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Disease ⇒ Parkinson's Disease {40000200}

Record Keys


Type:
Disease
Definition:
Parkinson's Disease
Parent:[  ]

Details


Initialisation date:
2021-02-05
Other Terms:
PD

Links


Meta Information


MedDra ID:
10061536
MedDra Level:
pt
ICD:[  ]
Category:
Neurology
Zone:[  ]
Mechanism:
Gut Inflammation, Leaky gut

Notes:


-A strain of Escherichia coli in the gut makes a protein called curli, which can prompt other proteins, including one called a-synuclein, to misfold. Some researchers suspect that these misfolded proteins transmit the error up the vagus nerve to the brain, where misfolded a-synuclei n is linked to disease symptoms.

- Bile > Clostridium located in appendix and Ileum > toxic bile acids > Triggering, Deteriorating PD
- PD is less frequent (~ 20%) in Appendectomy cases
- Cases of Roux-Y operation who developed PD
May other GI blind-loop-like structures:
-Increased incidence by aging parallel to Parkinson’s disease: Fistula (IBD), Diverticulosis, chronic Cholecystic, chronic appendicitis, …
- Induced blind loop structures: Roux-Y, other GI blind loop anastomoses
predispose to PD development in a similar way?

If yes, how can we target related treatments?
- Correcting surgical methods?
- Early correction of chronic structural GI diseases?
- Administration of specific substances to detoxify toxic bile acids?
- Aiming the responsible Clostridium Species (Other Microbiota ?) with specific antibiotics/ intraluminal antibodies and/or Phages.
- Creating a competitive environment by other beneficial Microbiota particularly Lactobacillus which can be considered as a possible preventive measure against parkinson's disease.
- It has been newly related to toxic bile acids produced by some clostridia species.

- Blautia is the unique genus consistently depleted across feces, blood, and brain samples of PD patients.
- host genes correlated with Blautia genus abundance were mainly involved in mitochondrial function and energy metabolism, and mapped to neurodegenerative diseases (NDDs) and metabolic diseases. (see 5)

