Intestinal Pathology and Gut Microbiota Alterations in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Mouse Model of Parkinson’s Disease

Abstract

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. Increasing evidence indicates 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. We investigated whether a neurotoxin model of PD induced by chronic low doses of MPTP is capable of reproducing the clinical intestinal pathology of PD, as well as whether gut microbial dysbiosis accompanies this pathology. C57BL/6 male mice were administered 18 mg/kg MPTP twice per week for 5 weeks via intraperitoneal injection. GI function was assessed by measuring the 1-h stool frequency and fecal water content; motor function was assessed by pole tests; and tyrosine hydroxylase and alpha-synuclein expression were analyzed. Furthermore, the inflammation, intestinal barrier and composition of the gut microbiota were measured. We found that MPTP caused GI dysfunction and intestinal pathology prior to motor dysfunction. 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. 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.

Neuroprotection of Fasting Mimicking Diet on MPTP-Induced Parkinson's Disease Mice via Gut Microbiota and Metabolites

“…However, according recent studies, MPTP can also produce DAergic selective neuron toxins in the enteric nervous system of animal models, causing damage and pathology in the gastrointestinal nerves [44][45][46]. Interestingly, Feng Lai and his colleagues found that MPTP caused gastrointestinal dysfunction and intestinal pathology prior to motor dysfunction, which explains the Braak staging theory that pathogenesis of PD from the gut to the brain [47]. The studies in consistent with this theory demonstrated that α-synuclein appears in the enteric nervous system during the early stages of PD, and this misfolded protein may spread to the central nervous system through the vagus nerve, resulting in nerve damage in the SN [48,49].…”

Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice

“…Recent studies with drugs that cause Parkinson's disease-like damage to the dopamine neuronal system, reported that they also induce gut dysbiosis [65,66]. This microbial imbalance was evidenced by increases in Enterobacteriaceae, and particularly of Proteus mirabilis, a species within this family [67].…”

Bottoms up: the role of gut microbiota in brain health

“…motor deficits (Lai et al, 2018). These studies are still mostly associative, although the presence of dysbiosis in multiple animal models strengthens the claim of GI dysfunction as a core aspect of disease.…”

“…Intriguingly, some of the changes in microbial composition in these rotenone‐exposed mice were similar to alterations observed in human PD patients. Alterations in gut microbiota composition as well as GI dysfunction were found in another toxicological model of PD, MPTP (Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) exposure, with GI abnormalities including intestinal α‐synuclein pathology preceding motor deficits (Lai et al ., ). These studies are still mostly associative, although the presence of dysbiosis in multiple animal models strengthens the claim of GI dysfunction as a core aspect of disease.…”