Disease ⇒ Parkinson’s Disease {40000200}
| Type: | Disease |
|---|---|
| Parent: | [ ] |
| Definition: | Parkinson’s Disease |
| Initialisation date: | 2021-02-05 |
|---|---|
| Other Terms: | PD |
| 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 Reference Notes
- [1.1]
- [1.2]
- 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 - [1.3] [#Inflamatory bowel disease]
- Patients with inflammatory bowel disease are more likely to develop Parkinson disease. - - 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.
- [1.4]
- Overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus. - [1.5]
- 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. - [1.6]
- FABP6 (fatty acid binding protein 6) is the intracellular bile acid transporter which returns bile acids to enterohepatic circulation. - In Parkinson’s 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. - [1.7]
- 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. - [1.8]
Toxic Bile acids produced by specifics Clostridium species may predispose to PD - [1.9]
- 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 - - 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
- [1.11]
- Increase of D-Laktat und Glykolat has amelorative effects on Parkinson’s disease. - D-Laktat is produced by lactobacillus bulgaricus. - [1.12]
- 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 - [1.13]
- 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 - [1.14]
- 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. - [1.15]
- #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. - [1.16]
- 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. - [1.17] [#L-Dopa]
- [1.18]
- [1.19] [#Caenorhabditis elegans]
- [#Proteus mirabilis]
- [1.21] [#Lipopolysaccharide]
- [1.22]
- [1.23]
- [1.24]
- [1.25]
- [1.26] [#Escherichia coli]
- 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. - [1.27]
- 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 - - 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
- [#Bilophila wadsworthia] - B. Wadsworthia > large quantities in PD patients > increased #Sulfite production in the intestine. - #Sulfite > neurotoxin > mediates the mitochondrial energy balance of the brain
- - #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.
- [#Enterococcaceae] - Increased Enterobacteriaceae > Postural instability in PD patients.
- - 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
- - Gut Microbiota > produce #Polyphenol > protect against neurological diseases with α-syn toxicity
- - Decreased #Prevotella > faster PD progression
- [1.28]
- [1.29]
- #Serotonin > protective factor of PD - [#Helicobacter pylori]
- [1.31]
- 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. - [1.32]
- [1.33]
- 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. - [#Alzheimer’s disease] - #Tryptophan metabolites can cross the blood-brain barrier > activate #AHR to regulate astrocytes and reduce central nervous system inflammation in AD and PD
- [#Bifidobacterium adolescentis] - PD patients, showing an increase in #Akkermansia, Bifidobacterium, and #Lactobacillus and a decrease in #Prevotella
- [#Short Chain Fatty Acid] - The onset age of PD is directly proportional to the SCFA level, suggesting that SCFAs may have a protective effect on PD
- [1.34]
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. - [1.35]
- 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. - [1.36]
- [1.37]
- 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 - - 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)
- [#Antibiotic Therapy] - 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.
- - 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
- [#Lipopolysaccharide] - 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
- [1.38]
- [1.39] [#Diabetes Type 2] [#Oral administration of Metformin]
- #Metformin reduces neuronal damage in the brains of PD patients via neuroprotection and the inhibition of oxidative stress and inflammatory responses, thus providing a novel strategy for the clinical treatment of 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
- - #Alpha-1-antitrypsin and #Zonulin are markers of intestinal hyperpermeability in PD
- [#Alpha-synuclein] - 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
- - #Aquabacterium, #Peptococcus, and #Sphingomonas are associated with motor complications in PD
- - #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
- - 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
- - 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.
- - 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
- [1.41]
- #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. - [1.42]
- [1.43] [#Butyrate, #Indole-3-propionic acid, #Short Chain Fatty Acid]
- in PD Patient > Fecal SCFA levels of butyric acid, #Valeric acid and propionic acid are reduced, whereas plasma levels were higher. - in PD Patient > Low fecal concentration of most SCFAs > increased plasma propionic acid concentration > More severe motor impairment - in PD Patient > Low fecal levels of butyric acid and higher plasma concentrations of butyric acid and #Valeric acid > More serious cognitive symptoms. - PD patient group, the abundance of proinflammatory microbes, such as #Clostridiales bacterium NK3B98 and #Ruminococcus sp AM07-15, significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially #Propionic acid.
- [1.44]
- 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. - [1.45]
- lower fecal #Butyrate and reduced counts of genera #Roseburia, #Romboutsia, and #Prevotella are related to depressive symptoms in PD patients. - Decreased levels of bacterially produced #Butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. - [1.46]
- positive correlation between #Enterobacteriaceae abundance and the motor phenotype, particularly postural instability and gait alterations - - greater prevalence of #Helicobacter pylori infection in patients with PD and poorer clinical status in patients with the infection; H. pylori eradication was found to be associated with clinical improvement.
