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Cited by 617Parkinson's Disease Mechanisms and TreatmentsGut microbiota and healthNeuroinflammation and Neurodegeneration Mechanisms

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Fecal microbiota transplantation protects rotenone-induced Parkinson’s disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis

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Zhao, Zhe, Ning, Jingwen, Bao, Xiu-qi, Shang, Meiyu, Ma, Jingwei, Li, Gen, Zhang, Dan·2021·Microbiome
DOI 10.1186/s40168-021-01107-9PMC PMC8597301
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Abstract

Background: Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis. Results: We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon. Conclusions: Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis.

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Fig. 1 FMT treatment alleviates motor symptoms and gastrointestinal dysfunctions of the rotenone-induced PD mouse model. A The flow chart of animal treatments. B The body weights of mice from week 5 to week 6. C Rota-Rod test. D Adhesive removal test. E Grip strength test. F Pole test. G Intestinal transit distances. H Colon lengths. I Water percentages of fecal pellets. J Numbers of total fecal pellets. K Time course of fecal output over 20 min. For B–F and I–K, n = 15 for each group. For G and H, n = 5 replicates in each group. Data are presented as mean ± SD. ##P < 0.01, ###p < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone group
Fig. 1 FMT treatment alleviates motor symptoms and gastrointestinal dysfunctions of the rotenone-induced PD mouse model. A The flow chart of animal treatments. B The body weights of mice from week 5 to week 6. C Rota-Rod test. D Adhesive removal test. E Grip strength test. F Pole test. G Intestinal transit distances. H Colon lengths. I Water percentages of fecal pellets. J Numbers of total fecal pellets. K Time course of fecal output over 20 min. For B–F and I–K, n = 15 for each group. For G and H, n = 5 replicates in each group. Data are presented as mean ± SD. ##P < 0.01, ###p < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone groupCC BY · PubMed Central
Fig. 2 FMT administration attenuates PD-associated histological features and inflammation in the SN and the colon of the rotenone-intoxicated mouse model. A Representative captures of immunofluorescence in the SN of nuclei (DAPI, blue), total dopaminergic neurons (TH, green), and astrocytes (GFAP, red). B Numbers of TH+ cells in the SN. C Numbers of GFAP+ cells (activated astrocytes) in the SN. D Representative captures of immunofluorescence in the SN of nuclei (DAPI, blue), total dopaminergic neurons (TH, green), and microglial cells (Iba-1, red). E Numbers of TH+ cells in the SN. F Numbers of Iba-1+ cells (activated microglial cells) in the SN. G Representative western blot brands of TH in the midbrain containing the SN. H The density analysis result of TH western blot in the midbrain containing the SN. I Representative western blot brands of α-syn in the midbrain containing the SN. J The density analysis result of α-syn western blot in the midbrain containing the SN. K Representative captures of immunofluorescence in the SN of α-syn. L Statistical analysis of α-syn density in the SN. M Representative captures of H&E staining in the colon; the black arrow indicates inflammatory infiltration. N Histological scores of colons based on H&E staining. For B and C; E and F; L; and N, n = 5 for each group. For H and J, n = 4 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone group
Fig. 2 FMT administration attenuates PD-associated histological features and inflammation in the SN and the colon of the rotenone-intoxicated mouse model. A Representative captures of immunofluorescence in the SN of nuclei (DAPI, blue), total dopaminergic neurons (TH, green), and astrocytes (GFAP, red). B Numbers of TH+ cells in the SN. C Numbers of GFAP+ cells (activated astrocytes) in the SN. D Representative captures of immunofluorescence in the SN of nuclei (DAPI, blue), total dopaminergic neurons (TH, green), and microglial cells (Iba-1, red). E Numbers of TH+ cells in the SN. F Numbers of Iba-1+ cells (activated microglial cells) in the SN. G Representative western blot brands of TH in the midbrain containing the SN. H The density analysis result of TH western blot in the midbrain containing the SN. I Representative western blot brands of α-syn in the midbrain containing the SN. J The density analysis result of α-syn western blot in the midbrain containing the SN. K Representative captures of immunofluorescence in the SN of α-syn. L Statistical analysis of α-syn density in the SN. M Representative captures of H&E staining in the colon; the black arrow indicates inflammatory infiltration. N Histological scores of colons based on H&E staining. For B and C; E and F; L; and N, n = 5 for each group. For H and J, n = 4 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone groupCC BY · PubMed Central
Fig. 3 FMT treatment restores BBB and intestinal barrier impairment in the rotenone-challenged mouse model. A Representative electron micrographs of the tight junction structures of BBB in the SN. B Representative western blot brands of ZO-1, occludin, and claudin-5 in the midbrain containing the SN. C–E The density analysis of ZO-1, occludin, and claudin-5 western blot in the midbrain containing the SN. F Representative electron micrographs of the tight junction structures of intestinal epithelium in the colon. G Concentrations of FD4 in serum indicating intestinal permeability. H Representative captures of immunofluorescence in the colon of ZO-1. I ZO-1 integrity score in the colon. J Representative western blot brands of ZO-1, occludin, and claudin-1 in the colon. K–M The density analysis of ZO-1, occludin, and claudin-1 western blot in the colon. N Serum levels of LPS endotoxin. O Serum levels of LBP. P Numbers of bacteria (CFU) in the livers, spleens, and MLNs of mice. Q–S Serum levels of inflammatory cytokines, including TNF-α (Q), IL-1β (R), and IL-6 (S). For C–E and K–M, n = 4 for each group. For G, n = 5 for each group. For I, n = 5 for each group. For N and O and Q–S, n = 8 for each group. For P, n = 6 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone group
