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Growing evidence indicates that persons with Parkinson disease (PD), have a unique composition of indigenous gut microbes. Given the long prodromal or pre-diagnosed period, longitudinal studies of the human and rodent gut microbiome before symptomatic onset and for the duration of the disease are currently lacking. PD is partially characterized by the accumulation of the protein α-synuclein (α-syn) into insoluble aggregates, in both the central and enteric nervous systems. As such, several experimental rodent and non-human primate models of α-syn overexpression recapitulate some of the hallmark pathophysiologies of PD. These animal models provide an opportunity to assess how the gut microbiome changes with age under disease-relevant conditions. Here, we used a transgenic mouse strain, which overexpress wild-type human α-syn to test how the gut microbiome composition responds in this model of PD pathology during aging. Using shotgun metagenomics, we find significant, age and genotype-dependent bacterial taxa whose abundance becomes altered with age. We reveal that α-syn overexpression can drive alterations to the gut microbiome composition and suggest that it limits diversity through age. Taxa that were most affected by genotype-age interaction were Lactobacillus and Bifidobacteria. In a mouse model, we showed direct link between alpha synuclein geneotype (hallmark of PD), a dysbiotic and low-diversity gut microbiome, and dysbiotic levels of Bifidobacteria and Lactobacillus (most robust features of PD microbiome). Given emerging data on the potential contributions of the gut microbiome to PD pathologies, our data provide an experimental foundation to understand how the PD-associated microbiome may arise as a trigger or co-pathology to disease., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All research conducted on animals was approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham. Consent for publication: All authors have read and approved the final manuscript for publication., (© 2025. The Author(s).)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) and the loss of dopaminergic neurons. Although microbial infection has been implicated in the pathogenesis of PD, the associated virulence factors and the underlying molecular mechanisms require further elucidation. Here, we found that intestinal infection with Nocardia farcinica induced a series of PD-like symptoms in Caenorhabditis elegans, such as the accelerated degeneration of dopaminergic neurons, impaired locomotion capacity, and enhanced α-syn aggregation, through the disturbance of mitochondrial functions. To identify the potential virulence factors involved in these effects, we knocked out the nbtB/C and nbtS genes in N. farcinica, which are localized in the gene clusters responsible for nocobactin biosynthesis. The deletion of either gene partially rescued the degenerative effects of wild-type N. farcinica on dopaminergic neurons by attenuating mitochondrial dysfunction. LC-MS analysis further identified a decrease in the abundance of several siderophores in the two mutants, including nocobactin NA-a, nocobactin NA-b, and nocardimicin B. Collectively, our results demonstrated that intestinal N. farcinica infection in C. elegans facilitates PD-like pathogenesis and provides novel evidence for the involvement of pathogenic bacteria in neurodegenerative diseases via non-neuroinvasive mechanisms., Competing Interests: Declarations. Ethics Approval: Not applicable to this study. Consent to Participate: Not applicable to this study. Consent for Publication: Not applicable to this study. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parkinson's disease is a progressive neurodegenerative disorder marked by the death of dopaminergic neurons in the substantia nigra region of the brain. Aggregation of alpha-synuclein (α-synuclein) is a contributing factor to Parkinson's disease pathogenesis. The objective of this study is to investigate the neuroprotective effects of gut microbes on α-synuclein aggregation using both in silico and in vivo approaches. We focussed on the interaction between α-synuclein and metabolites released by gut bacteria that protect from PD. We employed three probiotic microbe strains against α-synuclein protein: Lactobacillus casei, Escherichia coli, and Bacillus subtilis, with their chosen PDB IDs being Dihydrofolate reductase (3DFR), methionine synthetase (6BM5), and tryptophanyl-tRNA synthetase (3PRH), respectively. Using HEX Dock 6.0 software, we examined the interactions between these proteins. Among the various metabolites, methionine synthetase produced by E. coli showed potential interactions with α-synuclein. To further evaluate the neuroprotective benefits of E. coli, an in vivo investigation was performed using a rotenone-induced Parkinsonian mouse model. The motor function of the animals was assessed through behavioural tests, and oxidative stress and neurotransmitter levels were also examined. The results demonstrated that, compared to the rotenone-induced PD mouse model, the rate of neurodegeneration was considerably reduced in mice treated with E. coli. Additionally, histopathological studies provided evidence of the neuroprotective effects of E. coli. In conclusion, this study lays the groundwork for future research, suggesting that gut bacteria may serve as potential therapeutic agents in the development of medications to treat Parkinson's disease. fig. 1., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

