavior tests showed that inulin diet could significantly improve the proportion coefficient of successful consecutive access to different three arms of offspring mice,and the new object recognition coefficient was significantly higher,which significantly improved the working and the long learning memory ability of mice.The results of the three-compartment social communication test showed that inulin had a significant effect on social preference of mice and social novelty to unfamiliar mice.In addition,the effects of inulin on cognitive and social gene-related pathways in the hippocampal of offspring mice were analyzed by transcriptome sequencing and q RT-PCR,and the results showed that 564 genes were down-regulated and 247 genes were up-regulated in offspring treated with inulin diet compared with the offspring fed on control diet,and there was no significant difference in gene expression between male and female offspring,while inulin diet significantly increased PSD-95,RORA gene m RNA levels.Compared to MHFD-FD group mice(maternal generation on high-fat diet,offspring on inulin diet),significantly different genes in the MHFD-CD group(maternal generation on high-fat diet,offspring on control diet)mainly enriched in the KEGG pathway associated with gene transcription,translation and protein quality control and export,and consistent with this,significant upregulation of gene expression on KEGG pathway related to spliceosomal RNA processing.In addition,inulin had no significant effective on the brain microglia state and the m RNA expression level of inflammatory factor TNF-α in the offspring mice induced by maternal obesity,but it significantly increased the m RNA expression of the anti-inflammatory factor IL-10 gene.These results suggest that offspring dietary supplementation with inulin significantly improves maternal obesity-induced cognitive function and social impairment in the offspring.(2)To investigate the effects of dietary fiber inulin on maternal high-fat obesity-induced gut dysfunction in offspring,gas chromatography,16 S r RNA and q RT-PCR techniques were used for analysis.The results showed that inulin Intervention significantly improved maternal obesity-induced alterations in intestinal histomorphological traits of the offspring,such as intestinal muscle layer thickness,crypt length and number of goblet cells.In addition,inulin intervention significantly increased the m RNA levels of ZO-1 gene,a tight junction protein of colon and jejunum,and the expression level of claudin-1 protein,as well as the m RNA levels of IL-1β,a tract inflammatory factor,and GPR43 gene.Further study found that inulin intervention significantly increased the concentration of acetic acid and propionic acid in the feces of the offspring mice and changed the structure of the intestinal microbiota of the offspring mice.Bacteroides,S24-7 were prevalent in the MHFD-FD group feces samples,while Ruminococcus was prevalent in the MHFD-CD group mice feces samples.The correlation between the gut microbiota,short-chain fatty acids levels and behavioral test data was also performed,and it was found that the relative abundance of OTUs belonging to S24-7 and OTUs belonging to Bacteroides were positively correlated with the concentration of short-chain fatty acids and behavioral test results data.While the relative abundance of OTU belonging to Ruminococcus was negatively correlated with the concentration of short chain fatty acids and the data of behavioral test.The above results suggest that offspring dietary supplementation with inulin significantly improves maternal obesity-induced disorders in offspring gut microbiota and that there is a correlation between gut microbiota and offspring cognitive and social behaviour.(3)To further investigate the effects of inulin on gut microbiota-mediated cognitive function and social impairment in offspring mice,offspring mice were used as the study subjects.A maternal obese animal model was constructed by a high-fat diet or a high-fat inulin diet for 10 weeks.A 5-week co-housing intervention,in which MHFD-CD mice were caged with MFFD-CD mice(maternal high-fat and high dietary fiber diet,offspring control diet intervention)in 2:3 ratio,was used to explore the intervention effects of gut microbiota on maternal obesity-mediated cognitive function and social impairment in offspring mice and related mechanisms.The results showed that the co-housing treatment significantly improved the ratio of successful consecutive access to different three arms and the new object recognition index of the MHFD-CD offspring mice,which significantly improved the working and the long learning memory ability of mice,and significantly improved the social preference and the social novelty to unfamiliar mice.In addition,m RNA levels of cognition-related genes PSD-95,Fxr1,Fxr2,social-related genes sh Ank3 and postmitotic protein length,width were significantly increased by analysis of transmission electron microscopy images.The above results indicate that inulin-mediated intestinal microbiota had a significant effect on cognitive function and social impairment in the offspring mice.Inulin intervention can reduce maternal obesity-induced offspring cognitive function and social impairment by ameliorating offspring intestinal microbiota disorders,regulating SCFAs secretion,restricting gene transcription,translation,protein quality control and spliceosome RNA processing KEGG pathway,which provides a theoretical basis for maternal obesity offspring nutritional intervention research and a new idea for the development of health food with inulin as the main functional ingredient. |
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