Shared Notes


  • [1.34
    - Later age of onset correlated most strongly with MIND diet (Mediterranean diet and the DASH "Dietary Approaches to Stop Hypertension" diet) adherence in the females PD Patient
    - Greek Mediterranean adherence is associated with later PD onset
  • [1.35
    - Patients with inflammatory bowel disease are more likely to develop Parkinson disease.
    - People receiving drugs used to reduce inflammation—tumor necrosis factor (TNF) inhibitors—the incidence of the neurodegenerative disease dropped significantly.
    - Chronically inflamed gut may elevate alpha-synuclein levels locally and give rise to inflammation throughout the body, which in itself could increase the permeability of the gut and blood-brain barriers.
    - Circulating cytokines are increased that can promote inflammation.
  • [1.36
    - Overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus.
  • [1.37
    - There is a lower fungal DNA relative to bacterial DNA among PD patients.
    - No fungi differed in abundance.
    - No fungi association with motor, cognitive, or gastrointestinal features among PD patients.
  • [1.20
    - FABP6 (fatty acid binding protein 6) is the intracellular bile acid transporter which returns bile acids to enterohepatic circulation.
    - In Parkinson Disease, ileum and appendix had a strong decrease in fatty acid binding protein 6 (FABP6) and a decrease in lipid metabolism.
    - Primary bile acids or total bile acid levels in the PD appendix are not changed.
    - Secondary bile acids produced by the microbiota are elevated PD appendix.
  • [1.38
    - In 1817, the English surgeon James Parkinson described some of the first cases of the “shaking palsy” that would come to be known as Parkinson’s disease.
    - One individual had developed numbness and prickling sensations in both arms. Parkinson noticed that the man’s abdomen seemed to contain “considerable accumulation”. He dosed the man with a laxative, and ten days later his bowels were empty and his symptoms were gone.
  • [1.39
    Toxic Bile acids produced by specifics Clostridium species may predispose to PD
  • [1.40
    - PD is not one, but two diseases.
    - Some patients had damage to the brains dopamine system before damage in the intestines and heart occurred.
    - In other patients, scans revealed damage to the nervous systems of the intestines and heart before the damage in the brains dopamine system was visible
  • [1.17
    - PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease
    - The infection of mice that did not express PINK1 and/or PRKN with the Gram-negative bacterium Citrobacter rodentium triggered mitochondrial antigen presentation in the periphery. Furthermore, the intestinal infection led to cytotoxic CD8+ T cells being established, which targeted dopaminergic neurons in the brain, whereas non-dopaminergic neurons were not affected
  • [1.26
    - Increase of D-Laktat und Glykolat has amelorative effects on Parkinson disease.
    - D-Laktat is produced by lactobacillus bulgaricus.
  • [1.41
    - Higher number of bacterial mucin and host degradation enzymes link to PD.
    - The microbial contribute to the folate deficiency and hyperhomocysteinemia observed in patients with PD
  • [1.25
    - Enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations
  • [1.42
    - In skin sebum of PD patients, metabolites belonging to ceramide, triacylglycerol, and fatty acyl classes were downregulated whereas glycosphingolipid and fatty acyl metabolites were upregulated.
  • [1.43
    - Trichloroethylene (TCE) is an environmental contaminant and Parkinson's risk factor.
    - Chronic TCE treatment in rats caused dopaminergic neurodegeneration.
    - TCE exposure elevated LRRK2 kinase activity in the nigrostriatal tract and causes dopaminergic pathology, endolysosomal dysfunction, protein accumulation.
  • [1.44
    - The most common bacteria found in the stool samples are: Bacteroides, Faecalibacerium, Gemmiger, Roseburia, Prevotella, and Ruminococcus.
    - Severe constipation > Decreased Faecalibacterium.
    - Lowest physical activity and severe constipation > Increased Firmicutes
    - High physical activity > Increased Bacteroides.
  • [1.54
    - 38 E. coli genes promote neurodegeneration.
    - Two of these genes, csgA and csgB, code for proteins that form curli, one type of bacterial amyloid fibers.
    - Curli cross-seeds and colocalizes with α-syn both in C. elegans neurons and human neuroblastoma cells.
    - Curli-induced α-syn aggregations down-regulate mitochondrial genes, causing energy failure in neurons.
    - Curli may have general effects in promoting neuropathologies induced by different aggregation-prone proteins, such as A-β in Alzheimer’s disease, Huntingtin in Huntington’s disease, and SOD1 in amyotrophic lateral sclerosis.
  • [1.55
    - Increased in PD: Lactobacillus, Bifidobacterium, Verrucomicrobiaceae and Akkermansia
    - Lower Abundance in PD: Faecalibacterium, Roseburia, Coprococcus, Blautia, Prevotella and Prevotellaceae
    - Fecal SCFA levels: reduced in PD patients
    - Butyrate synthesis: is reduced in Parkinson's disease
    - Harmful amino acid metabolites: increased in PD > worsening intestinal inflammation and constipation.
    - α-Synuclein-toxic forms penetrate initially the ENS > finally reach the CNS via the vagus nerve > trigger motor symptoms of PD.
    - Butyrate and propionate > neuroprotective effects > help restore motor skills in PD.
    - Gut Microbiota > convert food flavanols into phenolic acids
  • - B. Wadsworthia > large quantities in PD patients > increased sulfite production in the intestine.
    - Sulfite > neurotoxin > mediates the mitochondrial energy balance of the brain
