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

Abstract

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.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

“…It was found that fecal microbiota transplantation on a PD mouse model gut reduces microbial dysbiosis, increases striatal neurotransmitters including dopamine and serotonin, and suppresses the activation of astrocytes and microglia in the substantia nigra region of the brain, revealing a neuroprotective effect of fecal microbiota transplantation on PD treatment [ 97 ]. Another study on a PD mouse model demonstrates a neuroprotective effect of propionate, a gut microbial metabolite, on reducing motor deficits and enhancing dopaminergic neurons in PD mice, which may exert its effects through the propionate receptor in the enteric nervous system [ 98 ].…”

Fecal microbiota transplantation protects rotenone-induced Parkinson’s disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis

“…In addition, the infection of Helicobacter pylori (Hp) has also been reported to be associated with PD [ 15 ]. Moreover, healthy mice receiving gut microbiota transplantation from PD diseased donors showed motor dysfunctions in some research [ 16 – 18 ]. Collectively, these reports suggest that gut microbiota dysbiosis plays a pivotal role in the pathogenesis of PD.…”

The Relationship Between the Gut Microbiome and Neurodegenerative Diseases

“…Also, the microbiome of PD patients is characterized by a decreased abundance of butyrate-producing bacteria with an increased abundance of pro-inflammatory Proteobacteria, which may trigger inflammation-induced misfolding of a-syn [30]. Osteocalcin ameliorates the motor deficits and dopaminergic neuronal loss in PD mice through increasing the potential of microbial propionate production and activating free fatty-acid receptor 3 in enteric neurons [31].…”