Table 4 Mechanistic studies of microbiota in animal models of PD
From: Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies
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 |