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Parkinson's disease (PD) is a clinically heterogenic disorder characterized by distinct clinical entities. Most studies on motor deficits dichotomize PD into tremor dominant (TD) or non-tremor dominant (non-TD) with akinetic-rigid features (AR). Different pathophysiological mechanisms may affect the onset of motor manifestations. Recent studies have suggested that gut microbes may be involved in PD pathogenesis. The aim of this study was to investigate the gut microbiota and metabolome composition in PD patients in relation to TD and non-TD phenotypes. In order to address this issue, gut microbiota and the metabolome structure of PD patients were determined from faecal samples using 16S next generation sequencing and gas chromatography-mass spectrometry approaches. The results showed a reduction in the relative abundance of Lachnospiraceae, Blautia , Coprococcus , Lachnospira , and an increase in Enterobacteriaceae, Escherichia and Serratia linked to non-TD subtypes. Moreover, the levels of important molecules (i.e., nicotinic acid, cadaverine, glucuronic acid) were altered in relation to the severity of phenotype. We hypothesize that the microbiota/metabolome enterotypes associated to non-TD subtypes may favor the development of gut inflammatory environment and gastrointestinal dysfunctions and therefore a more severe α-synucleinopathy. This study adds important information to PD pathogenesis and emphasizes the potential pathophysiological link between gut microbiota/metabolites and PD motor subtypes.

Background: Parkinson's disease (PD) is caused by abnormal aggregation of α-synuclein fibrils, called the Lewy bodies, in the central nervous system. Accumulating knowledge points to the notion that α-synuclein fibrils start from the dorsal vagal nucleus and ascend to the locus ceruleus and the substantia nigra (SN). Even in healthy elderly subjects without motor or cognitive impairment, α-synuclein fibrils are frequently observed in the brain and sometimes in the intestinal neural plexus. Enteroendocrine cells have a direct synapse to the vagal afferents, and the vagal nucleus has synaptic pathways to the SN and the striatum. Intestinal bacteria are likely to be involved in the formation of intestinal α-synuclein fibrils., Summary: A nonparametric meta-analysis of intestinal microbiota in PD in 5 countries, as well as scrutinization of the other reports from the other countries, indicates that mucin-degrading Akkermansia is increased in PD and that short-chain fatty acid (SCFA)-producing bacteria are decreased in PD. Both dysbiosis should increase the intestinal permeability, which subsequently facilitates exposure of the intestinal neural plexus to toxins like lipopolysaccharide and pesticide, which should lead to abnormal aggregation of α-synuclein fibrils. Decreased SCFA also downregulates regulatory T cells and fails to suppress neuronal inflammation. Key Messages: Therapeutic intervention may be able to be established against these mechanisms. Additional biochemical, cellular, and animal studies are required to further dissect the direct association between intestinal microbiota and PD., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Parkinson's disease (PD) ranks the second place among neurodegenerative diseases in terms of its morbidity, which affects 1-2% people aged over 65 years. In addition to genetics, some environmental factors may exert vital parts in PD occurrence as well. At present, more and more studies are conducted to elucidate the association between gut microbial dysbiosis and the incidence of PD. Gut microbial dysbiosis has a certain effect on both the central nervous system (CNS) and the enteric nervous system (ENS), which indicates that there is a gut-microbiota-brain axis that induces CNS disorders. Some gut microbial strains are suggested to suppress or weaken the neuroinflammation- and gut-inflammation-immune responses, which suggests the protective and pathogenic effects of certain gut microbial species on PD progression. Therefore, gut microbiome may contain plenty of targets for preventing and managing PD. Faecal microbiota transplantation (FMT) may serve as a direct and useful treatment for PD in the future. Nonetheless, there is little available scientific research in this field. The present work reviewed the latest research to examine the association of gut microbiota with PD, and the future prospects of FMT treatment.

