A neurotherapeutic approach with Lacticaseibacillus rhamnosus E9 on gut microbiota and intestinal barrier in MPTP-induced mouse model of Parkinson's disease.

The gut microbiota plays a crucial role in neural development and progression of neural disorders like Parkinson's disease (PD). Probiotics have been suggested to impact neurodegenerative diseases via gut-brain axis. This study aims to investigate the therapeutic potential of Lacticaseibacillus rhamnosus E9, a high exopolysaccharide producer, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of PD. C57BL/6 mice subjected to MPTP were fed L. rhamnosus E9 for fifteen days and sacrificed after the last administration. Motor functions were determined by open-field, catalepsy, and wire-hanging tests. The ileum and the brain tissues were collected for ELISA, qPCR, and immunohistochemistry analyses. The cecum content was obtained for microbiota analysis. E9 supplementation alleviated MPTP-induced motor dysfunctions accompanied by decreased levels of striatal TH and dopamine. E9 also reduced the level of ROS in the striatum and decreased the DAT expression while increasing the DR1. Furthermore, E9 improved intestinal integrity by enhancing ZO-1 and Occludin levels and reversed the dysbiosis of the gut microbiota induced by MPTP. In conclusion, E9 supplementation improved the MPTP-induced motor deficits and neural damage as well as intestinal barrier by modulating the gut microbiota in PD mice. These findings suggest that E9 supplementation holds therapeutic potential in managing PD through the gut-brain axis.

Twice subacute MPTP administrations induced time-dependent dopaminergic neurodegeneration and inflammation in midbrain and ileum, as well as gut microbiota disorders in PD mice.

Parkinson's disease (PD) is a common progressive neurodegenerative disease. PD produces a pathological state in the intestine and disordered gut microbiota (GM), which may be important for the pathogenesis and progression of PD, but it is not clear. To explore the conditions and characteristics of intestinal pathology and GM disorders when PD-related injuries occur, we used twice 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute administration with an interval of 3 weeks (each was an intraperitoneal injection of 25 mg/kg MPTP for 5 consecutive days). We observed the changes in intestinal and brain immune status, intestinal barrier function and GM in different injury states one day, one week, and three weeks after the first stimulus and one day and one week after the second stimulus. Our study found that two subacute administrations of MPTP induced dopaminergic (DAergic) neuron injury and inflammation in the midbrain and ileum, impaired intestinal barrier function and GM disorders closely related to administration. These changes recovered after the first administration, but after repeated administration, some indicators showed more dramatic changes than during the first administration. Our results suggest that the intestinal tract is sensitive to PD-related injury, and the GM is susceptible to disturbances caused by intestinal function, which may be concerned in local immune disorders of the intestine.

Antibiotic-induced microbiome depletion protects against MPTP-induced dopaminergic neurotoxicity in the brain.

Although the brain-gut axis appears to play a role in the pathogenesis of Parkinson's disease, the precise mechanisms underlying the actions of gut microbiota in this disease are unknown. This study was undertaken to investigate whether antibiotic-induced microbiome depletion affects dopaminergic neurotoxicity in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP significantly decreased dopamine transporter (DAT) immunoreactivity in the striatum and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra of water-treated mice. However, MPTP did not decrease DAT or TH immunoreactivity in the brains of mice treated with an antibiotic cocktail. Furthermore, antibiotic treatment significantly decreased the diversity and altered the composition of the host gut microbiota at the genus and species levels. Interestingly, MPTP also altered microbiome composition in antibiotic-treated mice. These findings suggest that antibiotic-induced microbiome depletion might protect against MPTP-induced dopaminergic neurotoxicity in the brain via the brain-gut axis.

Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice.

Recently, studies on the relationship between gut dysbiosis and Parkinson's disease (PD) have increased, but whether a specific gut bacterium may cause PD remains unexplored. Here, we report, for the first time, that a specific gut bacterium directly induces PD symptoms and dopaminergic neuronal damage in the mouse brain. We found that the number of Enterobacteriaceae, particularly Proteus mirabilis, markedly and commonly increased in PD mouse models. Administration of P. mirabilis isolated from PD mice significantly induced motor deficits, selectively caused dopaminergic neuronal damage and inflammation in substantia nigra and striatum, and stimulated α-synuclein aggregation in the brain as well as in the colon. We found that lipopolysaccharides, a virulence factor of P. mirabilis, may be associated in these pathological changes via gut leakage and inflammatory actions. Our results suggest a role of P. mirabilis on PD pathogenesis in the brain.