Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson’s disease

Autor: Yu-ying Yang, Wei Qing Wang, Chang Shan, Yan yun Gu, Qian qian Zhuang, Xiao ke Kong, Jian-min Liu, Hong Yan Zhao, Yan ling Gong, Si yue Zhuang, Shu-min Wang, Guang Ning, Bei Tao, Yan fang Hou, Sheng-Tian Li, Xing zhi Guo, Arijit Ghosh, Ke cheng Zhu, Li hao Sun
Rok vydání: 2021
Předmět:
Male
Microbiology (medical)
Agonist
medicine.medical_specialty
Parkinson's disease
medicine.drug_class
Osteocalcin
Gut microbiota
Gut flora
Microbiology
Neuroprotection
lcsh:Microbial ecology
Receptors
G-Protein-Coupled
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
Propionate
medicine
Animals
Infusions
Parenteral
Oxidopamine
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
biology
Dopaminergic Neurons
Research
Dopaminergic
Parkinson Disease
Fecal Microbiota Transplantation
medicine.disease
biology.organism_classification
Anti-Bacterial Agents
Gastrointestinal Microbiome
Disease Models
Animal
Neuroprotective Agents
Endocrinology
chemistry
Disease Progression
Parkinson’s disease
biology.protein
lcsh:QR100-130
Enteric nervous system
Propionates
030217 neurology & neurosurgery
Zdroj: Microbiome
Microbiome, Vol 9, Iss 1, Pp 1-17 (2021)
ISSN: 2049-2618
DOI: 10.1186/s40168-020-00988-6
Popis: Background Parkinson’s disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. Results The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. Conclusions Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate.
Databáze: OpenAIRE
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