Parkinson's Disease and gut microbiome - several studies

Strong association, unknown cause-affect direction

Note: Vitamin D massively changes the composiition of gut bacteria

• Vitamin D levels change Gut Microbiota – 25 study review Sept 2021
• Gut microbiome massively changed by weekly vitamin D – July 2015

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Those with PD have 7X higher/lower amounts of certain gut bacteria - Nov 2022

Parkinson's Disease May Start in the Gut and Spread to the Brain Trial Site News

• "For example, the bacterial species (Bifidobacterium dentium), which is known to cause anaerobic infections such as brain abscesses, were found to be elevated seven-fold in those with Parkinson's and a 7.5-fold reduction in the bacteria such as Roseburia intestinalis which is known to be inhabitant of healthy colons (constipation is a recognized symptom of Parkinson's) was also detected

Study = Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms - https://doi.org/10.1038/s41467-022-34667-x
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Perspective on pathogenesis and treatment (Butyrate may help) - Nov 2022

Gut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment
Journal of Advanced Research Nov 2022 https://doi.org/10.1016/j.jare.2022.10.013

PDF Table of Contents

Highlights

• The crosstalk between the gut and the brain serves as a route for the spread of PD pathology in a bottom-up or top-down manner.
• Gut dysbiosis is evident in PD patients and animal models and is associated with alterations in gut-derived microbial products and immune pathways promoting disease pathology.
• Diet induces changes in the GM, with western diet evoking and Mediterranean diet preventing neuroinflammation and neurodegeneration associated with PD.
• Gut-derived microbial products can be involved in the regulation of the immune system, the inflammation of both the intestine and the brain, and the integrity of intestinal epithelium and blood–brain barrier (BBB).
• Therapeutic strategies that function by reversing gut dysbiosis and mitochondrial dysfunction may prove beneficial to treat PD pathology.

Background
Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain.

Aim
of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved in neuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further explored in humans through clinical trials.

Key Scientific Concepts of Review:
Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
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New insights from meta-analysis - Jan 2022

Gut microbiome in Parkinson's disease: New insights from meta-analysis
Parkinsonism & Related Disorders Vol 94, Jan 2022, Pages 1-9 https://doi.org/10.1016/j.parkreldis.2021.11.017 PDF behind paywall

Background
Gut microbiome alterations have been reported in Parkinson's disease (PD), but with heterogenous findings, likely due to differences in study methodology and population. We investigated the main microbiome alterations in PD, their correlations with disease severity, and the impact of study and geographical differences.

Methods
After systematic screening, raw 16S rRNA gene sequences were obtained from ten case-control studies totaling 1703 subjects (969 PD, 734 non-PD controls; seven predominantly Caucasian and three predominantly non-Caucasian cohorts). Quality-filtered gene sequences were analyzed using a phylogenetic placement approach, which precludes the need for the sequences to be sourced from similar regions in the 16S rRNA gene, thus allowing a direct comparison between studies. Differences in microbiome composition and correlations with clinical variables were analyzed using multivariate statistics.

Results
Study and geography accounted for the largest variations in gut microbiome composition. Microbiome composition was more similar for subjects from the same study than those from different studies with the same disease status. Microbiome composition significantly differed between Caucasian and non-Caucasian populations. After accounting for study differences, microbiome composition was significantly different in PD vs. controls (albeit with a marginal effect size), with several distinctive features including increased abundances of Megasphaera and Akkermansia, and reduced Roseburia. Several bacterial genera correlated with PD motor severity, motor response complications and cognitive function.

Conclusion
Consistent microbial features in PD merit further investigation. The large variations in microbiome findings of PD patients underscore the need for greater harmonization of future research, and personalized approaches in designing microbial-directed therapeutics.

