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Cited by 170Parkinson's Disease Mechanisms and TreatmentsGut microbiota and healthNeuroinflammation and Neurodegeneration Mechanisms

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Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice

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Choi, Jin Gyu, Kim, Namkwon, Ju, In Gyoung, Eo, Hyeyoon, Lim, Su-Min, Jang, Se-Eun, Kim, Dong-Hyun, Oh, Myung Sook·2018·Scientific Reports
DOI 10.1038/s41598-018-19646-xPMC PMC5775305
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Abstract

Recently, studies on the relationship between gut dysbiosis and Parkinson’s disease (PD) have increased, but whether a specific gut bacterium may cause PD remains unexplored. Here, we report, for the first time, that a specific gut bacterium directly induces PD symptoms and dopaminergic neuronal damage in the mouse brain. We found that the number of Enterobacteriaceae, particularly Proteus mirabilis, markedly and commonly increased in PD mouse models. Administration of P. mirabilis isolated from PD mice significantly induced motor deficits, selectively caused dopaminergic neuronal damage and inflammation in substantia nigra and striatum, and stimulated α-synuclein aggregation in the brain as well as in the colon. We found that lipopolysaccharides, a virulence factor of P. mirabilis, may be associated in these pathological changes via gut leakage and inflammatory actions. Our results suggest a role of P. mirabilis on PD pathogenesis in the brain.

