Intragastric Administration Of Casein Leads To Nigrostriatal Disease Progressed Accompanied With Persistent Nigrostriatal-intestinal Inflammation Activited And Intestinal Microbiota-metabolic Disorders Induced In MPTP Mouse Model Of Parkinson’s Disease

Objective:Parkinson disease(PD)is currently one of the most common neurodegenerative diseases with progressive development.It will eventually lead to severe disability in patients.However,there is currently no effective treatment for this disease.The specific factors and pathways that promote the occurrence and progression of PD are also unclear.In recent years,it has been recognized that intestinal microecological disorders such as intestinal flora disorders may be closely related to the occurrence and progress of PD.Milk is a common cause that may cause food allergies,and epidemiological investigations have found that milk intake may be related to the occurrence of PD.Casein is the main substance in milk that causes allergies.Therefore,we studied whether the intake of casein may cause intestinal microecological imbalance,which is related to the progression of PD.Methods : The PD mouse model induced by MPTP(1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine),which is the most common model in the current research,the subacute model constructed by MPTP has the characteristics of intestinal microecological disorders,and related pathological changes will be restored to a greater extent after 2-3 weeks of MPTP administration.In this study,we administered casein gavage(6.75g/kg ig)to mice 2 days after MPTP subacute modeling(25 mg/kg ip×5days)for 21 days,and then the pathological changes such as exercise,dopaminergic nerve cell injury,intestinal and midbrain inflammation,intestinal flora and intestinal metabolic state were observed,and the effect of casein gavage on the recovery of pathological changes caused by MPTP were analyzed.Results:The results showed that the motor dysfunction persisted in MPTP mice 21 days after intragastric administration with casein;the content of dopamine in the striatum was significantly reduced,and the expression of Tyrosine hydroxylase(TH)in brain and ileum was reduced persistent;accompanied by the continuous increase in the expression of inflammatoryrelated factors such as Iba-1,CD4+,IL-22,and IFN-γ and the damage of the intestinal barrier;the fecal intestinal flora and metabolite scientific analysis found that the aggravated intestinal flora disorder and the abnormal intestinal bile secretion and the digestion and metabolism of sugar,lipids and protein,while the MPTP mice without gavage,the related pathological state has returned to the level of the blank control.The control mice given by casein intragastric administration did not have obvious related pathological changes.Conclusion:Our results suggest that casein may cause intestinal tissue pathology and intestinal barrier damage,intestinal flora and intestinal digestion and metabolism disorders in MPTP mice,which will disrupt the intestinal microecology,and promote the immune response and inflammation that lead to dopaminergic neuron damage.Continuous activation eventually promotes the damage of dopaminergic neurons in the intestine and midbrain.Therefore,avoiding diet and other factors that cause intestinal microecological disorders and adjusting the intestinal microecological balance may be an important way to prevent the progression of PD.