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Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies
Xuxiang Zhang, Beisha Tang, Jifeng Guo
Translational Neurodegeneration, 2023, 12(0): 59.   DOI: 10.1186/s40035-023-00392-8

Ref. Animal model Perturbation Control factors Test (phenotype and pathology) Outcomes Summarize
[45] Thy1-α-syn mice GF versus SPF Housed in sterile or autoclaved caging, receiving autoclaved food Beam traversal, pole descent, nasal adhesive removal, hindlimb clasping reflex, α-syn inclusions, microglia morphology Gut microbiota promotes α-syn-mediated motor impairments and brain damage; depletion of gut bacteria reduces microglial activation; SCFAs regulate microglia and exacerbate PD pathophysiology; in mice, gut microbiota from PD patients enhances motor impairment Gut microbes may play a key functional role in the pathogenesis of PD
[145] Pink1−/− mice Administration of Citrobacter rodentium Littermate mice,
kept in pathogen-free conditions		 Behavioural tests, grip strength test, basal locomotor activity, pole test,
histology for dopaminergic neurons		 Pink1−/− mice with intestinal infection exhibited dyskinesia;
significant reduction in dopaminergic axonal varicosities; mitochondria-specific CD8+ T cells in the brains of infected Pink1−/− mice killed dopaminergic neurons in vitro		 Supports PINK1 as an immune system suppressor and implies that intestinal infections may induce PD
[241] Caenorhabditis elegans Bacillus subtilis probiotic strain PXN21 feeding All strains were grown at 20 °C, bacteria were grown in SSM medium at 37 °C for 48 h Locomotion analysis, lifespan assays, quantification of life-traits, α-syn forms and expression levels, nematode RNA sequencing Bacillus subtilis PXN21 inhibits and reverses α-syn aggregation in a Caenorhabditis elegans model; probiotics alter host sphingolipid metabolism, whereas gut biofilm formation and bacterial metabolites diminish α-syn aggregation A foundation for exploring the disease-modifying potential of Bacillus subtilis as a dietary supplement
[242] Rotenone mouse model GF versus CR Age- and weight-matched, under sterile conditions Grip strength test, rotarod test, intestinal permeability measurement,
quantification of TH neurons		 Rotenone gavage caused TH neuron loss in GF and CR mice, but only CR mice had impaired motor strength and coordination; rotenone affected intestinal permeability in CR mice but not GF animals The gut microbiota has a potential role in modulating barrier dysfunction and motor deficits in PD
[243] MPTP- mouse model Administration
of Cb		 Animals were kept at 23 ± 2 °C with 12 h light/dark cycles Pole test, beam walking teat, forced swimming test, open field test, dopaminergic neuron loss, synaptic plasticity, microglial activation Oral administration of Cb ameliorates MPTP-induced motor deficits, dopaminergic neuron loss, synaptic dysfunction, and microglial activation in mice Cb exerts neuroprotective effects by modulating the abnormal microbiota-gut-brain axis
[244] Rotenone mouse model Administration of Lactobacillus plantarum PS128 Under standard laboratory conditions Rotarod test, narrow beam test, dopamine level, quantification of TH neurons, microglial activation, neuroinflammation PS128 dramatically improved motor impairments in PD-like animals by increasing brain dopamine levels, neurotrophic factor expression, decreasing dopaminergic neuron loss, microglial activation, inflammatory factors By modulating gut microbiota, PS128 improves motor function and neuroprotection in PD
[192] Thy1-α-syn mice Feeding a prebiotic high-fiber diet Housed in sterile, autoclaved cages with sterile water Beam traversal test, pole test, wire hang, hindlimb score, adhesive removal, fecal output, microglia isolation and sequencing, immunohistochemistry, α-syn aggregation, flow cytometry, gut microbiome profiling Prebiotic diet improves gut flora, lowers motility abnormalities, and reduces α-syn aggregation in the substantia nigra, mediated by microglia. Prebiotic diet decreases microglial activation and boosts disease resistance. Depletion of microglia reduces prebiotic benefits Gut microbiome digestion of dietary fiber changes CNS cell physiology and improves behavioural and pathologic outcomes