Background: Infection with Helicobacter pylori seems overrepresented in Parkinson's disease. Clinical observations suggest a suboptimal treatment effect of levodopa in Helicobacter positive patients., Objective: Describe and explain the connection between a Helicobacter pylori infection of the upper gut and changes in pharmacokinetics of oral levodopa treatment in Parkinson's disease., Methods: PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: Bioavailability, drug metabolism, dyskinesia, Helicobacter, L-dopa, levodopa, motor control, pharmacodynamics, pharmacokinetics, prevalence, unified Parkinson's disease rating scale., Results: The prevalence of Helicobacter pylori in Parkinson's disease patients is reported to be about 1.6-fold higher than in a control population in some studies. Helicobacter has therefore been assumed to be linked to Parkinson's disease, but the mechanism is unclear. As regards symptoms and treatment, patients with Parkinson's disease on levodopa therapy and with Helicobacter pylori infection display worse motor control than those without Helicobacter infection. Eradication of the infection improves levodopa response in Parkinson's disease, likely as a consequence of an increased oral pre-systemic bioavailability of levodopa, likely to be explained by reduced Helicobacter-dependent levodopa consumption in the stomach. In addition, small intestinal bacterial overgrowth may also have an impact on the therapeutic setting for levodopa treatment but is less well established., Conclusion: Eradication of Helicobacter pylori improves levodopa bioavailability resulting in improved motor control. Eradication of Helicobacter should be considered in patients with poor symptomatic control and considerable motor fluctuations.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and tremor. Recently, there has been a growing focus on the relationship between the gut and the development of PD. Emerging to the forefront, an interesting concept has developed suggesting that the initial pathophysiological changes occur in the gastrointestinal tract before changes are seen within the brain. This review is aimed at highlighting the relationship between PD and the gastrointestinal tract, along with the supporting evidence for this. Firstly, we will focus on the gastrointestinal conditions and symptoms which commonly affects patients, including both upper and lower gastrointestinal issues. Secondly, the impact of nutrition and diet on neurological health and PD physiology, with particular emphasis on commonly consumed items including macronutrients and micronutrients. Finally, variability of the gut microbiome will also be discussed and its link with both the symptoms and signs of PD. The evidence presented in this review highly suggests that the initial pathogenesis in the gut may proceed the development of prodromal PD subtypes, and therefore building on this further could be imperative and lead to earlier diagnosis with new and improved therapeutics.

Background: Although abnormalities in gut microbiota are hypothesized to influence the pathogenesis and clinical phenotype of Parkinson's disease (PD), prospective studies on de novo patients are lacking., Objective: To preliminarily investigate whether gut microbiota in early untreated PD may predict motor and non-motor features progression over a 3-year period., Methods: 16S ribosomal RNA gene amplicons were sequenced on fecal samples of 39 de novo PD patients. Multiple confounders were taken into account, including dietary habits. Motor and non-motor symptoms were assessed using validated scales at baseline and followed-up yearly for 3 years. At last follow-up, a detailed neuropsychological assessment was additionally performed. A general linear model for repeated measurements- adjusted by dopaminergic therapy at follow-up- was used to investigate the relationship between bacterial taxa abundance at baseline (stratified by the median of distribution at baseline) and outcome variables., Results: Twenty-five patients were included (11 refused, 2 lost at follow-up, 1 died). Lower abundance of Roseburia (Firmicutes phylum) at baseline was associated with worse evolution of motor, non-motor and cognitive functions at 3-year follow-up. Similarly, lower abundance of Ruminococcaceae and Actinobacteria at baseline was associated with faster worsening of global cognitive functions. At follow-up, frontal lobe functions were the features most robustly associated with baseline microbial abnormalities., Conclusion: In the present exploratory study on de novo PD, we found an association between abnormal distribution of specific bacterial taxa and the progression of motor and non-motor features over a 3-year period. This proof-of-principle study supports the design of a larger observational study aiming to determine whether these differences survive multiple-comparison correction and define microbiota-specific subgroups suitable for therapeutic targeting.

The non-tasting form of the bitter taste receptor, TAS2R38, has been shown as a genetic risk factor associated with the development of Parkinson's disease (PD). Specific taste receptors that are expressed in the lower gastrointestinal tract may respond to alteration in gut microbiota composition, detecting bacterial molecules, and regulate immune responses. Given the importance of brain-gut-microbiota axis and gene-environment interactions in PD, we investigate the associations between the genetic variants of TAS2R38 and gut microbiota composition in 39 PD patients. The results confirm that the majority of PD patients have reduced sensitivity to 6-n-propylthiouracil (PROP) and are carriers of at least one non-functional TAS2R38 AVI haplotype. Moreover, we found this correlation to be associated with a reduction in bacteria alpha-diversity with a predominant reduction of Clostridium genus. We hypothesised that the high frequency of the non-taster form of TAS2R38 associated with a diminuition of Clostridium bacteria in PD might determine a reduction in the activation of protective signalling-molecules useful in preserving gut homeostasis. This pilot study, by identifying a decrease in specific bacteria associated with a reduced sensitivity to PROP, adds essential information that opens new avenues of research into the association of PD microbiota composition and sensory modification., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding authors state that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The commensal microbiome is known to influence a variety of host phenotypes. Microbiome profiling followed by differential abundance analysis has been established as an effective approach to study the mechanisms of host-microbiome interactions. However, it is challenging to interpret the collective functions of the resultant microbe-sets due to the lack of well-organized functional characterization of commensal microbiome. We developed microbe-set enrichment analysis (MSEA) to enable the functional interpretation of microbe-sets by examining the statistical significance of their overlaps with annotated groups of microbes that share common attributes such as biological function or phylogenetic similarity. We then constructed microbe-set libraries by query PubMed to find microbe-mammalian gene associations and disease associations by parsing the Disbiome database. To demonstrate the utility of our novel MSEA methodology, we carried out three case studies using publicly available curated knowledge resource and microbiome profiling datasets focusing on human diseases. We found MSEA not only yields consistent findings with the original studies, but also recovers insights about disease mechanisms that are supported by the literature. Overall, MSEA is a useful knowledge-based computational approach to interpret the functions of microbes, which can be integrated with microbiome profiling pipelines to help reveal the underlying mechanism of host-microbiome interactions.

