Research feed 
Overview 
Microbiome Signature 
Interventions 
Research Feed 
Update History 
References 2024-11-11 15:04:47
Signature Added majorParkinson\'s Disease Microbiome Signature Added
Parkinson’s Disease
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Kimberly Eyer
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Kimberly Eyer
Kimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.
Parkinson’s disease (D) is a neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway, leading to progressive hypokinetic movements [1], and a range of non-motor symptoms including gastrointestinal (I) dysfunction [2]. Emerging evidence suggests that the gut microbiome may influence D through the gut–brain axis. D is one of the […]
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Karen Pendergrass
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Kimberly Eyer
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
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Kimberly Eyer
ID
Kimberly Eyer
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
Overview
Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway, leading to progressive hypokinetic movements [1], and a range of non-motor symptoms including gastrointestinal (GI) dysfunction [2]. Emerging evidence suggests that the gut microbiome may influence PD through the gut–brain axis. PD is one of the most common neurodegenerative disorders, affecting approximately 1 million people in the United States. The incidence rate is about 20 cases per 100,000 persons per year, equating to around 60,000 new cases annually. The prevalence of PD is about 1% in individuals aged 60 years and older, increasing to 1-3% in those aged 80 and above [3].
Causes
The disease predominantly affects individuals over 50 years of age. Its etiology includes various factors such as environmental toxins, genetic mutations, and comorbid conditions like manganese intoxication, basal ganglia calcification, brain tremors, strokes, microbiome dysbiosis, and viral infections.
What is the role of the Microbiome in Parkinson’s Disease?
The microbiome signature in PD is characterized by distinct changes in gut bacterial composition, which can influence disease pathogenesis through mechanisms like inflammation, neurotransmitter production, and alpha-synuclein pathology. Understanding these interactions opens new avenues for diagnosis and treatment, emphasizing the importance of the gut-brain axis in neurodegenerative diseases. Research indicates that alterations in the gut microbiome may influence neuroinflammatory and neurodegenerative processes associated with PD. Key points include:
Gut-Brain Axis
The gut-brain axis is a bidirectional communication system between the gastrointestinal tract and the central nervous system. The gut microbiome can affect brain function and behavior through various mechanisms, including the production of neurotransmitters, modulation of immune responses, and influence on the permeability of the gut and blood-brain barriers.
Dysbiosis in PD Patients
Studies have shown that PD patients often exhibit distinct changes in their gut microbiome composition compared to healthy individuals. Common findings include:
Reduction in Beneficial Bacteria: Decreased levels of bacteria such as Prevotella and short-chain fatty acid (SCFA) producers, which are essential for gut health and have anti-inflammatory properties.
Increase in Pathogenic Bacteria: Elevated levels of potentially harmful bacteria, such as Enterobacteriaceae, which may contribute to increased intestinal permeability and inflammation.
Mechanisms Linking Microbiome and PD
Inflammation: Dysbiosis may lead to increased gut permeability, allowing bacterial endotoxins to enter the bloodstream and trigger systemic inflammation. This inflammation can extend to the brain, contributing to neuroinflammation and the degeneration of dopaminergic neurons.
Neurotransmitter Production: The gut microbiome can influence the production of neurotransmitters like dopamine and serotonin. Alterations in these microbial populations can affect the synthesis and regulation of these critical neurotransmitters, potentially exacerbating PD symptoms.
Alpha-Synuclein Pathology: Misfolded alpha-synuclein proteins, a hallmark of PD, may originate in the gut and propagate to the brain via the vagus nerve. Gut microbiota might influence the aggregation and spread of alpha-synuclein.
What other mechanisms are implicated in the pathogenesis of Parkinson’s Disease?
| Mechanisms | Findings |
| MPTP Mechanism | In the nigrostriatal pathway, MPTP, a compound homologous to dopamine, is transported by the dopamine transporter (DAT) to the presynaptic neuron. In the synaptic cleft, MPTP is converted to MPP+ in the presence of monoamine oxidase B (MOA-B). MPP+ replaces dopamine in the synaptic cleft, is reabsorbed by DAT, stored in vesicles, and inhibits the electron transport chain (ETC) in mitochondria, particularly affecting complex II. This inhibition leads to decreased ATP production and neuronal degeneration. [4] |
| Reactive Oxygen Species (ROS) | Oxidative stress significantly contributes to dopaminergic neuron degeneration. The brain, consuming 20% of the body’s oxygen supply, generates ROS during oxygen metabolism. These ROS, in the presence of MAO-A and MAO-B, metabolize dopamine into neurotoxic quinones. Post-mortem analyses reveal increased cysteinyl adducts of dopamine in the substantia nigra of PD patients, indicating accelerated oxidation. [5] |
| Alpha-Synuclein | Alpha-synuclein is a presynaptic neuronal protein encoded by the SNCA gene, playing a role in synaptic vesicle transport and neurotransmitter release. Mutations in SNCA lead to misfolding of alpha-synuclein into an amyloid form, forming Lewy bodies—hallmarks of PD pathology. These protein aggregates disrupt dopamine vesicles, contributing to oxidative stress and neuronal degeneration. [6][7] [8] |
| Genetic Mutations | Mutations in genes such as LRRK2, PARK7, PINK1, PRKN, and SNCA are also implicated in the pathogenesis of PD. [5] |
Microbiome Signature: Parkinson’s Disease
Interventions
The section covers interventions for Parkinson’s Disease, such as pharmacological treatments, drug repurposing treatments, supplements, and dietary adjustments.
