Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice.

J Neuroinflammation

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.

Published: November 2020

AI Article Synopsis

  • The R1441G mutation in the LRRK2 gene is linked to late-onset Parkinson's disease (PD) and is influenced by peripheral inflammation and gut microbiota, particularly through chronic periodontitis caused by the bacterium Porphyromonas gingivalis (Pg).
  • In an experimental study, mice with the R1441G mutation were given Pg orally, which led to reduced dopaminergic neurons and increased inflammatory markers in the brain and colon, indicating a possible association between Pg-induced dysbiosis and PD.
  • The results suggest that inflammation triggered by oral Pg may significantly contribute to the development and progression of PD related to the LRRK2 gene mutation.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677837PMC
http://dx.doi.org/10.1186/s12974-020-02027-5DOI Listing

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