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A cause or a consequence? - 2020

Chapter 11 - The gut microbiome in Parkinson's disease: A culprit or a bystander?
Progress in Brain Research Volume 252, 2020, Pages 357-450 https://doi.org/10.1016/bs.pbr.2020.01.004

Abstract
In recent years, large-scale metagenomics projects such as the Human Microbiome Project placed the gut microbiota under the spotlight of research on its role in health and in the pathogenesis several diseases, as it can be a target for novel therapeutical approaches. The emerging concept of a microbiota modulation of the gut-brain axis in the pathogenesis of neurodegenerative disorders has been explored in several studies in animal models, as well as in human subjects. Particularly, research on changes in the composition of gut microbiota as a potential trigger for alpha-synuclein (α-syn) pathology in Parkinson's disease (PD) has gained increasing interest. In the present review, we first provide the basis to the understanding of the role of gut microbiota in healthy subjects and the molecular basis of the gut-brain interaction, focusing on metabolic and neuroinflammatory factors that could trigger the alpha-synuclein conformational changes and aggregation. Then, we critically explored preclinical and clinical studies reporting on the changes in gut microbiota in PD, as compared to healthy subjects. Furthermore, we examined the relationship between the gut microbiota and PD clinical features, discussing data consistently reported across studies, as well as the potential sources of inconsistencies. As a further step toward understanding the effects of gut microbiota on PD, we discussed the relationship between dysbiosis and response to dopamine replacement therapy, focusing on Levodopa metabolism.
We conclude that further studies are needed to determine whether the gut microbiota changes observed so far in PD patients is the cause or, instead, it is merely a consequence of lifestyle changes associated with the disease. Regardless, studies so far strongly suggest that changes in microbiota appears to be impactful in pathogenesis of neuroinflammation. Thus, dysbiotic microbiota in PD could influence the disease course and response to medication, especially Levodopa. Future research will assess the impact of microbiota-directed therapeutic intervention in PD patients.

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Exploring human-genome gut-microbiome interaction in Parkinson’s disease - Aug 2021

Nature: npj Parkinson's Disease Vol 7, # 74 (2021) https://doi.org/10.1038/s41531-021-00218-2
Zachary D. Wallen, William J. Stone, Stewart A. Factor, Eric Molho, Cyrus P. Zabetian, David G. Standaert & Haydeh Payami

The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we found evidence that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. Results put forth testable hypotheses on the role of gut microbiome in the pathogenesis of PD, the incomplete penetrance of PD susceptibility genes, and potential triggers of pathology in the gut.
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VitaminDWiki - Overview Parkinson's and Vitamin D contains

• Vitamin D associated with Parkinson’s Disease in 55 studies, more studies needed- March 2022
• Parkinson's category has 117 studies
• Parkinson’s Disease and Vitamin D – review of 52 studies – May 2022
• Parkinson patients: 60 % taking Vitamin D – Dec 2019
• Low Vitamin D increases Parkinson's by 3X– July 2010 "only" a 30 year test, need more study
• Parkinson's disease prevented by Vitamin D, but small doses do not treat it - Aug 2023
• 10 clinical trials for PD with vitamin D intervention as of June 2023
• Parkinson’s Disease Summer School – alternative therapies included 60-80 ng of Vitamin D – Sept 2019
• Associated with PD are: Meta-analyses (12 ), Cognition (24 studies), Multiple Sclerosis (18 studies), VIRUS (4 studies), Omega-3 (3 studies), Vitamin D Receptor (11 studies)
• Note by the Founder of VitaminDWiki: I have twice recommended lots of Vitamin D to treat PD. Both got much better, but one had his doctor him cut back to just 2,000 IU. All of his recovery got reversed. With lots of vitamin D he could sing and bike, but now he can barely talk or walk

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VitaminDwiki – Microbiome category contains

Some of the 38 Microbiome articles

• Nutrients, Microbiome, and Chronic Diseases - April 2023
• Fecal transplants - many studies
• Healthy microbiota might reduce COVID-19 – several studies
• Poor absorption of Vitamin D is strongly related to type of gut bacteria – Dec 2020
• Vitamin D and the Host-Gut Microbiome: A Brief Overview– June 2020
• Parkinson's Disease and gut microbiome - several studies
• Vitamin D levels change Gut Microbiota – 25 study review Sept 2021
• Gut Microbiota: improved by Vitamin D – narrative review – July 2021
• Gut microbiome massively changed by weekly vitamin D – July 2015
• Also: Google Scholar on Microbiome includes:The cancer microbiome - June 2019, The Healthy Microbiome—What Is the Definition of a Healthy Gut Microbiome? - Jan 2021, The gut microbiome in neurological disorders - Feb 2020, Understanding the role of the gut microbiome in gastrointestinal cancer: A review -Jan 2023, The human microbiome and COVID-19: A systematic review - June 2021, *Interaction between drugs and the gut microbiome - July 2020