Diseases, The Gut Microbiome
Gut Dysbiosis in Parkinson’s Disease
Gut dysbiosis is characterized by reduced microbial diversity and shifts in bacterial composition.
It is a prominent feature in Parkinson’s disease (PD), often preceding motor symptoms by years and contributing to disease initiation and progression via the microbiota-gut-brain axis.
PD patients exhibit consistent alterations, including depletion of short-chain fatty acid (SCFA)-producing bacteria and enrichment of pro-inflammatory taxa, which correlate with gastrointestinal symptoms (e.g., constipation), non-motor issues (e.g., depression, sleep disturbances), and motor severity (e.g., UPDRS scores).
These changes are influenced by factors like disease duration, medications, diet, and geography, with emerging evidence from 2024–2025 studies supporting a “gut-first” model.
In this model, dysbiosis drives α-synuclein pathology, neuroinflammation, and dopaminergic neuron loss.
Longitudinal profiling and fecal microbiota transplantation (FMT) models underscore causality, positioning dysbiosis as a modifiable target for early intervention. Microbial Alterations in PD
Meta-analyses and cohort studies reveal reproducible patterns, though alpha diversity reductions are often non-significant due to confounders.
Key shifts include decreased beneficial, anti-inflammatory genera and increased opportunistic pathogens, with fecal short-chain fatty acids (SCFA) levels (e.g., butyrate) reduced by 20–50%.
It is a prominent feature in Parkinson’s disease (PD), often preceding motor symptoms by years and contributing to disease initiation and progression via the microbiota-gut-brain axis.
PD patients exhibit consistent alterations, including depletion of short-chain fatty acid (SCFA)-producing bacteria and enrichment of pro-inflammatory taxa, which correlate with gastrointestinal symptoms (e.g., constipation), non-motor issues (e.g., depression, sleep disturbances), and motor severity (e.g., UPDRS scores).
These changes are influenced by factors like disease duration, medications, diet, and geography, with emerging evidence from 2024–2025 studies supporting a “gut-first” model.
In this model, dysbiosis drives α-synuclein pathology, neuroinflammation, and dopaminergic neuron loss.
Longitudinal profiling and fecal microbiota transplantation (FMT) models underscore causality, positioning dysbiosis as a modifiable target for early intervention. Microbial Alterations in PD
Meta-analyses and cohort studies reveal reproducible patterns, though alpha diversity reductions are often non-significant due to confounders.
Key shifts include decreased beneficial, anti-inflammatory genera and increased opportunistic pathogens, with fecal short-chain fatty acids (SCFA) levels (e.g., butyrate) reduced by 20–50%.
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Pattern
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Key Taxa Changes
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Correlations & Evidence
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Reduced Diversity & Beneficial Depletion
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↓ Faecalibacterium prausnitzii, Roseburia spp., Blautia, Prevotella, Butyricicoccus, Lachnospiraceae family; non-significant ↓ alpha diversity (Shannon index)
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Lower SCFA production correlates with constipation, disease progression (e.g., Hoehn & Yahr stage), and motor/non-motor symptoms (NMSS scores ↑); observed in fecal/ileal samples from PD (n=44) vs. HC (n=21).
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Pro-Inflammatory Enrichment
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↑ Lactobacillus, Streptococcus, Akkermansia, Bifidobacterium (non-significant), Enterobacteriaceae (e.g., Klebsiella, Escherichia coli, Proteus), Bilophila, Parabacteroides, Verrucomicrobia, Oscillospiraceae
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Increased gut permeability and inflammation (fecal calprotectin ↑); links to α-syn aggregation and motor deficits (e.g., beam walking time ↑ in FMT models); ileal SFB erosion in PD mice/patients.
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Other Shifts
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↓ Segmented filamentous bacteria (SFB) in ileum; variable Bifidobacterium (depleted in ileal biopsies)
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Disrupts Th17 homeostasis; precedes systemic inflammation; consistent in single/multiple-donor FMT paradigms.
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Key Mechanisms:
Dysbiosis initiates a cascade from gut to brain, with bidirectional gut-brain signaling via vagus nerve, metabolites, and immune cells.
- Increased Intestinal Permeability (“Leaky Gut”):
Depleted Prevotella impairs mucin production, thinning colonic mucus, and downregulating tight junctions (e.g., ZO-1, occludin).
Sulfate-reducing bacteria (e.g., Bilophila) produce excess H₂S, degrading mucus.
Reduced SCFAs weaken barriers, allowing pathobionts/LPS translocation; TNF-α internalizes ZO-1, elevating fecal calprotectin.
In PD ileum, this correlates with CD11b+ immune cell influx and pro-inflammatory cytokines (TNF, IL-6, IL-8). - Neuroinflammation and Immune Dysregulation:
Pro-inflammatory taxa (e.g., Enterobacteriaceae) activate TLR4/NF-κB, elevating cytokines (IL-17, IL-1β) and shifting Th17 from homeostatic to inflammatory phenotypes (↓ CD4+/IL-17+ cells, ↑ CD8+ IL-17).
