Intestinal Pathology And Gut Microbiota In A MPTP Mouse Model Of Parkinson's Disease

Objective: Patients with parkinson's disease(PD)often have non-motor symptoms related to gastrointestinal(GI)dysfunction,such as constipation and delayed gastric emptying,which manifest prior to the motor symptoms of PD.The exact pathogenesis of PD is unclear,and genetic factors,environmental factors,oxidative stress and other factors may be involved in the progress of PD.There is increasing evidence that changes in the composition of the gut microbiota may be related to the pathogenesis of PD.However,it is unclear how GI dysfunction occurs and how gut microbial dysbiosis is caused.Since GI dysfunction and the gut microbiota play important roles in PD,we investigated whether a neurotoxin model of PD induced by chronic low doses of MPTP is capable of reproducing the clinical pathological features of PD,as well as whether gut microbial dysbiosis accompanies this pathology.Methods: 40 C57BL/6 male mice,aged 10 weeks,were administered 18 mg/kg MPTP twice per week for 5 weeks via intraperitoneal injection.GI function was assessed by measuring the 1-hour stool frequency and fecal water content;motor function was assessed by pole tests;tyrosine hydroxylase(TH)and alpha-synuclein(?-syn)expression of substantia nigra(SN)and ileum were analyzed by western blotting(WB)and immunofluorescence(IF);the content of dopamine(DA)in striatum and ileum was measured by liquid chromatography-mass spectrometry(LC-MS);the inflammatory expression of SN was analyzed by IF and enzyme linked immunosorbent assay(ELISA);the inflammatory expression of ileum was analyzed by immunofluorescence(IHC)and ELISA;the expression of diamine oxidase(DAO)and d-lactic(D-LA)acid in the serum were measured by ELISA to evaluate the intestinal barrier damage;furthermore,the composition of the gut microbiota were measured by high-throughput sequencing.Results: We found that MPTP caused GI dysfunction and intestinal pathology prior to motor dysfunction;the expression of TH and ?-syn in SN and ileum of PD mice were changed;the content of DA in striatum and ileum of PD mice were decreased;MPTP induced inflammation in SN and ileum of mice;the expression of DAO and D-LA were increased,indicating the intestinal barrier had been impaired;the high-throughput sequencing result displayed the composition of the gut microbiota was changed;in particular,the change in the abundance of Lachnospiraceae,Erysipelotrichaceae,Prevotellaceae,Clostridiales,Erysipelotrichales and Proteobacteria was significant.Conclusion: These results indicate that a chronic low-dose MPTP model can be used to evaluate the progression of intestinal pathology and gut microbiota dysbiosis in the early stage of PD,which may provide new insights into the pathogenesis of PD and new ideas for the treatment of PD from the perspective of improving GI health.