Fig. 3 FMT treatment restores BBB and intestinal barrier impairment in the rotenone-challenged mouse model. A Representative electron micrographs of the tight junction structures of BBB in the SN. B Representative western blot brands of ZO-1, occludin, and claudin-5 in the midbrain containing the SN. C–E The density analysis of ZO-1, occludin, and claudin-5 western blot in the midbrain containing the SN. F Representative electron micrographs of the tight junction structures of intestinal epithelium in the colon. G Concentrations of FD4 in serum indicating intestinal permeability. H Representative captures of immunofluorescence in the colon of ZO-1. I ZO-1 integrity score in the colon. J Representative western blot brands of ZO-1, occludin, and claudin-1 in the colon. K–M The density analysis of ZO-1, occludin, and claudin-1 western blot in the colon. N Serum levels of LPS endotoxin. O Serum levels of LBP. P Numbers of bacteria (CFU) in the livers, spleens, and MLNs of mice. Q–S Serum levels of inflammatory cytokines, including TNF-α (Q), IL-1β (R), and IL-6 (S). For C–E and K–M, n = 4 for each group. For G, n = 5 for each group. For I, n = 5 for each group. For N and O and Q–S, n = 8 for each group. For P, n = 6 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone groupCC BY · PubMed Central
Fig. 4 FMT administration inhibits the TLR4/MyD88/NF-κB signaling pathway in the SN and the colon of rotenone-induced PD mouse model. A Levels of LPS endotoxin in the midbrain containing the SN. B Levels of LPS endotoxin in the colon. C Fecal levels of LPS endotoxin. D Fecal levels of LBP. E Representative western blot brands of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the midbrain containing the SN. F–J The density analysis results of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the midbrain containing the SN. K mRNA expression of Tlr4 in the midbrain containing the SN. L Representative western blot brands of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the colon. M–Q The density analysis results of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the colon. R mRNA expression of Tlr4 in the colon. S Representative captures of immunofluorescence in the SN of TLR4. T Numbers of TLR4+ cells in the SN. U Representative captures of immunofluorescence in the colon of TLR4. V Numbers of TLR4+ cells in the colon. For A–D, n = 8 for each group. For F–J and M–Q, n = 4 for each group. For K and R, n = 3 for each group. For T and V, n = 5 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone group
Fig. 4 FMT administration inhibits the TLR4/MyD88/NF-κB signaling pathway in the SN and the colon of rotenone-induced PD mouse model. A Levels of LPS endotoxin in the midbrain containing the SN. B Levels of LPS endotoxin in the colon. C Fecal levels of LPS endotoxin. D Fecal levels of LBP. E Representative western blot brands of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the midbrain containing the SN. F–J The density analysis results of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the midbrain containing the SN. K mRNA expression of Tlr4 in the midbrain containing the SN. L Representative western blot brands of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the colon. M–Q The density analysis results of TLR4, MyD88, p-IκB-α, IκB-α, and NF-κB in the colon. R mRNA expression of Tlr4 in the colon. S Representative captures of immunofluorescence in the SN of TLR4. T Numbers of TLR4+ cells in the SN. U Representative captures of immunofluorescence in the colon of TLR4. V Numbers of TLR4+ cells in the colon. For A–D, n = 8 for each group. For F–J and M–Q, n = 4 for each group. For K and R, n = 3 for each group. For T and V, n = 5 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone groupCC BY · PubMed Central
Fig. 5 FMT treatment suppresses the generation of pro-inflammatory molecules both in the SN and the colon of rotenone-challenged mice. A Representative western blot brands of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the midbrain containing the SN. B–F The density analysis results of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the midbrain containing the SN. G TNF-α levels in the midbrain containing the SN. H Representative western blot brands of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the colon. I–M The density analysis results of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the colon. N TNF-α levels in the colon. For B–F and I–M, n = 4 for each group. For G and N, n = 8 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone group
Fig. 5 FMT treatment suppresses the generation of pro-inflammatory molecules both in the SN and the colon of rotenone-challenged mice. A Representative western blot brands of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the midbrain containing the SN. B–F The density analysis results of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the midbrain containing the SN. G TNF-α levels in the midbrain containing the SN. H Representative western blot brands of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the colon. I–M The density analysis results of TNF-α, IL-1β, IL-6, iNOS, and COX2 in the colon. N TNF-α levels in the colon. For B–F and I–M, n = 4 for each group. For G and N, n = 8 for each group. Data are presented as mean ± SD. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone groupCC BY · PubMed Central
Fig. 6 FMT treatment alleviates fecal microbiota dysbiosis of rotenone-induced PD mice. A Analysis of alpha diversity of gut microbiota by Shannon analysis. B Analysis of alpha diversity of gut microbiota by Simpson analysis. C PCoA plots of beta diversity based on weighted UniFrac analysis in different groups. D Beta diversity based on weighted UniFrac ANOSIM analysis in different groups. E Relative abundances of gut microbiota at the genus level in the 3 groups. F Heatmap analysis of relative abundances of gut microbiota at the genus level in different groups. G–L Relative abundances of 6 significantly altered bacterial genera: Akkermansia (G), Barnesiella (H), Butyricicoccus (I), Desulfovibrio (J), Helicobacter (K), Roseburia (L). M Graphical phylogenetic analysis of gut microbiota alterations among 3 groups. The size of each dot represents the relative abundance. N Heatmap of the association between microbiota and other experimental results. In this figure, n = 8 for each group. Each boxplot represents the median, interquartile range, minimum and maximum values. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone group