The immune system has been increasingly recognized as a major contributor in the pathogenesis of Parkinson's disease (PD). The double-edged nature of the immune system poses a problem in harnessing immunomodulatory therapies to prevent and slow the progression of this debilitating disease. To tackle this conundrum, understanding the mechanisms underlying immune-mediated neuronal death will aid in the identification of neuroprotective strategies to preserve dopaminergic neurons. Specific innate and adaptive immune mediators may directly or indirectly induce dopaminergic neuronal death. Genetic factors, the gut-brain axis and the recent identification of PD-specific T cells may provide novel mechanistic insights on PD pathogenesis. Future studies to address the gaps in the identification of autoantibodies, variability in immunophenotyping studies and the contribution of gut dysbiosis to PD may eventually provide new therapeutic targets for PD.

Introduction: Increasing evidence shows that gut microbiota dysbiosis may play important roles in the occurrence and progression of Parkinson's disease (PD), but the findings are inconsistent. Besides, the effect of family environment on gut microbiota dysbiosis remains unclear., Methods: We characterized the gut microbial compositions of 63 PD patients, 63 healthy spouses (HS) and 74 healthy people (HP) using 16S rRNA sequencing. Clinical phenotypes and microbial composition were analyzed comprehensively., Results: There were markedly different microbial compositions among PD, HS and HP samples by alpha/beta diversity. We also found differential microbial compositions among Hoehn & Yahr stage/disease duration. Eight inflammation-associated microbial genera shared a continuously increase trend with increased Hoehn & Yahr stage and disease duration, indicating characteristic bacteria associated with deterioration in PD. Additionally, seven bacterial markers were identified for accurately differentiating PD patients from the controls (area under the curve [AUC]: 0.856)., Conclusions: Our study shows altered gut microbiota in PD patients. Importantly, inflammation-associated microbial genera may play roles in PD progression. Differential microbial compositions in HS and HP samples demonstrate that the gut microbiota are also affected by family environment. Disease-associated metagenomics studies should consider the family environmental factor. Our research provides an important reference and improves the understanding of gut microbiota in PD patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder that has been shown to be influenced by the intestinal milieu. The gut microbiota is altered in PD patients, and murine studies have begun suggesting a causative role for the gut microbiota in progression of PD. We have previously shown that repeated infection with the intestinal murine pathogen Citrobacter rodentium resulted in the development of PD-like pathology in Pink1 -/- mice compared to wild-type littermates. This addendum aims to expand this work by characterizing the gut microbiota during C. rodentium infection in our Pink1 -/- PD model. We observed little disturbance to the fecal microbiota diversity both between infection timepoints and between Pink1 -/- and wild-type control littermates. However, the level of short-chain fatty acids appeared to be altered over the course of infection with butyric acid significantly increasing in Pink1 -/- mice and isobutyric acid increasing in wild-type mice.