With the recognition of the importance of the gut-brain axis in Parkinson's disease (PD) etiology, there is increased interest in developing therapeutic strategies that target α-synuclein, the hallmark abhorrent protein of PD pathogenesis, which may originate in the gut. Research has demonstrated that inhibiting the aggregation, oligomerization, and fibrillation of α-synuclein are key strategies for disease modification. Polyphenols, which are rich in fruits and vegetables, are drawing attention for their potential role in this context. In this paper, we reviewed how polyphenols influence the composition and functional capabilities of the gut microbiota and how the resulting microbial metabolites of polyphenols may potentially enhance the modulation of α-synuclein aggregation. Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome.

Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson's disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies., (© 2024. The Author(s).)

Parkinson's disease (PD) etiology is associated with aggregation and accumulation of α-synuclein (α-syn) proteins in midbrain dopaminergic neurons. Emerging evidence suggests that in certain subtypes of PD, α-syn aggregates originate in the gut and subsequently spread to the brain. However, mechanisms that instigate α-syn aggregation in the gut have remained elusive. In the brain, the aggregation of α-syn is induced by oxidized dopamine. Such a mechanism has not been explored in the context of the gastrointestinal tract, a niche harboring 46% of the body's dopamine reservoirs. Here, we report that Enterobacteriaceae , a bacterial family prevalent in human gut microbiotas, induce α-syn aggregation. More specifically, our in vitro data indicate that respiration of nitrate by Escherichia coli K-12, which results in production of nitrite that mediates oxidation of Fe 2+ to Fe 3+ , creates an oxidizing redox potential. These oxidizing conditions enabled the formation of dopamine-derived quinones and α-syn aggregates. Exposing nitrite, but not nitrate, to enteroendocrine STC-1 cells induced aggregation of α-syn that is natively expressed in these cells, which line the intestinal tract. Taken together, our findings indicate that bacterial nitrate reduction may be critical for initiating intestinal α-syn aggregation.

Less than ten years ago, evidence began to accumulate about association between the changes in the composition of gut microbiota and development of human synucleinopathies, in particular sporadic form of Parkinson's disease. We collected data from more than one hundred and thirty experimental studies that reported similar results and summarized the frequencies of detection of different groups of bacteria in these studies. It is important to note that it is extremely rare that a unidirectional change in the population of one or another group of microorganisms (only an elevation or only a reduction) was detected in the patients with Parkinson's disease. However, we were able to identify several groups of bacteria that were overrepresented in the patients with Parkinson's disease in the analyzed studies. There are various hypotheses about the molecular mechanisms that explain such relationships. Usually, α-synuclein aggregation is associated with the development of inflammatory processes that occur in response to the changes in the microbiome. However, experimental evidence is accumulating on the influence of bacterial proteins, including amyloids (curli), as well as various metabolites, on the α-synuclein aggregation. In the review, we provided up-to-date information about such examples.