[44] Aged male Fischer 344 rats; α-syn-expressing C. elegans Exposed to curli-producing bacteria Rats: antibiotic treatment; C. elegans: standard conditions Swimming tests, α-syn accumulation and aggregation, inflammation Exposure to curli-producing bacteria in rats showed increased α-syn deposition in the gut and brain, increased microgliosis and astrogliosis, and elevated brain TLR2, IL-6, and TNF expression. α-syn-expressing C. elegans fed with curli-producing bacteria showed increased α-syn aggregation Amyloid proteins in the microbiota have a role in the onset and progression of neurodegenerative illness
[171] MPTP/p, MPTP, 6-OHDA-induced mice Administration of P. mirabilis Conditions: 23 ± 1 °C, relative humidity 60% ± 10%, 12 h light/dark cycle Pole test, open field test, rotarod test, dopaminergic neuronal damage, activated microglia, LPS levels, colonic pathology, α-syn filament quantitation, α-syn expression Administration of P. mirabilis significantly induced motor impairments, dopaminergic neuron loss, and inflammation in the substantia nigra and striatum and increased α-syn aggregation in the brain and colon P. mirabilis may have a role in the etiology of PD
[245] 6-OHDA rat model Antibiotic treatment Conditions: 22 °C, 12/12 h light/dark cycles Cylinder test, forepaw stepping test, amphetamine-induced rotation test, quantification of DA, its metabolites, and 5-HT, [3H]-DA uptake, DA neuron depletion, TH immunoreactivity, DAT expression and function, pro-inflammatory markers Antibiotics decreased motor impairments, TH loss in the striatum and substantia nigra, and pro-inflammatory cytokines Expands knowledge of gut microbiota’s function in DA neuronal vulnerability, motor behavior, and neuroinflammatory responses in PD
[125] Thy1-α-syn mice Colonization with curli-producing gut bacteria Housed in sterile or autoclaved caging, receiving autoclaved food Beam traversal, pole descent, fecal output, wire hang, adhesive removal and hindlimb scoring, α-syn pathology, inflammatory responses, microglia morphologies Gut exposure to bacterial amyloid worsens motor impairments and α-syn brain disease via CsgA aggregation These findings reveal a trans-kingdom link between the gut microbiome and mammalian amyloids, implying that some bacterial taxa may worsen neurologic illness
[242] Rotenone mouse model GF versus CR Age/gender-matched GF mice were treated under sterile conditions Grip strength test, rotarod test, quantification of TH neurons, intestinal permeability measurement Chronic rotenone treatment disrupts colonic epithelial permeability and causes motor symptoms exclusively in CR mice with complex microbiota but not in GF mice Demonstrate that gut microbiota may regulate PD barrier dysfunction and motor impairments
[121] C. elegans Feeding with E. coli knockout mutants C. elegans were maintained at 20 °C C. elegans basal slowing response assays, C. elegans butanone associative learning assays, cell viability assay, mitochondrial respiration assay, level of α-syn, the colocalization between CsgA and α-syn Genetically deleting or pharmacologically suppressing the curli main subunit CsgA in E. coli lowered α-syn-induced neuronal mortality, increased mitochondrial health, and enhanced neuronal functioning. Through cross-seeding, CsgA colocalized with α-syn within neurons and enhanced its aggregation Bacterial components (e.g., curli) can directly affect neurodegenerative lesions
[246] MPTP- mouse model FMT from healthy mice Kept at 22-26 °C, 12 h light/dark cycle Pole test, traction test, SCFAs analysis, α-syn expression, TH level, microglial marker, neuroinflammation FMT improved physical function and lowered fecal SCFAs. FMT also reduced the expression of α-syn, prevented microglial activation in the SN, and hindered TLR4/PI3K/AKT/NF-κB signaling in the SN and striatum FMT may protect mice against PD by reducing α-syn expression and inactivating TLR4/PI3K/AKT/NF-κB signaling
[247] MPTP- mouse model FMT from PD patients or healthy human controls Conditions: 21 ± 1 °C, humidity 55% ± 5%, 12 h light/dark cycle Pole test, rotarod test, gut inflammation, phosphorylated AMPK and SOD2 expression, TH expression, glial activation, CD13, PDGFRβ, CD31 FMT derived from healthy human controls may repair gut dysbacteriosis and improve neurodegeneration by suppressing microgliosis and astrogliosis, improving mitochondrial deficits via the AMPK/SOD2 pathway, and restoring nigrostriatal pericytes and BBB integrity Human gut microbiota changes may be a risk factor for PD, and FMT may be used for preclinical therapy
Table 4 Mechanistic studies of microbiota in animal models of PD
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