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Figure 1 P. mirabilis is an isolated bacterium from the increased bacterial colonies in PD animal models. (A) Schematic diagram of isolation and identification processes of P. mirabilis. (B–D) The colonies of Enterobacteriaceae were increased in the feces of MPTP/p, MPTP, and 6-OHDA-induced PD mice compared with the normal group, respectively. (E) The colonies of Proteus sp. in MPTP/p mice were only increased compared with the normal group whereas those of E. coli and Klebsiella sp. were no different from each normal group. (F) The colonies of Proteus sp. in MPTP mice were also increased compared with the normal group. Values were expressed as means ± SEM. #p < 0.05 and ##p < 0.01 vs. each normal group (unpaired t-test; n = 4). n.s; not significant, CFU; colony-forming unit.
Figure 1 P. mirabilis is an isolated bacterium from the increased bacterial colonies in PD animal models. (A) Schematic diagram of isolation and identification processes of P. mirabilis. (B–D) The colonies of Enterobacteriaceae were increased in the feces of MPTP/p, MPTP, and 6-OHDA-induced PD mice compared with the normal group, respectively. (E) The colonies of Proteus sp. in MPTP/p mice were only increased compared with the normal group whereas those of E. coli and Klebsiella sp. were no different from each normal group. (F) The colonies of Proteus sp. in MPTP mice were also increased compared with the normal group. Values were expressed as means ± SEM. #p < 0.05 and ##p < 0.01 vs. each normal group (unpaired t-test; n = 4). n.s; not significant, CFU; colony-forming unit.CC BY · PubMed Central
Figure 2 Aggravation of MPTP-induced motor impairment and dopaminergic neuronal damage by P. mirabilis treatment. (A) P. mirabilis exacerbated MPTP-induced motor deficits (pole test and rotarod test; n = 10). (B) P. mirabilis also reinforced MPTP-induced striatal dopaminergic neuronal damage compared with the premotor stage induced by MPTP (15 mg/kg/d, i.p., for 5 d) injection (MPTP 15; n = 5). Values were expressed as means ± SEM. #p < 0.05, ##p < 0.01, and ###p < 0.001 vs. normal group (unpaired t-test); $p < 0.05 and $$p < 0.01 vs. the MPTP 15 group (unpaired t-test). IHC; immunohistochemistry.
Figure 2 Aggravation of MPTP-induced motor impairment and dopaminergic neuronal damage by P. mirabilis treatment. (A) P. mirabilis exacerbated MPTP-induced motor deficits (pole test and rotarod test; n = 10). (B) P. mirabilis also reinforced MPTP-induced striatal dopaminergic neuronal damage compared with the premotor stage induced by MPTP (15 mg/kg/d, i.p., for 5 d) injection (MPTP 15; n = 5). Values were expressed as means ± SEM. #p < 0.05, ##p < 0.01, and ###p < 0.001 vs. normal group (unpaired t-test); $p < 0.05 and $$p < 0.01 vs. the MPTP 15 group (unpaired t-test). IHC; immunohistochemistry.CC BY · PubMed Central
Figure 3 P. mirabilis treatment impairs motor function in mice. Two behavioral tests (rotarod test and open field test) were performed at 8th and 16th day after last administration of P. mirabilis. Values were expressed as means ± SEM. #p < 0.05 and ##p < 0.01 vs. each normal group (unpaired t-test; n = 8). n.s; not significant.
Figure 3 P. mirabilis treatment impairs motor function in mice. Two behavioral tests (rotarod test and open field test) were performed at 8th and 16th day after last administration of P. mirabilis. Values were expressed as means ± SEM. #p < 0.05 and ##p < 0.01 vs. each normal group (unpaired t-test; n = 8). n.s; not significant.CC BY · PubMed Central
Figure 4 Dopaminergic neuronal damage in normal mice with PM administration. (A) Dopaminergic neuronal cell death was shown in the SNpc of mice brain at 8th and 16th day after PM treatment. (B) The loss of dopaminergic terminals was also shown in the ST of mice brain at the same time points. Values were expressed as means ± SEM. ##p < 0.01 and ###p < 0.001 vs. each normal group (ANOVA following Tukey’s post hoc test; n = 8). IHC; immunohistochemistry.
Figure 4 Dopaminergic neuronal damage in normal mice with PM administration. (A) Dopaminergic neuronal cell death was shown in the SNpc of mice brain at 8th and 16th day after PM treatment. (B) The loss of dopaminergic terminals was also shown in the ST of mice brain at the same time points. Values were expressed as means ± SEM. ##p < 0.01 and ###p < 0.001 vs. each normal group (ANOVA following Tukey’s post hoc test; n = 8). IHC; immunohistochemistry.CC BY · PubMed Central
Figure 5 Glial activation in normal mice with P. mirabilis administration. (A) The number of activated microglia (Iba1 (green)-positive cells) was significantly increased in the SNpc of the brain (TH (red)-positive area) after P. mirabilis treatment, respectively. (B) This tendency was also consistent with that found in the ST region. Values were expressed as means ± SEM. ###p < 0.001 vs. normal group (ANOVA following Tukey’s post hoc test; n = 8). IF; immunofluorescence.
Figure 5 Glial activation in normal mice with P. mirabilis administration. (A) The number of activated microglia (Iba1 (green)-positive cells) was significantly increased in the SNpc of the brain (TH (red)-positive area) after P. mirabilis treatment, respectively. (B) This tendency was also consistent with that found in the ST region. Values were expressed as means ± SEM. ###p < 0.001 vs. normal group (ANOVA following Tukey’s post hoc test; n = 8). IF; immunofluorescence.CC BY · PubMed Central
Figure 6 P. mirabilis treatment stimulates the elevation of fecal and serum LPS levels, colonic barrier disruption, and inflammation. (A) The levels of endotoxin LPS were elevated in the feces and serum of mice after P. mirabilis administration, respectively. The blots were processed in parallel using the samples derive from the same experiment. (B) P. mirabilis treatment induces the decrease of the epithelial barrier tight junction protein (occludin) and release of inflammatory cytokines (TNF-α) via activation of TLR4 by LPS in distal colon. Values were expressed as means ± SEM. #p < 0.05 and ###p < 0.001 vs. each normal group (unpaired t-test; n = 4). WB; western blotting.
Figure 6 P. mirabilis treatment stimulates the elevation of fecal and serum LPS levels, colonic barrier disruption, and inflammation. (A) The levels of endotoxin LPS were elevated in the feces and serum of mice after P. mirabilis administration, respectively. The blots were processed in parallel using the samples derive from the same experiment. (B) P. mirabilis treatment induces the decrease of the epithelial barrier tight junction protein (occludin) and release of inflammatory cytokines (TNF-α) via activation of TLR4 by LPS in distal colon. Values were expressed as means ± SEM. #p < 0.05 and ###p < 0.001 vs. each normal group (unpaired t-test; n = 4). WB; western blotting.CC BY · PubMed Central
Figure 7 LPSP. mirabilis induces inflammation in the nigrostriatal regions of the brain. (A, B) Microglial activation (Iba1 (green)-positive cells) was increased in the SNpc (TH (red)-positive area) and ST of mice with intra-rectal administration of LPSP. mirabilis, respectively. Values were expressed as means ± SEM. #p < 0.05 and ###p < 0.001 vs. each normal group (unpaired t-test; n = 4). IF; immunofluorescence.
Figure 7 LPSP. mirabilis induces inflammation in the nigrostriatal regions of the brain. (A, B) Microglial activation (Iba1 (green)-positive cells) was increased in the SNpc (TH (red)-positive area) and ST of mice with intra-rectal administration of LPSP. mirabilis, respectively. Values were expressed as means ± SEM. #p < 0.05 and ###p < 0.001 vs. each normal group (unpaired t-test; n = 4). IF; immunofluorescence.CC BY · PubMed Central
Figure 8 P. mirabilis treatment triggers aggregation of α-synuclein both in the colon and in the brain. The blots were processed in parallel using the samples derive from the same experiment. (A) The protein levels of α-synuclein filament was overexpressed in the distal colon of P. mirabilis -treated mice (n = 3). (B,C) P. mirabilis treatment stimulated immunoreactivity of α-synuclein filament (red) in the SNpc (TH (green)-positive area) and ST brain regions, respectively. Values were expressed as means ± SEM. #p < 0.05 and ###p < 0.001 vs. each normal group (unpaired t-test; n = 4). DB; dot blotting, IF; immunofluorescence, α-syn; α-synuclein.
Figure 8 P. mirabilis treatment triggers aggregation of α-synuclein both in the colon and in the brain. The blots were processed in parallel using the samples derive from the same experiment. (A) The protein levels of α-synuclein filament was overexpressed in the distal colon of P. mirabilis -treated mice (n = 3). (B,C) P. mirabilis treatment stimulated immunoreactivity of α-synuclein filament (red) in the SNpc (TH (green)-positive area) and ST brain regions, respectively. Values were expressed as means ± SEM. #p < 0.05 and ###p < 0.001 vs. each normal group (unpaired t-test; n = 4). DB; dot blotting, IF; immunofluorescence, α-syn; α-synuclein.CC BY · PubMed Central
Figure 9 Schematic summary of P. mirabilis-induced PD pathogenesis in the colon and in the brain.
Figure 9 Schematic summary of P. mirabilis-induced PD pathogenesis in the colon and in the brain.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Paxinos, G. & Franklin, K. Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates 4th Edition. 4th edn, (Academic Press, 2012).