  • - Decreased Lachnospiraceae > reduction in anti-inflammatory and neuroprotective metabolite in PD
    Increased Bacteroides and Verrucomicrobia > Metabolites correlated positively with the frequency of the proinflammatory cytokines TNF-α and IFN-γ
  • - Decreased Prevotella > faster PD progression
  • - Increased Enterobacteriaceae > Postural instability in PD patients.
  • - Gut Microbiota > produce polyphenol > protect against neurological diseases with α-syn toxicity
  • - Chronic constipation: one of the most important and widespread early symptoms of PD > affecting around 80% of patients and recognizing as signal decades before diagnosis.
  • - Bacterial overgrowth of the small intestine (SIBO): 25% of PD patients > inflammation-mediated effect.
    -SIBO > gastrointestinal dysfunction > increasing intestinal permeability, proinflammatory cytokine activation and, consequently, microglial activation > a deterioration in motor skills and can also affect the absorption of levodopa > PD
  • [1.32
    - Serotonin > protective factor of PD
  • [1.30
    - Aromatic (ar)-turmerone is a main component of turmeric oil extracted from Curcuma longa and has anti-inflammatory activity in cultured microglia.
    - ar-turmerone analogs > directly and potently protected dopaminergic neurons.
  • [1.57
    - There is a significant inverse relationship between the onset of Alzheimer's disease/Parkinson's disease (AD/PD) and cancer.
    - An increase in PIN1 expression is related to a delay in the onset age of sporadic AD, whereas a decrease in PIN1 expression is associated with a reduced risk of various cancers.
    - prostate, ovarian, and lung cancers show the greatest negative correlation with AD.
  • - PD patients, showing an increase in Akkermansia, Bifidobacterium, and Lactobacillus and a decrease in Prevotella
  • - The onset age of PD is directly proportional to the SCFA level, suggesting that SCFAs may have a protective effect on PD
  • - Tryptophan metabolites can cross the blood-brain barrier > activate AHR to regulate astrocytes and reduce central nervous system inflammation in AD and PD
  • [1.58
    The neuropathological hallmark of PD is the widespread appearance of alpha-synuclein aggregates in both the central and peripheral nervous systems, including the ENS.
    - Gut toxins can > induce the formation of α-syn aggregates in the ENS > transmitted in a prion-like manner to the CNS through the Vagus N.
  • [1.59
    - exposure to air pollution is associated with an increased risk for development of Parkinson's disease
    - Several potential mechanisms by which air pollution could act to increase the risk for development of Parkinson’s disease, including direct neuronal toxicity, induction of systemic inflammation leading to central nervous system inflammation, and alterations in gut physiology and the microbiome.
  • [1.61
    - increased relative abundance of the Akkermansia genera over time among individuals with PD across multiple geographic locations (Finland, Germany, Japan, Russia, and United States)
    - an increase in the relative abundance of genus Akkermansia, a genus of mucin-metabolizing bacteria that are commonly elevated among individuals with PD, in individuals with RBD (REM sleep behavior disorder)
  • - Depletion of the gut microbiota through administration of antibiotics was associated with statistically significant improvement in various motor symptoms (duration and severity of dyskinesia, duration of medication “off” state, functional impact of motor functions, and complexity of motor fluctuations) among 14 individuals with PD.
  • - those with PD have a higher relative abundance of bacteria from the genera Akkermansia, Lactobacillus, and Bifidobacterium, and lower relative abundances of Prevotella, Faecalibacterium, Bacteroidetes, and Blautia genera
    - Lactobacillus, Enterococcus, Escherichia, and Proteus genera have been positively associated, and Blautia, Faecalibacterium, and Ruminococcus have been negatively associated with the Unified Parkinson’s Disease Rating Scale
    - Members of the Lachnospiraceae family have been found to be negatively associated with postural instability and gait disturbances and those of Enterobacteriaceae have been positively linked to general symptom severity.
    - ↓SCFAs: Akkermansia, Escherichia/Shigella, Flavonifractor, Intestinimonas, Phascolarctobacterium, Sporobacter; ↑SCFAs: Butyricicoccus, Clostridium sensu stricto, Roseburia.
    - The presence of bacterial overgrowth and dysbiosis may be detected by increased urinary indoxyl sulfate and possibly low abundance of fecal Prevotellaceae a bacterial family often found to be depleted in PD and inversely correlated with motor score severity.
    - intestinal permeability in PD patients to be significantly correlated with intestinal expression of α-syn, presence of Escherichia coli in the gut, and increased levels of LPS-binding proteins in serum
    - increased levels of fecal calprotectin zonulin and alpha-1-antitrypsin in PD patients compared to age-matched controls, indicating increased intestinal inflammation and disrupted barrier function in this population.
    - Increased intestinal permeability results in microbial translocation and the introduction of bacterial-derived toxins and host-derived inflammatory cytokines (TNF, IL-6, IL-1) into the blood stream (Figure 1C), providing an avenue for direct interaction with the nervous system mediated by compromised integrity of the BBB (Obrenovich, 2018). These cytokines have been found to be significantly elevated in the serum of individuals with PD compared to healthy controls and may correlate with symptom severity and progression of disease