- - In patients with PD > decrease in the abundance of hydrogen-producing bacteria and lower serum decrease in the abundance of hydrogen-producing bacteria and lower serum #Lipopolysaccharide-binding protein levels, which suggests greater intestinal permeability to this #Lipopolysaccharide-binding protein levels in patients with PD, which suggests greater intestinal permeability to this #Lipopolysaccharide
- [1.47]
- [1.48] [#Alzheimer’s disease, #Multiple Sclerosis] [#Short Chain Fatty Acid]
- SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of Neuro-Degenerative Diseases and cognitive decline by regulating inflammation and oxidative stress. - SCFAs functions as a cofactor for the host’s mitochondrial enzymes. - The properties of SCFAs depend on the G-protein coupled receptors (GPCR), histone deacetylases (HDAC) & peroxisome proliferator-activated receptor gamma (PPARγ) and regulatory T cells (Tregs) activation. - [1.49]
- PD patients may show altered levels of blood proinflammatory cytokines, which are signaling molecules released by immune cells such as helper T cells (Th) and macrophages. - enhanced levels of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 8 (IL-8) have been found in PD patients. - elevated levels of chemokine C–X3–C motif ligand 1 (CX3CL1) have been reported in PD. - [#Vitamin D deficiency] - lack of #Vitamin D also leads to central loss of dopaminergic neurons, as well as delayed gastric emptying in PD
- - an abundance of #Bacteroides (Gram-negative bacteria present in the gut microbiome) is associated with the severity of motor symptoms in PD
- - Other possible inflammatory markers of PD are #Calprotectin and #Zonulin. - The first is a marker of inflammation, while the second is a junction protein, which, if modulated by proinflammatory signals (e.g., LPS), can lead to an increase in intestinal membrane permeability. - both fecal and serum levels of #Calprotectin and #Zonulin are elevated in patients with PD
- - #Vitamin B6 is a critical cofactor for a wide range of biochemical reactions, including the synthesis of #Dopamine. - #Vitamin B6 intake was associated with a reduced risk of developing PD.
- [#Keto diet] - Ketogenic Diet increases ketone bodies and reduces oxidative stress brought on by excessive ROS. Evidence from animal models of PD showed promise, as ketone bodies acted neuroprotectively and improved motor skills.
- [#Lactobacillus] - most PD patients (about 70% of patients) develop gastrointestinal disorders such as constipation, dysphagia, and gastroesophageal reflux. Strikingly, these gastrointestinal dysfunctions (particularly constipation and delayed gastric emptying) can be detected up to 20 years prior to PD diagnosis. - reduction in their number of #Prevotellaceae bacteria compared to controls. Strikingly, this alteration was associated with the severity of the motor symptoms. - PD patients may exhibit not only a decreased abundance of Prevotella but also an increased abundance of Lactobacilliceae. - These alterations may be associated with reduced levels of #Ghrelin, an important gut hormone involved in the survival and efficacy of dopaminergic neurons.
- [#Lipopolysaccharide] - high serum LPS levels in PD patients can reflect altered intestinal permeability already in the early stages of the disease. - animal models of PD > administration of LPS (stereotaxic, systemic, or intranasal) can reproduce the specific motor features of PD. - LPS-elicited neurotoxicity in PD. - Altered levels of LPS can, in turn, activate Toll-like receptors (TLRs), a family of receptors that constitute a sort of immune system against bacteria. Overstimulation of this system may provoke proinflammatory reactions, as well as enteric neuroglial activation, eventually eliciting α-Syn pathology
- [#Omega 3] - high omega-3 PUFA intake has been associated with lower risk PD risk
- - #Smoking is associated with a reduced risk of developing PD as tobacco may regulate striatal activity through the dopaminergic system
- - higher #Vitamin E intake may be associated with a reduced risk of developing PD
- [#Western-style diet] - in a mouse model > a high-energy diet such as the Western diet led to decreased parasympathetic functioning and α-Syn accumulation in the brainstem
- [1.51] [#Alpha-synuclein]
- [1.52]
- [1.53]
- Paper spray ionization mass spectrometry (PS-MS), which allows the direct analysis of compounds from paper, has previously been demonstrated to detect small molecules (50–800 Da) from unprocessed biofluids such as blood, urine, and CSF, (13−16) but not to date with sebum. - [1.54]
- decreased genera (Roseburia, Faecalibacterium, Blautia, Lachnospira, and Prevotella) and five increased genera (Streptococcus, Bifidobacterium, Lactobacillus, Akkermansia, and Desulfovibrio) in PD. - [1.55]
- #Tryptophan, an essential amino acid only derived from microbiome or diet, is the rate limiting precursor to #Serotonin. #Tryptophan biosynthesis pathway was reduced in PD. - spore forming bacteria modulate #Serotonin production and enhance gut motility - #Constipation, a common symptom of PD, may be related to the depletion of spore forming bacteria. - - PD is not one disease, and each disease mechanism may have a different microbiome signature.
