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Published on: October 4, 2021
FLZ attenuates Parkinson's disease pathological damage by increasing glycoursodeoxycholic acid production via
Meiyu Shang1, Jingwen Ning1, Caixia Zang1
1State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Abstract:
Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.
Insights
FLZ treatment alleviates Parkinson's disease (PD) by modulating gut microbiota and increasing glycoursodeoxycholic acid (GUDCA). This neuroprotective agent restores the gut-brain axis, offering a novel therapeutic strategy for PD.
Area of Science:
- Neuroscience
- Microbiology
- Pharmacology
Background:
- Parkinson's disease (PD) pathogenesis is increasingly linked to gut microbiota dysbiosis.
- FLZ demonstrates neuroprotective effects in PD models and can alleviate gut dysbiosis.
- The precise mechanisms by which FLZ exerts its effects remain to be fully elucidated.
Purpose of the Study:
- To investigate the detailed mechanisms underlying FLZ's neuroprotective effects in Parkinson's disease.
- To explore the role of gut microbiota and microbial metabolites in FLZ's therapeutic action.
- To elucidate the gut-brain axis modulation by FLZ in PD.
Main Methods:
- Utilized metabolomics and 16S rRNA sequencing to analyze gut microbiota and metabolite changes.
- Investigated the regulation of glycoursodeoxycholic acid (GUDCA) by specific gut bacteria, including *Clostridium innocuum*.
- Assessed the protective effects of GUDCA in Parkinson's disease models, including Nrf2 pathway activation.
Main Results:
- FLZ treatment significantly altered microbial metabolites, with glycoursodeoxycholic acid (GUDCA) being the most affected.
- Clostridium innocuum negatively regulated GUDCA production by inhibiting bile salt hydrolase (BSH).
- GUDCA demonstrated protective effects in PD models by activating the Nrf2 pathway, confirming FLZ's mechanism.
Conclusions:
- FLZ ameliorates Parkinson's disease by targeting the microbiota-gut-brain axis.
- FLZ promotes GUDCA production, which activates the Nrf2 pathway and protects dopaminergic neurons.
- Modulating microbial metabolites represents a promising therapeutic strategy for Parkinson's disease.
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