Effect Of Water Extract Of Eucommia Ulmoides Oliv On High Fat And High Sugar Diet-induced Neuroinflammation

OBJECTIVE: Previous studies have confirmed that high-fat and high-sugar diets(HFSD)can easily induce the activation of microglia,neuroinflammation,contributing to injury of nervous system.The homeostasis of the gut microbiota has a great impact on glial cell activation and inflammatory response.Eucommia ulmoides Oliv as a natural production performs role of anti-neuroinflammation and neuroprotection in mice.However,it is unclear whether it can effectively reverse intestinal dysbacteriosis and hippocampal neuroinflammation induced by HFHS.In view of such situation,we constructed HFHS mouse model to study whether gut microbiota shows effects on microglia activation and how water extract of eucommia ulmoides oliv(WEU)inhibits neuroinflammation induced by HFSD.METHODS: Male ICR mice were received standard diet,high-fat and high-sugar diet(23% lard,15% sugar,2.5% cholesterol,0.2 %bile salt,and high-nutritional basic feed)and high-fat and high-sugar diet daily accompanied with WEU intervention(400mg/kg)for four weeks.Immunofluorescence staining was used to examine the density of microglia,neuroblasts and radial glial cells in hippocampus.The real-time fluorescent quantitative PCR was performed to investigate the expression of IL-1? and IL-6 m RNA in hippocampal tissues.Animal behaviors were examined by open field test and marris water maze test.16 S r RNA sequencing method was used to detect the change of gut microbiota in cecum faeces of mice.RESUITS: HFSD induced obesity of ICR mice and increased serum cholesterol content.The cognitive impairment in obese mice was detected by open field test and Morris water maze test.We found an increase in the density of microglia in the dentate gyrus of obese mice by immunofluorescence staining.Further study by RT-q PCR demonstrated the increased expression of IL-1? and IL-6 m RNA in hippocampus of the obese mice.Subsequently,we observed that the density of neuroblasts and radial glial cells in the SGZ region increased abnormally,and the proportion of symmetrical cell division increased in the hippocampus of the obese mice.The expression of BDNF m RNA in the hippocampus was increased.In addition,we also found the strong correlation between the density of neuroblast cells and microglia cells in the same brain slice.We observed dybiosis in the composition and metabolic function of the gut microbiota of obese mice by16 S r RNA sequencing method.These results suggested that HFSD induced hippocampal microglia activation and an inflammatory response.Hippocampal inflammation induced by HFSD may lead to pathological increases in adult neurogenesis and BDNF expression.In addition,HFSD also resulted in intestinal dysbacteriosis of the obese mice.We found that the WEU can effectively inhibit obesity,decrease serum cholesterol content and improve the cognitive impairment in obese mice.Moreover,the WEU has inhibitory effects on the density of microglia and the expression of inflammatory cytokines,such as IL-1? and IL-6 m RNA in the hippocampus of obese mice.Our further research found that the WEU can reverse the division patterns of neural stem cells,decrease the density of radial glial cells and neuroblasts in obese mice.In addition,the WEU can remodel the structure and function of gut microbiota in obese mice.CONCLUSION: In the present study,we found that the application of WEU can inhibit HFSD-induced hippocampal neuroinflammation,reverse neural stem cells division and proliferation,and improve the cognition in obese mice.In addition,WEU can also remodel the structure and functional of gut microbiota in obese mice.These results will provide a theoretical basis for eucommia ulmoides oliv to prevent central nervous system damage related to dietary obesity.