The gut-brain communication is increasingly being recognized as a profound effector on Parkinson's disease (PD). Gut microbiota changes have become the focus of attention. However, the mechanism leading to changes in the gut microbiota is not clear. In the present study, we found that knockout of Dcf1 (Dcf1 -/- ) caused changes in the gut microbiota in mice. Results indicated that the increased Proteobacteria (phylum-level) and decreased Prevotellaceae (family-level) in the microbiota composition of Dcf1 -/- (KO) mice, which is consistent with the situation of PD patients. On species-level, Prevotellaceae_UCG-001 and Helicobacter_ganmani were significantly different between KO and WT mice, suggesting glycolipid metabolism disorders and inflammatory lesions in KO mice. In the behavior of Y-maze and Open field test, KO mice showed typical PD symptoms such as memory deficits, slowness of movement and anxiety. Further Nissl staining of brain tissue sections confirmed that the deletion of Dcf1 caused damage to amygdala neurons. These results provide a new mechanism for understanding gut microbiota changes, and provide a new basis for PD treatment from a new perspective of Gut-brain axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: There is increasing evidence of the association between microbiome dysfunction and Parkinson's disease (PD). Moreover, some PD patients suffer from unintentional weight loss (WL) which may precede the motor manifestations of the disease. Materials & methods: Gut microbiota profiling by 16S rRNA gene sequencing was performed in PD patients with an unintended WL, in steady weight patients (non-WL [NWL]) and in matched normal subjects. KEGG functional predictions were carried out. Results: Microbiota profiles revealed a dissimilarity between WL and NWL. Moreover, WL pathways were characterized by fatty acid biosynthesis, while NWL by inflammation pathways. Conclusion: The gut microbiota could participate in weight alteration observed in PD by the presence of bacteria involved in weight gain and inflammation, or conversely by bacteria implicated in energy expenditure.

Microbiome data consists of operational taxonomic unit (OTU) counts characterized by zero-inflation, over-dispersion, and grouping structure among samples. Currently, statistical testing methods are commonly performed to identify OTUs that are associated with a phenotype. The limitations of statistical testing methods include that the validity of p-values/q-values depend sensitively on the correctness of models and that the statistical significance does not necessarily imply predictivity. Predictive analysis using methods such as LASSO is an alternative approach for identifying associated OTUs and for measuring the predictability of the phenotype variable with OTUs and other covariate variables. We investigate three strategies of performing predictive analysis: (1) LASSO: fitting a LASSO multinomial logistic regression model to all OTU counts with specific transformation; (2) screening+GLM: screening OTUs with q-values returned by fitting a GLMM to each OTU, then fitting a GLM model using a subset of selected OTUs; (3) screening+LASSO: fitting a LASSO to a subset of OTUs selected with GLMM. We have conducted empirical studies using three simulation datasets generated using Dirichlet-multinomial models and a real gut microbiome data related to Parkinson's disease to investigate the performance of the three strategies for predictive analysis. Our simulation studies show that the predictive performance of LASSO with appropriate variable transformation works remarkably well on zero-inflated data. Our results of real data analysis show that Parkinson's disease can be predicted based on selected OTUs after the binary transformation, age, and sex with high accuracy (Error Rate = 0.199, AUC = 0.872, AUPRC = 0.912). These results provide strong evidences of the relationship between Parkinson's disease and the gut microbiome., Competing Interests: The authors have declared that no competing interests exist.

The gut microbiome is increasingly implicated in modifying susceptibility to and progression of neurodegenerative diseases (NDs). In this review, we discuss roles for the microbiome in aging and in NDs. In particular, we summarize findings from human studies on microbiome alterations in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We assess animal studies of genetic and environmental models for NDs that investigate how manipulations of the microbiome causally impact the development of behavioral and neuropathological endophenotypes of disease. We additionally evaluate the likely immunological, neuronal, and metabolic mechanisms for how the gut microbiota may modulate risk for NDs. Finally, we speculate on cross-cutting features for microbial influences across multiple NDs and consider the potential for microbiome-targeted interventions for NDs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Identification of the gut microbiome compositions associated with disease has become a research focus worldwide. Emerging evidence has revealed the presence of gut microbiota dysbiosis in Parkinson's disease. In this study, we aimed to identify the gut microbiome associated with Parkinson's disease and subsequently to screen and to validate potential diagnostic biomarkers of Parkinson's disease. This case-control study investigated gut microbial genes in faeces from 40 volunteer Chinese patients with Parkinson's disease and their healthy spouses using shotgun metagenomic sequencing. Furthermore, the identified specific gut microbial gene markers were validated with real-time PCR in an independent Chinese cohort of 78 Parkinson's disease patients, 75 control subjects, 40 patients with multiple system atrophy and 25 patients with Alzheimer's disease. We developed the first gut microbial gene catalogue associated with Parkinson's disease. Twenty-five gene markers were identified that distinguished Parkinson's disease patients from healthy control subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.896 (95% confidence interval: 83.1-96.1%). A highly accurate Parkinson's disease index, which was not influenced by disease severity or Parkinson's disease medications, was created. Testing these gene markers using quantitative PCR distinguished Parkinson's disease patients from healthy controls not only in the 40 couples (AUC = 0.922, 95% confidence interval: 86.4-98.0%), but also in an independent group of 78 patients with Parkinson's disease and 75 healthy control subjects (AUC = 0.905, 95% confidence interval: 86.0-95.1%). This classifier also performed a differential diagnosis power in discriminating these 78 patients with Parkinson's disease from a cohort of 40 patients with multiple system atrophy and 25 patients with Alzheimer's disease based on the panel of 25 biomarkers. Based on our results, the identified Parkinson's disease index based on the gene set from the gut microbiome may be a potential diagnostic biomarker of Parkinson's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition., Methods: Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants., Results: Among risk and prodromal markers, physical activity, occupational solvent exposure, and constipation showed associations with α-diversity. Physical activity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β-diversity. Subthreshold parkinsonism and physical activity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with α- and β-diversity. Physical inactivity and constipation were highest in individuals with the Firmicutes-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical activity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations., Interpretation: Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2020;88:320-331., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