Fig. 6 FMT treatment alleviates fecal microbiota dysbiosis of rotenone-induced PD mice. A Analysis of alpha diversity of gut microbiota by Shannon analysis. B Analysis of alpha diversity of gut microbiota by Simpson analysis. C PCoA plots of beta diversity based on weighted UniFrac analysis in different groups. D Beta diversity based on weighted UniFrac ANOSIM analysis in different groups. E Relative abundances of gut microbiota at the genus level in the 3 groups. F Heatmap analysis of relative abundances of gut microbiota at the genus level in different groups. G–L Relative abundances of 6 significantly altered bacterial genera: Akkermansia (G), Barnesiella (H), Butyricicoccus (I), Desulfovibrio (J), Helicobacter (K), Roseburia (L). M Graphical phylogenetic analysis of gut microbiota alterations among 3 groups. The size of each dot represents the relative abundance. N Heatmap of the association between microbiota and other experimental results. In this figure, n = 8 for each group. Each boxplot represents the median, interquartile range, minimum and maximum values. #P < 0.05, ##P < 0.01, ###P < 0.001 versus the control group; *P < 0.05, **P < 0.01, ***P < 0.001 versus the rotenone groupCC BY · PubMed Central
Fig. 7 Correlations among different results support the possible involvement of the microbiota-gut-brain axis in the development of the rotenone-induced mouse model. A LPS levels in the colon were positively correlated with relative abundance of Akkermansia. B Relative expression of ZO-1 in the colon detected by western blot was inversely correlated with relative abundance of Desulfovibrio. C Levels of LPS in the midbrain containing the SN were significantly positively correlated with relative abundance of Desulfovibrio. D TH+ cell numbers were negatively correlated with relative abundance of Akkermansia. E Rota-Rod test data were significantly positively correlated with relative expression of ZO-1 in the colon detected by western blot. F TH+ cell numbers were negatively correlated with H&E histological scores in the colon. G Correlations among different experimental results of microbiota-gut-brain axis. The blue nodes represent gut microbiota. The red nodes represent the results in the SN of the mouse model and the purple nodes represent the data in the colon. The red lines represent positive correlations while the blue lines represent negative correlations. The solid lines mean significant correlations, and the dotted lines represent no correlations
Fig. 7 Correlations among different results support the possible involvement of the microbiota-gut-brain axis in the development of the rotenone-induced mouse model. A LPS levels in the colon were positively correlated with relative abundance of Akkermansia. B Relative expression of ZO-1 in the colon detected by western blot was inversely correlated with relative abundance of Desulfovibrio. C Levels of LPS in the midbrain containing the SN were significantly positively correlated with relative abundance of Desulfovibrio. D TH+ cell numbers were negatively correlated with relative abundance of Akkermansia. E Rota-Rod test data were significantly positively correlated with relative expression of ZO-1 in the colon detected by western blot. F TH+ cell numbers were negatively correlated with H&E histological scores in the colon. G Correlations among different experimental results of microbiota-gut-brain axis. The blue nodes represent gut microbiota. The red nodes represent the results in the SN of the mouse model and the purple nodes represent the data in the colon. The red lines represent positive correlations while the blue lines represent negative correlations. The solid lines mean significant correlations, and the dotted lines represent no correlationsCC BY · PubMed Central
Fig. 8 Schematic diagram of the protective effects of FMT administration on the rotenone-induced PD mouse model through the microbiota-gut-brain axis. Briefly, FMT treatment restores the gut microbiota dysbiosis induced by rotenone, which decreases the generation of pathogenic LPS in the gut and inhibits the intestinal inflammation by downregulating the TLR4 signaling pathway. Then, the reduced intestinal barrier permeability decreases the leakage of microbes, LPS, and pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) into the systemic circulation. As a consequence of reduced systemic inflammation, lower levels of LPS and pro-inflammatory cytokines get access to the SN across the BBB, which inhibits neuroinflammation (activated astrocytes and microglia) through suppressing LPS-TLR4 signaling pathway activation in the SN. Eventually, the dopaminergic neuronal death is attenuated in the SN. This diagram demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, it is shown that microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis
Fig. 8 Schematic diagram of the protective effects of FMT administration on the rotenone-induced PD mouse model through the microbiota-gut-brain axis. Briefly, FMT treatment restores the gut microbiota dysbiosis induced by rotenone, which decreases the generation of pathogenic LPS in the gut and inhibits the intestinal inflammation by downregulating the TLR4 signaling pathway. Then, the reduced intestinal barrier permeability decreases the leakage of microbes, LPS, and pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) into the systemic circulation. As a consequence of reduced systemic inflammation, lower levels of LPS and pro-inflammatory cytokines get access to the SN across the BBB, which inhibits neuroinflammation (activated astrocytes and microglia) through suppressing LPS-TLR4 signaling pathway activation in the SN. Eventually, the dopaminergic neuronal death is attenuated in the SN. This diagram demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, it is shown that microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axisCC BY · PubMed Central