Drug Repurposing
Researchers in the field of drug repurposing have discovered that both creatine and minocycline offer neuroprotective affects in parkinsonism showed promise for phase 3 trials, focusing on safety, tolerability, activity, and cost.
What repurposed drugs have been investigated as treatment options for Parkinson’s Disease?
| Repurposed Drugs | Findings |
| Minocycline (Pre-Clinical Trials) | Several animal models have demonstrated the neuroprotective effects of minocycline in parkinsonism. In one study, 8-week-old male mice with iNOS deficiency received four intraperitoneal injections of MPTP-HCl. Minocycline treatment increased the survival of TH-positive neurons in the substantia nigra pars compacta (SNpc) and induced interleukin-1β formation, suggesting microglial anti-inflammatory actions play a crucial role in mitigating MPTP neurotoxicity. [9] Another in-vivo study with mesencephalic and cerebellar granule neurons (CGN) showed that minocycline inhibits MPP+-induced iNOS expression and NO-induced neurotoxicity. Minocycline also blocked NO-induced phosphorylation of p38 MAPK, with the p38 MAPK inhibitor SB203580 preventing NO toxicity in CGN. [10] |
| Minocycline (Clinical Trials) | A randomized, double-blind phase 2 clinical trial prioritized creatine and minocycline for PD treatment, involving 195 participants diagnosed with PD within five years who did not require medication for symptom management. The primary outcome measured was the change in the Unified Parkinson’s Disease Rating Scale (UPDRS) score over 12 months or until symptomatic PD therapy was needed. Participants were randomly assigned to creatine (10 g/day), minocycline (200 mg/day), or a placebo. The threshold was set at a 30% reduction in UPDRS progression, with p-values ≤0.1. [11] |
Non-Pharmacological
Modulating the gut microbiome through probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation (FMT) could offer novel therapeutic strategies for managing PD symptoms and potentially slowing disease progression.
Research Feed
The therapeutic role of minocycline in Parkinson’s disease
February 18, 2019
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Brain Health •
Brain Health
Did you know?
The gut microbiome produces over 90% of the body’s serotonin, a key neurotransmitter that regulates mood, sleep, and cognition.
The review by Cankaya et al. explores minocycline’s neuroprotective potential in Parkinson's disease (PD), highlighting its anti-inflammatory, antioxidant, and anti-apoptotic effects. While preclinical studies show promising neuroprotective results, clinical trials have yet to confirm its efficacy in slowing PD progression. The review emphasizes the need for further research to validate minocycline as a therapeutic agent for PD and other neurodegenerative disorders.
What Was Reviewed?
The review focused on the potential therapeutic role of minocycline, a semisynthetic tetracycline-derived antibiotic, in Parkinson’s disease (PD). It encompassed both preclinical and clinical studies to evaluate minocycline’s neuroprotective effects and its mechanisms of action in various experimental models of neurodegenerative diseases, including cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), multiple sclerosis (MS), and specifically Parkinson’s disease (PD).
Who Was Reviewed?
The review analyzed data from multiple sources, including:
Animal Models: Various in vivo and in vitro studies were conducted on rodents and other animals to observe the neuroprotective effects of minocycline.
Clinical Trials: Human studies, including randomized, double-blind clinical trials, that assessed the efficacy of minocycline in treating PD and other neurodegenerative disorders.
Literature Reviews: Retrospectively recorded results from studies available on databases such as PubMed, Scopus, and ISI Web of Science, focusing on keywords like “minocycline and Parkinson’s disease,” “minocycline and neuroprotection,” “minocycline,” and “neurodegeneration.”
Most Important Findings
Anti-Inflammatory Effects: Minocycline modulates microglia activation, reduces the release of proinflammatory cytokines, and inhibits pathways leading to neuroinflammation. This helps in attenuating neuroinflammation, a critical aspect of PD pathogenesis.
Antioxidant Effects: The drug reduces oxidative stress by inhibiting the production of reactive oxygen species (ROS) and stabilizing mitochondrial function.
