国内团队:肠道菌群产生的丙酸盐缓解小鼠的帕金森病
创作:lzm 审核:szx 02月04日
  • 在6-OHDA诱导的PD小鼠模型中,腹膜内注射OCN可显著改善运动功能障碍和多巴胺能神经元丢失;
  • OCN处理可恢复PD小鼠的肠道菌群失调,增加拟杆菌门并减少厚壁菌门,增加丙酸盐产生菌及粪便丙酸盐水平;
  • 抗生素处理显著降低OCN的神经保护作用,粪菌移植实验也表明肠道菌群介导了OCN的神经保护作用;
  • 口服丙酸盐2个月可通过肠神经元依赖性的方式,恢复PD小鼠的运动功能及多巴胺能神经元;
  • FFAR3(丙酸盐受体)激动剂也有类似的神经保护作用。
主编推荐语
szx
许多证据表明肠道菌群参与了帕金森病(PD)的发病机制。成骨细胞分泌的骨钙蛋白(OCN)可调节脑功能。来自上海交通大学医学院附属瑞金医院的刘建民团队、顾燕云团队及上海交通大学的李胜天团队在Microbiome上发表的一项最新研究,发现OCN可通过调节PD小鼠模型的肠道菌群,富集丙酸盐产生菌并增加丙酸盐水平,丙酸盐作用于肠神经元上的FFAR3以发挥其神经保护作用,从而缓解小鼠的运动功能障碍及多巴胺能神经元丢失。
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Microbiome [IF:11.607]

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

在帕金森病小鼠模型中,肠道菌群产生的丙酸盐介导了骨钙蛋白的神经保护作用

10.1186/s40168-020-00988-6

01-31, Article

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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.

First Authors:
Yan-fang Hou

Correspondence Authors:
Yan-yun Gu,Sheng-tian Li,Jian-min Liu

All Authors:
Yan-fang Hou,Chang Shan,Si-yue Zhuang,Qian-qian Zhuang,Arijit Ghosh,Ke-cheng Zhu,Xiao-ke Kong,Shu-min Wang,Yan-ling Gong,Yu-ying Yang,Bei Tao,Li-hao Sun,Hong-Yan Zhao,Xing-zhi Guo,Weiqing Wang,Guang Ning,Yan-yun Gu,Sheng-tian Li,Jian-min Liu

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