- Blautia, Faecalibacterium, Fusicatenibacter, Roseburia and Ruminococcus, are reduced in PD, and Bifidobacterium, Hungatella, Lactobacillus, Methanobrevibacter and Porphyromonas, are elevated in PD
- - At one end of the spectrum, #Bifidobacterium dentium was elevated by 7-fold, #Actinomyces oris by 6.5-fold, #Streptococcus mutans by 6-fold. At the other end of the spectrum, #Roseburia intestinalis was reduced by 7.5-fold, and #Blautia wexlerae by 5-fold.
- - #Curli, an amyloidogenic protein produced by Gram-negative Escherichia coli, induces #Alpha-synuclein aggregation and accelerates disease in the gut and neurodegeneration in the brain. - Many Enterobacteriaceae species encode #Curli.
- - #Alpha-synuclein fibrils injected into gut induce #Alpha-synuclein pathology which spreads from gut to brain, and that #Vagotomy stops the spread. - persons who had complete truncal #Vagotomy decades earlier had substantially reduced incidence of PD later in life
- - #Bifidobacterium and #Lactobacillus species, which are common constituents of commercial probiotics, were more abundant in PD than NHC metagenomes.
- - elevated levels of #Tyrosine decarboxylase/aspartate 1-decarboxylase gene-family, which removes #Tyrosine, a required precursor of #Dopamine.
- - #Enterococcus faecium and #Enterococcus faecalis tdc genes metabolize L-dopa efficiently, and their abundance in the gut correlates directly with reduced efficacy of L-dopa for the patient. - the species, E. faecium and E. faecalis, were elevated in PD.
- [#Lipopolysaccharide] - of the 29 species that are reduced in PD, only 1 is a canonical Gram-negative organism, #Prevotella copri, which interestingly, produces an LPS that not only does not induce inflammation, but can inhibit TLR4 activation by others. - Eleven of the 55 species that are enriched in PD are canonical Gram-negative organisms including those with highly stimulatory LPS (#Escherichia coli, #Klebsiella species, and #Porphyromonas asaccharolytica).
- - #Firmicutes enrichment as the primary driving force, and depletion of #Prevotella as secondary as it remained significant after removing #Firmicutes.
- - In the PD metagenome, we noted a decrease in #Glutamate/glutamine synthesis gene-families and pathways, and a concomitant increase in both #Glutamate and #GABA degradation.
- - increases in gene-families involved in the synthesis of #Lipoteichoic acid (LTA), a component of Gram-positive bacteria cell envelope which shares many of the pathogenic properties of LPS.
- [#Mucin glycans] - the upregulated #Threonine pathway, utilize protein sources derived from diet or the host, including mucin. Mucin is an important component of the protective gut mucus layer. Increased capacity to degrade host mucin raises the possibility that the gut microbiome contributes to the degradation and increased permeability of the gut barrier in PD
- [#Murein/bacterial lipoprotein (BLP)] - enrichment in PD of murein/bacterial lipoprotein (BLP) gene-family [lpp] K06078. - BLP is highly immune stimulatory by triggering inflammatory TLR2 signaling
- [#Nicotinamid] - two-fold increase in the nicotinamidase gene family, suggesting the PD gut microbiome degrades this neuroprotective molecule.
- - PD metagenome was enriched in glycogen metabolism pathway, suggesting an enrichment in bacteria with a preference for #Non-plant-based polysaccharides.
- [#Prevotella copri] - #Prevotella has been reported as decreased in PD by some and increased by others. - #Prevotella copri was decreased, and the pathogenic species of #Prevotella were increased as a group, confirming, and resolving the seemingly contradictory reports on #Prevotella.
- [#Short Chain Fatty Acid] - PD > a dramatic ~2.5-fold reduction for several SCFA producing species, and as much as 5 to 7.5 fold reduction in #Roseburia species.
- - Circulating levels of #TMAO, a gut microbiome derived oxidation product of #TMA, are reportedly elevated in PD and correlate with disease progression and severity. Gene families involved in #TMA production were elevated in PD, including cutC (choline lyase) which cleaves choline to produce #TMA , and caiT (L-carnitine/gamma-butyrobetaine antiporter) which exchanges carnitine for gamma-butyrobetaine before #TMA can be produced.