  • - High levels of LPS have been shown to activate vagal afferent neurons, resulting in hypophagia (reduction in food intake and eating behavior) and weight loss – common non-motor symptoms of PD
  • - gut bacterial amyloid proteins, chiefly expression by curli proteins derived from Escherichia coli, promote the aggregation of α-syn in both the gut and the brain, resulting in behavioral deficits, intestinal dysfunction, and motor impairments
  • - a positive correlation between intestinal inflammation and expression of α-syn and observed α-syn to exhibit immune-modulatory or chemo-attractive properties that induce migration of neutrophils and monocytes and stimulate dendritic cells maturation.
    - dysbiosis and exposure to bacterial endotoxin possibly initiate α-syn misfolding by prompting GI inflammation and hyperpermeability in PD patients.
    - exposure to bacteria-producing amyloid protein curli can induce α-syn accumulation in the gut and brain of mice
  • - detection of calprotectin, a faecal marker of inflammation by ELISA, may be helpful in detecting early signs of the activated colonic immune system in PD
  • - Alpha-1-antitrypsin and zonulin are markers of intestinal hyperpermeability in PD
  • - Certain bacterial species of the genus Corynebacterium, Porphyromonas, and Prevotella have been noted to be significantly abundant in PD and associated with SCNA genes.
    - An overabundance of the unusually low Corynebacterium and endotoxins of the Porphyromonas and Prevotella can trigger the PD pathology in the gut.
  • - Prevotellaceae (Prevotella), Ruminococcaceae (Faecalibacterium), Lachnospiraceae (Blautia, Roseburia) that produce SCFA and help in the synthesis of mucin to maintain the intestinal integrity are considerably lower in abundance in PD
  • - a few putative pathobionts of the family Enterobacteriaceae, Enterococcaceae, which are assumed to possibly reduce the production of SCFA, produce endotoxins and neurotoxins that promote intestinal inflammation, are enriched in PD
  • - Mucin degrading genus Akkermansia of the phylum Verrucomicrobia has been widely reported to be significantly abundant in PD by most studies. Akkermansia and Christensenellaceae may symbiotically play a role in PD pathology and progression
  • - Intestinal mucus layer is rich in protein mucin. Akkermansia utilises mucin as a nutritional source and degrades it into SCFA acetate, which acts as a substrate for other beneficial bacteria to produce butyrate, an energy source for the intestinal epithelial cells.
    - Akkermansia is a symbiont that degrades mucin and encourages cells to produce more mucin.
    - A compensatory effect of richness in Akkermansia is possibly due to depleting cellulose-degrading bacteria in the PD gut
  • - Aquabacterium, Peptococcus, and Sphingomonas are associated with motor complications in PD
  • [1.63
    - metformin-mediated AMPK activation may reduce the level of neuronal loss and alleviate several phenotypes associated with these disorders.
    - a metformin therapy for more than 4 years significantly decreased the risk of developing both PD and AD.
  • [1.31
    - Fecal SCFA levels of butyric acid, valeric acid and propionic acid are reduced, whereas plasma levels were higher.
    - Low fecal concentration of most SCFAs > increased plasma propionic acid concentration > More severe motor impairment
    - Low fecal levels of butyric acid and higher plasma concentrations of butyric acid and valeric acid > More serious cognitive symptoms.
  • [1.65
    - Tyrosine decarboxylase (TyrDC), present in gut microbes, converts L-dopa into dopamine, which does not cross the blood-brain barrier and accumulates in the gut, causing many side effects such as cardiac arrhythmias and nausea.
    - levodopa can be metabolized by Clostridium sporogenes to 3-(3,4-dihydroxyphenyl) propionic acid (DHPPA), a metabolite that inhibits muscle contraction in the ileum, reduces intestinal movement, and impairs absorption in the small intestine.
  • [1.66
    - The relative abundance of Enterobacteriaceae is positively associated with the severity of postural instability and gait difficulty.
  • [1.67
    - The gastrointestinal tract is the major site for L-dopa decarboxylation
    - L-dopa > decarboxylation > generation of dopamine in the periphery > cannot cross the blood-brain barrier and causes unwanted side effects.
    - L-dopa is coadministered with drugs that block peripheral metabolism, including the AADC inhibitor carbidopa.
    - Even with carbidopa, up to 56% of L-dopa fails to reach the brain.
    - Enterococcus faecalis (enzyme (PLP-dependent tyrosine decarboxylase or TyrDC)) consume dopamine > producing meta-tyramine as a by-product > may contribute to some of the noxious L-dopa side effects.
    - carbidopa may not be able to penetrate the microbial cells or the slight structural variance could prevent the drug from interacting with the bacterial enzyme.
  • [1.68
    - Gut-to-brain propagation of pathologic α-synuclein via the vagus nerve causes PD
    - Dopamine neurons degenerate in the pathologic α-synuclein gut-to-brain model of PD
    - Gut injection of pathologic α-synuclein causes PD-like motor and non-motor symptoms
    - PD-like pathology and symptoms require endogenous α-synuclein.
  • [1.69
    - The relative abundance of mucin-degrading Verrucomicrobiae and LPS-producing Gammaproteobacteria were greater in PD patients.
    - Severe patients exhibited elevated levels of Verrucomicrobiae.
    - High levels of Verrucomicrobiae in the severe PD may increase intestinal leakiness, facilitating translocation of luminal LPS to the enteric nervous system or systemic circulation.
    - Systemic LPS has been linked to intestinal inflammation, which in turn is associated with enteric Thy1-αSyn aggregation.

Common References