New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota
Abstract
1. Introduction
2. Evidences for an Altered Gut–Brain Axis in Parkinson’s Disease
2.1. Neuropathological, Epidemiological, and Experimental Animal Model Evidence
2.2. Metagenomic Evidence
3. Important Co-Factors for Gut–Brain Disturbances in PD
3.1. Aging
3.2. Neuroinflammation
3.3. Genetics
4. Targeting the Gut–Brain Axis in PD
4.1. Antibiotics
4.2. Probiotics
Probiotics and L-dopa
4.3. Prebiotics
4.4. Synbiotics
4.5. Dietary Interventions
4.5.1. Mediterranean Diet
4.5.2. Omega-3 Fatty Acids
4.5.3. Vitamins
4.6. Fecal Microbiota Transplant (FMT)
4.7. Live Biotherapeutic Products (LBPs)
5. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Phylum | Family | Genus | Increased Abundance | Decreased Abundance | References |
---|---|---|---|---|---|
Actinobacteria | 5 | 0 | [99,103,115,117,119] | ||
Actinobacteria | Bifidobacteriaceae | 5 | 0 | [98,103,104,107,119] | |
Actinobacteria | Bifidobacteriaceae | Bifidobacterium | 6 | 2 | [95,97,98,100,102,107,111,119] |
Bacteroidetes | 2 | 5 | [95,97,99,101,104,109,119] | ||
Bacteroidetes | Prevotellaceae | 0 | 5 | [24,60,97,105,109] | |
Bacteroidetes | Prevotellaceae | Prevotella | 3 | 5 | [24,60,95,98,100,107,110,111] |
Firmicutes | 3 | 4 | [60,101,103,104,113,115,117] | ||
Firmicutes | Enterococcaceae | 3 | 1 | [96,97,99,106] | |
Firmicutes | Lachnospiraceae | 0 | 9 | [98,101,103,104,106,107,117,118,119] | |
Firmicutes | Lachnospiraceae | Roseburia | 0 | 10 | [98,101,103,106,107,111,114,117,118,119] |
Firmicutes | Lachnospiraceae | Blautia | 0 | 6 | [95,98,99,101,111,119] |
Firmicutes | Lactobacillaceae | 5 | 1 | [96,97,98,103,106,117] | |
Firmicutes | Lactobacillaceae | Lactobacillus | 5 | 1 | [95,98,100,102,110,111] |
Firmicutes | Ruminococcaceae | 3 | 2 | [24,98,99,109,117] | |
Firmicutes | Ruminococcaceae | Faecalibacterium | 0 | 10 | [95,97,98,99,104,111,112,114,117,118] |
Proteobacteria | 4 | 0 | [99,101,103,119] | ||
Proteobacteria | Enterobacteriaceae | 6 | 0 | [24,97,99,103,104,106] | |
Verrucomicrobia | 6 | 0 | [101,103,105,113,115,119] | ||
Verrucomicrobia | Verrucomicrobiaceae | 8 | 0 | [60,98,101,103,105,106,109,119] | |
Verrucomicrobia | Verrucomicrobiaceae | Akkermansia | 13 | 0 | [60,97,98,101,103,105,109,110,113,114,115,118,119] |
Antibiotic | Neuroprotection | References |
---|---|---|
Minocycline | • Modulates MPTP/6-OHDA-induced microglia activation: o Inhibits p38 MAPK activation o Decreases the release of cytokines o Decreases iNOs activation, thus reducing the production of NO • Inhibits caspase-1 expression | [210,211,212,213,214] |
Doxycycline | • Modulates MPTP/6-OHDA-induced microglia and astrocyte activation: o Decreases iNOs activation, thus reducing the production of NO o Downregulation of MMP-3 activity • In vitro biochemical assay: reshapes α-syn oligomers towards non-toxic structures | [202,218,219,220,221] |
Ceftriaxone | • Modulates MPTP/6-OHDA-induced toxicity: oIncreases GLT-1 expression oPrevents MPTP-induced motor impairment • Reduces pro-inflammatory cytokine and factors: TNF-α and IL-β • Restores the levels of endogenous antioxidant enzymes • In vitro biochemical assay: blocks α-syn polymerization | [222,223,225,226,227] |
Rifampicin | • Modulates rotenone-induced toxicity: o Upregulates GRP78 via the PERK-eIF2α-ATF4 pathway • Modulates rotenone-induced microglial activation: o Downregulates NF-kB and MAPKs pathways o Decreases the release of pro-inflammatory cytokines and factors: TNF-α, IL-β and IL-6 o Decreases iNOs activation, thus reducing the production of NO • Activates the autophagy pathway • Diminishes oxidative stress induced by MPTP toxicity • In vitro biochemical assay: inhibits α-syn fibrillation and aggregation | [228,229,230,231,232,233,234,235] |
Probiotic Type | Concentrations | Treatment Duration | Tested in | Main Results | References |
---|---|---|---|---|---|
Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium animalis subsp. lactis, Bifidobacterium breve | X | Co-culture with probiotic | In vitro. Peripheral blood mononuclear cells from PD patients. | • Decrease of pro-inflammatory cytokines • Increase of anti-inflammatory cytokines • Reduced ROS production | [244] |
Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium animalis subsp. lactis, Bifidobacterium breve | X | 1h probiotic exposure or 1 h probiotic + inflammatory stressor | In vitro. Caco-2 cell line | • Restored the integrity of the epithelial damaged cells | [244] |
Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium animalis subsp. lactis, Bifidobacterium breve | X | 48 h | In vitro. Escherichia coli and Klebsiella pneumoniae inoculation | • Inhibited the growth of potential pathogen bacteria | [244] |
Bacillus subtilis | X | 13 days | In vivo. Caenorhabditis elegans (C. elegans) model of synucleinopathy | • Inhibited α-syn aggregation • Cleared preformed aggregates | [245] |
Lacobacillus rhamnosus GG, Bifidobacterium animalis lactis and Lactobacillus acidophilus | 2 × 106 CFU | 1X a day for 4 weeks | In vivo. MPTP-induced mouse model and Rotenone-induced mouse model. | • Neuroprotective effects on dopaminergic cells against MPTP and Rotenone-induced toxicity: o Upregulate expression of BDNF and GDNF o Downregulate expression of MAO-B o Increase levels of butyrate • Prevented behavioral impairment | [246] |
Lactobacillus plantarum PS128 | 1 × 109 CFU | 1X a day for 28 days | In vivo. MPTP-induced mouse model | • Neuroprotective effects on dopaminergic cells against MPTP induced toxicity: o Upregulates expression of BDNF o Decreases the expression of pro-inflammatory cytokines o Reduces glial reactivity • Improved behavioral impairment | [248] |
Clostridium butyricum | 5 × 108 CFU | 1X a day for 4 weeks | In vivo. MPTP-induced mouse model | • Neuroprotective effects on dopaminergic cells against MPTP induced toxicity: o Improved microglia activation and synaptic dysfunction o Increased levels of colonic GLP-1 and GLP-1 receptor in the brain. • Improved behavioral impairment | [249] |
Bifidobacterium bifidum, Bifidobacterium longum, Lactobacillus rhamnosis, Lactobacillus rhamnosus GG, Lactobacillus plantarum and Lactococcus lactis | 1 × 1010 CFU | 1X a day for 16 weeks | In vivo. MitoPark mouse model | • Attenuated motor impairment • Reduced dopaminergic cell loss | [252] |
Lactobacillus acidophilus, Bifidobacterium bifigum, Lactobacillus reuteri and Lactobacillus fermentum (capsules) | 8 × 109 CFU | 1X a day for 12 weeks | PD patients | • Decreased MDS-UPDRS scores | [253] |
Lactobacillus casei Shirota (fermented milk) | 6.5 × 109 CFU | 1X a day for 5 weeks | PD patients | • Improved stool consistency • Reduced bloating and abdominal pain | [145] |
Streptococcus salivarius, subsp. Thermophilus, Enterococcus faecium, Lactobacillus rhamnosus GG, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii, subsp. Bulgaricus and Bifidobacterium (fermented milk) + Prebiotic fiber | 2.5 × 1011 CFU | 1X a day for 4 weeks | PD patients | • Improved constipation symptoms | [250] |
Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus gasseri, Lactobacillus rhamnosus, Bifidobacterium bifidum, Bifidobacterium longum, Enterococcus faecalis, Enterococcus faecium (capsules) | 1 × 1010 CFU | 1X a day for 4 weeks | PD patients | • Improved constipation symptoms | [251] |
Lactobacillus acidophilus and Bifidobacterium infantis (tablets) | 120 mg/day X | 2X a day for 12 weeks | PD patients | • Reduced bloating and abdominal pain | [146] |
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Lorente-Picón, M.; Laguna, A. New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota. Biomolecules 2021, 11, 433. https://doi.org/10.3390/biom11030433
Lorente-Picón M, Laguna A. New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota. Biomolecules. 2021; 11(3):433. https://doi.org/10.3390/biom11030433
Chicago/Turabian StyleLorente-Picón, Marina, and Ariadna Laguna. 2021. "New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota" Biomolecules 11, no. 3: 433. https://doi.org/10.3390/biom11030433
APA StyleLorente-Picón, M., & Laguna, A. (2021). New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota. Biomolecules, 11(3), 433. https://doi.org/10.3390/biom11030433