Anti-Apoptotic Effects: Minocycline inhibits apoptotic pathways by stabilizing mitochondrial membranes, reducing the release of cytochrome c, and modulating the expression of B-cell lymphoma 2 (Bcl-2) proteins, thereby preventing neuronal cell death.
Efficacy in Experimental Models:
Parkinson’s Disease Models: In MPTP and 6-OHDA-induced PD models, minocycline reduced dopaminergic neuron degeneration and improved behavioral deficits.
Other Neurodegenerative Models: Minocycline demonstrated neuroprotective effects in models of ALS, HD, and MS by inhibiting microglial activation and reducing neuronal death.
Greatest Implications
The therapeutic role of minocycline in Parkinson’s disease as a Potential Neuroprotective Agent: Despite mixed results in clinical trials, the extensive preclinical data support the potential of minocycline as a neuroprotective agent that could modify disease progression in PD and possibly other neurodegenerative diseases. This highlights the need for further research and well-designed clinical trials to determine its efficacy conclusively.
Mechanistic Insights: The review provides a comprehensive understanding of the mechanisms through which minocycline exerts its effects, such as anti-inflammatory, antioxidant, and anti-apoptotic pathways. This knowledge could be pivotal in developing targeted therapies for neurodegenerative diseases.
Future Research Directions: The findings underline the importance of exploring combination therapies that might enhance the efficacy of minocycline. Additionally, investigating different dosing regimens, treatment durations, and patient populations could yield more definitive results regarding its therapeutic potential.
Broader Implications for Neurodegenerative Diseases: The review suggests that minocycline's therapeutic benefits might extend beyond PD to other conditions like ALS, HD, and MS, making it a promising candidate for broader neuroprotective applications.
Update History
Drug Repurposing
Drug repurposing involves identifying new therapeutic uses for existing drugs, offering a cost-effective and time-efficient pathway to enhance treatment options and address unmet medical needs.
Fecal Microbiota Transplantation (FMT)
Fecal Microbiota Transplantation (FMT) involves transferring fecal bacteria from a healthy donor to a patient to restore microbiome balance.
References
- Diet and the gut microbiome in patients with Parkinson’s disease. . Kwon, D., Zhang, K., Paul, K.C. et al. . (Parkinsons Dis. (April 22, 2024))
- Parkinson’s disease and its management: Part 1: Disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis.. DeMaagd G, Philip A.. (Pharm Ther 40:504 Dementia (n.d.) (2015))
- The MPTP story.. Langston JW.. (J Parkinsons Dis 7:S11. (2017))
- The role of oxidative stress in Parkinson’s disease.. Dias V, Junn E, Mouradian MM.. (J Parkinsons Dis 3:461. (2013))
- α-Synuclein in Parkinson’s disease.. Stefanis L.. (https://doi.org/10.1101/CSHPERSPECT.A009399)
- Alpha-Synuclein aggregation in Parkinson’s disease.. Srinivasan E, Chandrasekhar G, Chandrasekar P et al.. (Front Med 8. (2021))
- The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates.. Wakabayashi K, Tanji K, Mori F, Takahashi H.. (Neuropathology 27:494–506. (2007))
- The role of oxidative stress in Parkinson’s disease.. Dias V, Junn E, Mouradian MM.. (J Parkinsons Dis 3:461. (2013))
- Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.. Wu DC, Jackson-Lewis V, Vila M et al.. (J Neurosci (2002))
- Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease.. Du Y, Ma Z, Lin S et al.. (Proc Natl Acad Sci (2001))
- A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease.. Ravina B, Kieburtz K, Tilley B et al.. (Neurology 66:664–671. (2006))
Kwon, D., Zhang, K., Paul, K.C. et al.
Diet and the gut microbiome in patients with Parkinson’s disease.Parkinsons Dis. (April 22, 2024)
DeMaagd G, Philip A.
Parkinson’s disease and its management: Part 1: Disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis.Pharm Ther 40:504 Dementia (n.d.) (2015)
Dias V, Junn E, Mouradian MM.
The role of oxidative stress in Parkinson’s disease.J Parkinsons Dis 3:461. (2013)
Srinivasan E, Chandrasekhar G, Chandrasekar P et al.
Alpha-Synuclein aggregation in Parkinson’s disease.Front Med 8. (2021)
Wakabayashi K, Tanji K, Mori F, Takahashi H.
The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates.Neuropathology 27:494–506. (2007)
Dias V, Junn E, Mouradian MM.
The role of oxidative stress in Parkinson’s disease.J Parkinsons Dis 3:461. (2013)
Wu DC, Jackson-Lewis V, Vila M et al.
Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.J Neurosci (2002)
Du Y, Ma Z, Lin S et al.
Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease.Proc Natl Acad Sci (2001)
Ravina B, Kieburtz K, Tilley B et al.
A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease.Neurology 66:664–671. (2006)