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. 2023 Nov 17;11(1):254.
doi: 10.1186/s40168-023-01685-w.

Oral pathogens exacerbate Parkinson's disease by promoting Th1 cell infiltration in mice

Xue-Bing Bai #  1   2   3   4   5   6   7 , Shuo Xu #  2   3   4   5   6   7   8 , Lu-Jun Zhou  1   2   3   4   5   6   7 , Xiao-Qian Meng  2   3   4   5   6   7 , Yu-Lin Li  1   2   3   4   5   6   7 , Yan-Lin Chen  2   3   4   5   6   7 , Yi-Han Jiang  2   3   4   5   6   7 , Wen-Zhen Lin  1   2   3   4   5   6   7 , Bo-Yan Chen  2   3   4   5   6   7 , Lin-Juan Du  2   3   4   5   6   7 , Guo-Cai Tian  2   3   4   5   6   7 , Yan Liu  2   3   4   5   6   7 , Sheng-Zhong Duan  9   10   11   12   13   14 , Ya-Qin Zhu  15   16   17   18   19   20
Affiliations

Oral pathogens exacerbate Parkinson's disease by promoting Th1 cell infiltration in mice

Xue-Bing Bai et al. Microbiome. .

Abstract

Background: Parkinson's disease (PD) is a common chronic neurological disorder with a high risk of disability and no cure. Periodontitis is an infectious bacterial disease occurring in periodontal supporting tissues. Studies have shown that periodontitis is closely related to PD. However, direct evidence of the effect of periodontitis on PD is lacking. Here, we demonstrated that ligature-induced periodontitis with application of subgingival plaque (LIP-SP) exacerbated motor dysfunction, microglial activation, and dopaminergic neuron loss in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.

Results: The 16S rRNA gene sequencing revealed that LIP-SP induced oral and gut dysbiosis. Particularly, Veillonella parvula (V. parvula) and Streptococcus mutans (S. mutans) from oral ligatures were increased in the fecal samples of MPTP + LIP-SP treated mice. We further demonstrated that V. parvula and S. mutans played crucial roles in LIP-SP mediated exacerbation of motor dysfunction and neurodegeneration in PD mice. V. parvula and S. mutans caused microglial activation in the brain, as well as T helper 1 (Th1) cells infiltration in the brain, cervical lymph nodes, ileum and colon in PD mice. Moreover, we observed a protective effect of IFNγ neutralization on dopaminergic neurons in V. parvula- and S. mutans-treated PD mice.

Conclusions: Our study demonstrates that oral pathogens V. parvula and S. mutans necessitate the existence of periodontitis to exacerbate motor dysfunction and neurodegeneration in MPTP-induced PD mice. The underlying mechanisms include alterations of oral and gut microbiota, along with immune activation in both brain and peripheral regions. Video Abstract.

