Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease.
Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease.
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肠道微生物群衍生的丙酸盐介导帕金森病小鼠模型中骨钙素的神经保护作用
DOI：
10.1186/s40168-020-00988-6
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发表时间：
2021-01-31
期刊：
影响因子：
15.5
通讯作者：
Liu JM
中科院分区：
文献类型：
--
作者：
Hou YF;Shan C;Zhuang SY;Zhuang QQ;Ghosh A;Zhu KC;Kong XK;Wang SM;Gong YL;Yang YY;Tao B;Sun LH;Zhao HY;Guo XZ;Wang WQ;Ning G;Gu YY;Li ST;Liu JM
帕金森病(PD)是一种神经退行性疾病，没有绝对的治疗方法。肠道微生物区系参与帕金森病发病机制的证据表明，有必要确定来源于肠道微生物区系的某些分子(S)，它具有治疗帕金森病的潜力。骨钙素(OCN)是一种成骨细胞分泌的蛋白质，已被证明可以调节大脑功能。因此，研究OCN是否能对帕金森病起到保护作用，如果是的话，其潜在的机制是否在于随后肠道微生物区系的变化，这是很有意义的。腹腔注射OCN可有效改善6-羟基多巴胺诱导的帕金森病小鼠模型的运动功能障碍和多巴胺能神经元的丢失。进一步的抗生素治疗和粪便微生物区系移植实验证实，肠道微生物区系对于OCN诱导的帕金森病小鼠的保护是必要的。OCN增加了PD小鼠肠道微生物区系中的类杆菌和枯竭的菲米特菌，提高了微生物产生丙酸的潜力，并得到了粪便丙酸水平的证实。口服丙酸两个月后，成功地挽救了帕金森病小鼠的运动缺陷和多巴胺能神经元丢失。此外，丙酸受体FFAR3的激动剂AR420626模拟丙酸的神经保护作用，阻断肠神经元可阻断丙酸对帕金森病小鼠多巴胺能神经元的保护作用。结果表明，OCN可改善PD小鼠的运动功能障碍和多巴胺能神经元的丢失，调节肠道微生物群和升高丙酸水平可能是其神经保护作用的机制之一，而肠道神经系统表达的FFAR3可能是丙酸的主要作用部位。视频摘要在线版本包含补充材料，可在10.1186/s40168020-00988-6上查阅。
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. 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. 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. Video abstract The online version contains supplementary material available at 10.1186/s40168-020-00988-6.
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影响因子：
4.8
作者：
Guo XZ;Shan C;Hou YF;Zhu G;Tao B;Sun LH;Zhao HY;Ning G;Li ST;Liu JM
通讯作者：
Liu JM
DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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