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Metadata

Authors
Zhao, Z., Ning, J., Bao, X.-Q., Shang, M., Ma, J., Li, G., & Zhang, D.
Affiliations
Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author
Zhang, Dan
ORCID
Venue
Microbiome
Publisher
Springer Science and Business Media LLC
Published
2021-11-17
Volume
9
Issue
1
Pages
226-226
ISSN
2049-2618 (ISSN-L)
DOI
10.1186/s40168-021-01107-9
PMC
PMC8597301
OpenAlex
W3211876735
Cited by
616
References
100
Citations by year
2026: 122 · 2025: 179 · 2024: 183 · 2023: 91 · 2022: 39
FWCI
37.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Microbiome (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Sciences Foundation of China (81773718, 81630097, 81773589)
  • The National Key Research and Development Program of China (SQ2018YFA090025-04)
  • CAMS Innovation Fund for Medical Sciences (2016-I2M-3-011)
  • The Drug Innovation Major Project (2018ZX09711001-003-020, 2018ZX09711001-003-005, 2018ZX09711001-008-005)
  • CAMS The Fundamental Research Funds for the Central Universities (2018RC350002)
  • CAMS & PUMC Innovation Fund for Graduate (2019-1007-23)
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
Parkinson's disease, fecal microbiota transplantation, microbiota-gut-brain axis, rotenone-induced neurotoxicity, gut dysbiosis, lipopolysaccharide, TLR4/MyD88/NF-κB signaling, neuroinflammation, blood-brain barrier, dopaminergic neuron damage, Akkermansia, Desulfovibrio, intestinal barrier dysfunction, gastrointestinal dysfunction
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Brain-Gut Axis, Animals, Inflammation, Lipopolysaccharides, Mice, Inbred C57BL, Parkinson Disease, Rotenone, Signal Transduction, Toll-Like Receptor 4, Mice

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