Altered Gut Microbiome in Parkinson's Disease and the Influence of Lipopolysaccharide in a Human α-Synuclein Over-Expressing Mouse Model
Altered Gut Microbiome in Parkinson's Disease and the Influence of Lipopolysaccharide in a Human α-Synuclein Over-Expressing Mouse Model
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DOI：
10.3389/fnins.2019.00839
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发表时间：
2019-08-07
影响因子：
4.3
通讯作者：
Anderton, Ryan S.
中科院分区：
文献类型：
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作者：
Gorecki, Anastazja M.;Preskey, Leah;Anderton, Ryan S.
帕金森病 (PD) 中肠道微生物群与 α-突触核蛋白 (alpha Syn) 聚集之间的相互作用正受到越来越多的关注。本研究的目的是研究肠道微生物群以及炎症脂多糖 (LPS) 触发剂对人类 α Syn 过表达 PD 小鼠模型 (Thy1-alpha Syn) 的影响。使用 16S 核糖体 RNA 测序分析来自确诊 PD 患者和 Thy1-alpha Syn 小鼠的粪便样本。与健康对照相比，PD患者中降解粘蛋白的疣微菌和产生LPS的γ变形菌的相对丰度更高。在小鼠中，Thy1-α Syn 和野生型 (WT) 动物中 Gammaproteobacteria 的丰度可以忽略不计，而 Thy1-alpha Syn 小鼠中疣微菌的丰度则有所减少。使用肠上皮 (IEC-6) 细胞在体外研究 LPS 对肠屏障功能的影响，并通过在 Thy1-alpha Syn 小鼠饮用水中施用 LPS 进行体内研究。免疫组织化学显示，体外急性暴露于 LPS 会导致 IEC-6 细胞细胞膜周围紧密连接标记 ZO-1 和 e-Cadherin 的减少和分布改变。 Thy1-alpha Syn 小鼠接受 LPS 治疗后，在第 10 周时出现了早期运动表现，而未治疗的小鼠在该年龄时仍无症状。这项研究再次证实帕金森病患者体内存在微生物组的改变，并支持促炎性肠道微生物组环境作为帕金森病发病机制的触发因素的观点。
The interaction between the gut microbiota and alpha-synuclein (alpha Syn) aggregation in Parkinson's disease (PD) is receiving increasing attention. The objective of this study was to investigate gut microbiota, and effects of an inflammatory lipopolysaccharide (LPS) trigger in a human alpha Syn over-expressing mouse model of PD (Thy1-alpha Syn). Stool samples from patients with confirmed PD and Thy1-alpha Syn mice were analyzed using 16S ribosomal RNA sequencing. Compared to healthy controls, the relative abundance of mucin-degrading Verrucomicrobiae and LPS-producing Gammaproteobacteria were greater in PD patients. In mice, the abundance of Gammaproteobacteria was negligible in both Thy1-alpha Syn and wild-type (WT) animals, while Verrucomicrobiae were reduced in Thy1-alpha Syn mice. The effect of LPS on intestinal barrier function was investigated in vitro using intestinal epithelial (IEC-6) cells, and in vivo via administration of LPS in drinking water to Thy1-alpha Syn mice. Acute exposure to LPS in vitro resulted in a reduction and altered distribution of the tight junction markers ZO-1 and e-Cadherin around the cell membrane in IEC-6 cells, as shown by immunohistochemistry. LPS administration in Thy1-alpha Syn mice resulted in the emergence of early motor manifestations at 10 weeks, compared to untreated mice who were still asymptomatic at this age. This study reaffirms that an altered microbiome exists in patients with PD, and supports the notion of a proinflammatory gut microbiome environment as a trigger for PD pathogenesis.