- - The disaccharide #Trehalose has garnered significant interest as a therapeutic molecule in PD and other neurodegenerative diseases- . This is likely due to its activities on autophagocytic pathways which limit the accumulation of pathogenic alpha-synuclein and other protein aggregates. - two-fold increase was observed in the PD metagenome of the #Trehalose degradation pathway - increased metabolism of #Trehalose by bacteria, a potential outcome of which is reduced availability of #Trehalose for the host.
- [1.56] [#Covid-19] [#Alpha-synuclein]
- overexpression of α-synuclein in PD patients may limit SARS-CoV-2 neuroinvasion and degeneration of dopaminergic neurons; however, on the other hand, this virus can speed up the α-synuclein aggregation. - [1.57] [#Antibiotic Therapy]
-The strongest connection with PD risk was found for oral exposure to macrolides and lincosamides - exposure to antianaerobics and tetracyclines 10 to 15 years before the index date, sulfonamides and trimethoprim 1 to 5 years before the index date, and antifungal medications 1 to 5 years before the index date were positively associated with PD risk. - [1.58]
- The relative abundance of Enterobacteriaceae is positively associated with the severity of postural instability and gait difficulty. - [1.59]
- - PD > increased relative abundance of family Enterobacteriaceae, genera #Akkermansia, #Lactobacillus, #Bifidobacterium. - PD > decreased relative abundance of family #Lachnospiraceae, #Faecalibacterium
- [#Lipopolysaccharide] - LPS can activate microglia and promote neurodegeneration
- [1.61]
- [1.62] [#Dementia with Lewy bodies (DLB)] [#Short Chain Fatty Acid]
- short-chain fatty acids-producing genera were decreased in DLB. - #Ruminococcus torques and #Collinsella were increased in DLB, which were not changed in PD. - high #Ruminococcus torques and high #Collinsella, which presumably increase intestinal permeability, as well as low #Bifidobacterium, which are also observed in #Alzheimer’s disease, were predictive of DLB. - [1.63]
- [1.64]
- [1.65]
- enhancing mitophagy promotes the survival of dopaminergic neurons. - #Probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage - [1.66] [#Fecal Microbiota Transplantation]
- Colonic FMT > improvement and longer maintenance of efficacy compared with nasointestinal. Two patients achieved self-satisfying outcomes that last for more than 24 months. - The score of PSQI, HAMD, HAMA, PDQ-39, NMSQ and UPDRS-III significantly decreased at 1 month after FMT. - The quality of sleep and life improved after FMT treatment. - anxiety and depression were also partially relieved. - [1.67] [#Alzheimer’s disease, #Multiple Sclerosis]
- [1.68] [#Multiple Sclerosis]
- microbial dysbiosis showed the highest similarity between the two diseases, MS and PD - - #Spermidine was significantly reduced in cerebrospinal fluid (CSF) of patients with PD and #Multiple system atrophy (MSA)
- - In the case of PD, the concentrations of #Putrescine, #N1-acetylspermidine, and #Putrescine #Spermidine-1 were found to be increased.
- [1.69] [#Alpha-synuclein]
- - higher tissue #Polyamine levels have been reported in various diseases like #Dementia due to #Alzheimer’s disease (AD), Parkinson’s disease, #Cancer, and mental disorders like #Depression.
- [1.71] [#Clostridium clusters XIVa]
- elevated levels of #Anaerotruncus spp., Clostridium XIVa, and #Lachnospiraceae in Parkinson’s disease patients were associated with dyskinesia symptoms in Parkinson’s disease patients, while elevations in #Akkermansia were associated with non-motor impairments in Parkinson’s disease patients - - #Butyricicoccus and #Clostridium XIVb were significantly elevated in Parkinson’s disease patients > cognitive dysfunction
- [1.72] [#Inflamatory bowel disease] [#Akkermansia muciniphila] [#Antibiotic Therapy]
- Conditions like inflammatory bowel disease (IBD), #Salmonella typhimurium infection or post-antibiotic reconstitution may not benefit from #Akkermansia supplementation. - using #Akkermansia in patients with endocrine and gynecological disorders—such as #Polycystic ovary syndrome (PCOS) or #Endometriosis—that have a higher risk of developing IBD, should be critically evaluated. - the gut microbiota of patients suffering from Parkinson’s disease or #Multiple Sclerosis exhibits a characteristic signature of #Akkermansia municiphila abundance. - [1.73]
The potential neuroprotective effects of #Progesterone were then analyzed in this system. Treatment of cultured ENS neurons with #Progesterone reduced cell death by 45%, underscoring the tremendous neuroprotective potential of #Progesterone in the ENS. - [1.74]
- 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. - [1.75] [#Idiopathic rapid-eye-movement sleep behavior disorder]
- [1.76]
- 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. - [1.77]
- 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.
References Notes
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