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Metadata

Authors
Choi, J. G., Kim, N., Ju, I. G., Eo, H., Lim, S.-M., Jang, S.-E., Kim, D.-H., & Oh, M. S.
Affiliations
Kyung Hee University (KR)
Corresponding author
  • Kim, Dong-Hyun
  • Oh, Myung Sook
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-01-19
Volume
8
Issue
1
Pages
1275-1275
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-19646-x
PMC
PMC5775305
OpenAlex
W2782946155
Cited by
170
References
65
Citations by year
2026: 12 · 2025: 19 · 2024: 23 · 2023: 32 · 2022: 23 · 2021: 25 · 2020: 19 · 2019: 14 · 2018: 3
FWCI
10.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Research Foundation (2015R1A2A2A01004341)
  • National Research Foundation of Korea (NRF-2017R1A5A2014768, 2017R1A5A2014768, NRF-2015R1A2A2A01004341)
  • Ministry of Science and ICT, South Korea (NRF-2017R1A5A2014768, 2017R1A5A2014768)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Proteus mirabilis, Parkinson's disease, dopaminergic neurons, motor impairment, gut dysbiosis, Enterobacteriaceae, lipopolysaccharide, leaky gut, neuroinflammation, substantia nigra, striatum, alpha-synuclein aggregation, gut-brain axis, oral administration
MeSH terms
Gastrointestinal Microbiome, Animals, Colon, Corpus Striatum, Lipopolysaccharides, Male, Mice, Inbred C57BL, Movement, Proteus mirabilis, Substantia Nigra, MPTP Poisoning, Mice, Dopaminergic Neurons

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