SFB erosion reduces Th17 induction, promoting chronic gut inflammation that propagates systemically (↑ plasma IFNγ, IL-6) and to brain (microglial Iba1+/Trem2+ activation, NLRP3 inflammasome).
This exacerbates dopaminergic loss in the substantia nigra (SN; ~30% TH+ neurons ↓). - α-Synuclein Aggregation and Propagation:
Pathobionts like E. coli (curli proteins) and Proteus mirabilis (hemolysin A) induce ENS α-syn misfolding/phosphorylation (p-α-syn ↑), propagating caudo-rostrally via vagus to dorsal motor nucleus (DMV) and SN. Dubosiella disrupts lysosomal function via branched-chain amino acid buildup.
TMAO from dysbiosis promotes aggregation/NF-κB. p-α-syn correlates with mitochondrial fragmentation (TOM20+ ↓) and precedes motor deficits in FMT models (week 3 onset). - Oxidative Stress and Mitochondrial Dysfunction:
Dysbiosis reduces antioxidants (e.g., via ↓ NMNAT2/NAD+), upregulates NOX4/ROS, and inhibits Nrf2.
Bacterial PAMPs/mitochondrial DAMPs (e.g., cardiolipin) activate caspase-1/IL-1β;
Sleep deprivation worsens via adenosine-NOX4. Leads to SN ATP ↓ (~52% striatal dopamine reduction) and BBB (Blood-Brain Barrier) leakage (IgG+ leaks). - Neurotransmitter and Metabolite Imbalance: ↑ Tyrosine decarboxylase in gut bacteria converts L-dopa prematurely, reducing efficacy.
↓ SCFAs compromise BBB;
↑ Secondary bile acids/TMAO impair autophagy/mitochondria.
Disrupts dopamine/serotonin synthesis, linking to hyposmia and mood symptoms.
Evidence from Preclinical and Clinical Studies
2024–2025 research emphasizes ileal dysbiosis and FMT causality, with human cohorts (n>60) and mouse models replicating PD-like pathology.
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Study Type/Source
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Key Findings
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Model/Population
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Outcomes/Implications
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Human Cohort (Fecal/Ileal) (Mol Neurodegener, Oct 2024)
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↑ Lactobacillus/Streptococcus, ↓ Faecalibacterium/Roseburia; ileal SFB ↓, Enterobacteriaceae ↑; correlates with gut inflammation (ZO-1 ↓, cytokines ↑) and motor scores.
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PD patients (n=44 fecal, n=2 ileal) vs. HC (n=21)
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Supports gut-first model; ileal biomarkers for early detection.
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FMT Mouse Model (Front Neurosci, Jun 2025)
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PD-FMT induces dysbiosis (↓ Roseburia, ↑ Akkermansia), leaky gut, α-syn spread, SN neuron loss; reversed by HC-FMT.
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MPTP/rotenone mice (n>50/group)
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Time-resolved progression (gut week 3, brain week 4); vagal propagation confirmed.
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Longitudinal Cohort (Front Neurosci, Jun 2025)
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Dysbiosis predicts progression; mucin-degraders/SCFA-producers as biomarkers.
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PD cohorts (meta-analysis, n>1,000)
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Links to GI/non-motor symptoms; 2024 Fang et al.: FMT via C/EBPβ/AEP.
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Mechanistic FMT (Mol Neurodegener, Oct 2024)
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PD-dysbiome erodes Th17/SFB, triggers inflammation → BBB leak → p-α-syn/mito damage.
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WT mice post-FMT (n=16 PD, n=13 HC)
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Motor deficits (beam walking ↑); no anxiety/memory changes yet.
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Review/Mechanisms (Front Neurosci, Jun 2025)
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2025 Wu et al.: Dubosiella → lysosomal disruption; Zhu et al.: sleep-adenosine-NOX4 via microbiota.
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Multi-model synthesis
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Highlights metabolite roles (TMAO, SCFAs); probiotics mitigate.
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Therapeutic Implications:
Targeting dysbiosis offers disease-modifying potential, with 2025 trials focusing on early-stage PD.
- FMT: Restores diversity, ↑ SCFAs/ZO-1, ↓ α-syn/inflammation (TLR4/NF-κB); RCTs (n=40–60) show UPDRS ↓15–30%, constipation/anxiety relief (PDQ-39 ↑); colonoscopic > nasal delivery; mild AEs (bloating).
- Probiotics/Synbiotics: L. plantarum PS128/DP189, B. breve CCFM1067, C. butyricum reduce α-syn/ROS via GLP-1/miR-155; pilots: motor/QoL improvements (8–12 weeks).
- Prebiotics/Diet/SCFA Supplementation: High-fiber diets boost SCFA producers; butyrate (1–2 g/day) enhances immune barriers/autophagy; a Mediterranean diet slows disease progression.
- Emerging: Anti-IL-17/TNF drugs for Th17; ginkgolide C/Nrf2 activators; multi-omics for personalization.
Challenges: reversion post-FMT, medication interactions; Phase II trials (2025) target prodromal stages for 20–40% delay.
Source Grok X AI