Introduction: Research has suggested a link between the gut microbiota and Parkinson's Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in patients. A mechanism review was performed to investigate whether the neurodegenerative cascade begins in the gut; mediated by gut dysbiosis and retrograde transport of α-synuclein. This review provides a summary of microbiome composition associated with PD, and evaluates pathophysiological mechanisms from animal and in vitro models of PD., Method: A systematic literature search was performed in PubMed; 82 of 299 papers met the inclusion criteria., Results: All twenty-two human case-control studies demonstrated an altered gut microbiota in PD compared to healthy controls, with results suggesting a proinflammatory phenotype present in PD. A germ-free animal study has demonstrated that gut microbiota are required for microglia activation, α-synuclein pathology and motor deficits. Accumulation of phosphorylated α-synuclein has been observed in the enteric nervous system prior to the onset of motor symptoms in animal models of PD, and there is data to support retrograde transport of α-synuclein from the gut to the brain. Different animal models of PD have demonstrated neuroinflammation, microglial activation and loss of dopaminergic neurons in the brain., Conclusion: Evidence from this review supports the hypothesis that pathology spreads from the gut to the brain. Future animal studies using oral LPS or microbiota transplants from human PD cases could provide further insight into the entire mechanism. Prospective longitudinal microbiome studies and novel modelling approaches could help to identify functional dysbiosis and early biomarkers for PD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is the second most common neurodegenerative disease amongst the middle‑aged and elderly populations. Several studies have confirmed that the microbiota‑gut‑brain axis (MGBA) serves a key role in the pathogenesis of PD. Changes to the gastrointestinal microbiome (GM) cause misfolding and abnormal aggregation of α‑synuclein (α‑syn) in the intestine. Abnormal α‑syn is not eliminated via physiological mechanisms and is transported into the central nervous system (CNS) via the vagus nerve. The abnormal levels of α‑syn aggregate in the substantia nigra pars compacta, not only leading to the formation of eosinophilic Lewis Bodies in the cytoplasm and mitochondrial dysfunction in dopaminergic (DA) neurons, but also leading to the stimulation of an inflammatory response in the microglia. These pathological changes result in an increase in oxidative stress (OS), which triggers nerve cell apoptosis, a characteristic of PD. This increase in OS further oxidizes and intensifies abnormal aggregation of α‑syn, eventually forming a positive feedback loop. The present review discusses the abnormal accumulation of α‑syn in the intestine caused by the GM changes and the increased levels of α‑syn transport to the CNS via the MGBA, resulting in the loss of DA neurons and an increase in the inflammatory response of microglial cells in the brain of patients with PD. In addition, relevant clinical therapeutic strategies for improving the GM and reducing α‑syn accumulation to relieve the symptoms and progression of PD are described.

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., (© 2020 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) has long been considered a brain disease, but studies now point to the gastrointestinal (GI) tract as a potential starting point for PD. In particular, the human vermiform appendix has been implicated in PD. The appendix is a tissue rich in immune cells, serving as part of the gut-associated lymphoid tissue and as a storehouse for the gut microbiome. The functions of the appendix converge with recent evidence demonstrating that gut inflammation and shifts in the microbiome are linked to PD. Some epidemiological studies have linked removal of the appendix to lowered PD risk, though there is controversy among these associations. What is apparent is that there is an abundance of aggregated forms of α-synuclein in the appendix relevant to PD pathology. α-Synuclein pathology is thought to propagate from gut to brain via the vagus nerve, which innervates GI tract locations, including the appendix. Remarkably, α-synuclein aggregates in the appendix occur not only in PD patients, but are also present in healthy individuals. This has led to the proposal that in the appendix α-synuclein aggregates are not unique to PD. Moreover, the molecular events leading to PD and the mechanisms by which α-synuclein aggregates transfers from gut to brain may be identifiable in the human appendix. The influence of the appendix on GI inflammation, autoimmunity, microbiome storage, and the lymphatic system may be yet unexplored mechanisms by which the appendix contributes to PD. Overall, the appendix represents a promising tissue site to advance our understanding of PD pathobiology.

Parkinson's disease is the most common neurodegenerative movement disorder. It arises as a result of neuronal cell death in specific brain regions, notably the substantia nigra pars compacta, and is characterized by the accumulation of α-synuclein in these brain regions. Current pharmacological therapies alleviate the motor symptoms of the disease and are particularly effective in the early stages of the disease. Ongoing drug development efforts focus on disease-modifying strategies that aim to halt or slow disease progression. In this review, we explore a number of emerging disease-modifying strategies with a focus on direct and indirect targeting of α-synuclein dysfunction. We summarize newer classes of small molecules and biological agents intended to attenuate protein aggregation or to target enzymes that may increase the degradation of the pathogenic forms of α-synuclein. Finally, we discuss emerging strategies that are demonstrating the potential for disease modification at the preclinical stage., (© 2018 The British Pharmacological Society.)