Keywords: Oral pathogens; Parkinson’s disease; Periodontitis; T helper 1 cells.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
LIP-SP exacerbates motor dysfunction and dopaminergic neuronal loss in MPTP-induced PD mice. A Schematic illustration of the experimental procedure. MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. LIP, ligature-induced periodontitis. SP, subgingival plaque. LIP-SP, ligature-induced periodontitis with application of subgingival plaque. B Bar plots of performance in behavioral tests, including rotarod test and traction test. n = 5:5:10:10. C-D Representative immunohistochemical staining (C) and quantification (D) of tyrosine hydroxylase (TH)-positive fibers in striatum (ST). n = 5:5:5:5. E–F Representative immunohistochemical staining (E) and quantification (F) of TH-positive neurons in substantia nigra (SN). n = 5:5:5:5. Scale bar: 200 μm. G Western blotting analysis and quantification (H) of TH in ST. n = 5:5:5:5. I Representative immunofluorescence staining of dopaminergic neuron marker TH (red) and microglia marker Iba-1 (green) in SN. DAPI: 4’,6-diamidino-2-phenylindole dihydrochloride. J Quantitative analysis of the number of microglia in SN. n = 5:5:5:5. Scale bar: 200 μm.Values are expressed as mean ± SEM (standard error of the mean). Two-way ANOVA followed by Tukey’s multiple comparison test was used for statistical analysis. ns, not significant. *P < 0.05, **P < 0.01
Fig. 2
Fig. 2
LIP-SP alters both the oral and gut microbiota of MPTP-induced PD mice. A Alpha diversity of oral and gut microbiota assessed by Chao 1, Faith’s phylogenetic diversity (Faith’s pd), and Shannon index. 16S rRNA gene sequencing was used to analyze the microbiota in oral ligatures and feces of mice. B Principal coordinate analysis (PCoA) of oral and gut microbiota. C Random forest analysis of oral and gut microbiota at the species level. D Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of Veillonella parvula and Streptococcus mutans in oral ligatures. n = 5:5. E qRT-PCR analysis of Veillonella parvula and Streptococcus mutans in feces. n = 5:5. Data are presented as mean ± SEM. Student’s t-test was used for statistical analysis. *P < 0.05, **P < 0.01
Fig. 3
Fig. 3
LIP-mix aggravates MPTP-induced motor dysfunction and dopaminergic neuronal loss. A Schematic illustration of the experimental procedure. B Bar plots of performance in behavioral tests, including rotarod test and traction test. Mix: V. parvula and S. mutans mixture. LIP-mix: ligature-induced periodontitis and oral infection of V. parvula and S. mutans mixture. n = 10:10:10:10. C-D Representative immunohistochemical staining (C) and quantification (D) of TH-positive fibers in ST. n = 5:5:5:5. E–F Representative immunohistochemical staining (E) and quantification (F) of TH-positive neurons in SN. n = 5:5:5:5. Scale bar: 200 μm. G Western blotting analysis of TH in ST. n = 5:5:5:5. Values are expressed as mean ± SEM. Two-way ANOVA followed by Tukey’s multiple comparisons test was used for statistical analysis. ns, not significant. *P < 0.05, **P < 0.01
Fig. 4
Fig. 4
LIP-mix stimulates MPTP-induced microglial activation and CD4+ T cell infiltration in mouse brain. A Representative flow cytometry analysis and quantification of CD45low CD11b+ microglia in mouse brain. B-E Representative flow cytometry analysis and quantifications of CD3+ CD4.+ T cells in mouse brain (B), cervical lymph nodes (C), ileum (D), and colon (E). n = 5–8 per group. Values are expressed as mean ± SEM. Two-way ANOVA followed by Tukey’s multiple comparisons test. ns, not significant. *P < 0.05, **P < 0.01
Fig. 5
Fig. 5
LIP-mix promotes the accumulation of Th1 cells in MPTP-induced PD mice. Representative flow cytometry analysis and quantifications of CD4+IFNγ.+ Th1 cells in mouse brain (A), cervical lymph nodes (B), ileum (C) and colon (D). n = 5:5:5. Values are expressed as mean ± SEM. Two-way ANOVA followed by Tukey’s multiple comparisons test. ns, not significant. ns, not significant. *P < 0.05, **P < 0.01
Fig. 6
Fig. 6
Neutralization of IFNγ alleviates dopaminergic neuronal loss in MPTP + LIP-mix treated mice. A Schematic illustration of the experimental procedure. Anti-IFNγ, IFNγ-neutralizing antibody. B Western blotting analysis of TH in ST. C-D) Representative immunohistochemical staining (C) and quantification (D) of TH-positive fibers in ST. E–F Representative immunohistochemical staining (E) and quantification (F) of TH-positive neurons in SN. n = 5:5:5:5. Scale bar: 200 μm. Values are expressed as mean ± SEM. Two-way ANOVA followed by Tukey’s multiple comparisons test was used for statistical analysis. ns, not significant. *P < 0.05, **P < 0.01
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