口腔 P. gingivalis 损害肠道通透性，并介导与 LRRK2 R1441G 小鼠神经退行性变相关的免疫反应。
Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice.
机构信息
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China.
Department of Neurology, Hainan General Hospital; Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, China.
出版信息
J Neuroinflammation. 2020 Nov 19;17(1):347. doi: 10.1186/s12974-020-02027-5.
BACKGROUND
The R1441G mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in late-onset Parkinson's disease (PD). Peripheral inflammation and gut microbiota are closely associated with the pathogenesis of PD. Chronic periodontitis is a common type of peripheral inflammation, which is associated with PD. Porphyromonas gingivalis (Pg), the most common bacterium causing chronic periodontitis, can cause alteration of gut microbiota. It is not known whether Pg-induced dysbiosis plays a role in the pathophysiology of PD.
METHODS
In this study, live Pg were orally administrated to animals, three times a week for 1 month. Pg-derived lipopolysaccharide (LPS) was used to stimulate mononuclear cells in vitro. The effects of oral Pg administration on the gut and brain were evaluated through behaviors, morphology, and cytokine expression.
RESULTS
Dopaminergic neurons in the substantia nigra were reduced, and activated microglial cells were increased in R1441G mice given oral Pg. In addition, an increase in mRNA expression of tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) as well as protein level of α-synuclein together with a decrease in zonula occludens-1 (Zo-1) was detected in the colon in Pg-treated R1441G mice. Furthermore, serum interleukin-17A (IL-17A) and brain IL-17 receptor A (IL-17RA) were increased in Pg-treated R1441G mice.
CONCLUSIONS
These findings suggest that oral Pg-induced inflammation may play an important role in the pathophysiology of LRRK2-associated PD.
背景
富含亮氨酸重复激酶 2（LRRK2）基因中的 R1441G 突变导致迟发性帕金森病（PD）。外周炎症和肠道微生物群与 PD 的发病机制密切相关。慢性牙周炎是一种常见的外周炎症，与 PD 有关。牙龈卟啉单胞菌（Pg）是引起慢性牙周炎最常见的细菌，可引起肠道微生物群的改变。尚不清楚 Pg 诱导的肠道菌群失调是否在 PD 的病理生理学中起作用。
方法
在这项研究中，活体 Pg 通过口服每周三次给予动物，持续 1 个月。使用 Pg 衍生的脂多糖（LPS）体外刺激单核细胞。通过行为、形态和细胞因子表达来评估口服 Pg 给药对肠道和大脑的影响。
结果
给予口服 Pg 的 R1441G 小鼠，黑质中的多巴胺能神经元减少，激活的小胶质细胞增加。此外，在 Pg 处理的 R1441G 小鼠的结肠中检测到肿瘤坏死因子（TNF-α）和白细胞介素-1β（IL-1β）的 mRNA 表达增加以及α-突触核蛋白的蛋白水平降低，同时检测到紧密连接蛋白-1（Zo-1）减少。此外，在 Pg 处理的 R1441G 小鼠中，血清白细胞介素-17A（IL-17A）和脑白细胞介素-17 受体 A（IL-17RA）增加。
结论
这些发现表明，口服 Pg 诱导的炎症可能在 LRRK2 相关 PD 的发病机制中起重要作用。
Zotero 插件