The incidence of Parkinson's disease (PD) increases with age. PD is a neurodegenerative disease with an incidence of 1 in 200 individuals aged over 65 years. In patients with PD, α-synuclein may accumulate abnormally and damage cells in the substantia nigra. Abnormal proteins (α-synuclein) in peripheral tissues were recently found to be transferred to the brain rather than originating in the brain. Furthermore, changes in intestinal microbiota appear to be related to observed treatment effects and disease development in patients with PD. This review will report on recent studies of intestinal microbiota potentially involved in PD symptoms and progression.

Background: Parkinson's disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we addressed this question by an analysis of stool samples from the Luxembourg Parkinson's Study (n = 147 typical PD cases, n = 162 controls)., Results: All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool samples from these individuals were first analysed by 16S rRNA gene sequencing. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include the following. Eight genera and seven species changed significantly in their relative abundances between PD patients and healthy controls. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. Particularly, the relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. Furthermore, personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in the predicted secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The predicted microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms., Conclusion: Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype.

The 'Dual Hit' hypothesis, stating that Parkinson's disease (PD) begins via olfactory pathways and the gut, and the gastrointestinal symptoms PD individuals face, have largely driven the interest of the gut's involvement in PD. Studies have since observed gut microbiota differences between PD groups and controls, with these alterations potentially relating to PD pathophysiology. However, differences in the studies' methodologies precludes unanimity on the relationships of gut microbiota to PD. Thirteen observational case-control studies investigating gut microbiota in PD and controls were reviewed to assess how microbiota abundance and diversity relates to PD. Nine studies showed butyrate producing gut microbiota had lower abundances in PD compared to controls. Three studies reported α-diversity was higher, with one reporting it was lower, in PD compared to controls. Given most studies show abundance, not diversity, differences of butyrate producing bacteria between groups, we propose abundance differences are more associated with PD than microbiota diversity. As current research is observational, investigating how specific bacteria and their metabolites may alter throughout PD progression is warranted., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is the second most common neurodegenerative disease. Eigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is known to exert a beneficial effect on PD patients. Although some mechanisms were suggested to underlie this intervention, it remains unknown if the EGCG-mediated protection was achieved by remodeling gut microbiota. In the present study, 0.1 mM or 0.5 mM EGCG was administered to the Drosophila melanogaster with PINK1 (PTEN induced putative kinase 1) mutations, a prototype PD model, and their behavioral performances, as well as neuronal/mitochondrial morphology (only for 0.5 mM EGCG treatment) were determined. According to the results, the mutant PINK1 B9 flies exhibited dopaminergic, survival, and behavioral deficits, which were rescued by EGCG supplementation. Meanwhile, EGCG resulted in profound changes in gut microbial compositions in PINK1 B9 flies, restoring the abundance of a set of bacteria. Notably, EGCG protection was blunted when gut microbiota was disrupted by antibiotics. We further isolated four bacterial strains from fly guts and the supplementation of individual Lactobacillus plantarum or Acetobacter pomorum strain exacerbated the neuronal and behavioral dysfunction of PD flies, which could not be rescued by EGCG. Transcriptomic analysis identified TotM as the central gene responding to EGCG or microbial manipulations. Genetic ablation of TotM blocked the recovery activity of EGCG, suggesting that EGCG-mediated protection warrants TotM. Apart from familial form, EGCG was also potent in improving sporadic PD symptoms induced by rotenone treatment, wherein gut microbiota shared regulatory roles. Together, our results suggest the relevance of the gut microbiota-TotM pathway in EGCG-mediated neuroprotection, providing insight into indirect mechanisms underlying nutritional intervention of Parkinson's disease., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.)

Based on the "brain-mind theory" of traditional Chinese medicine, the dysfunction of brain mind is the mechanism of the Parkinson's disease in pathogenesis. In modern medicine, the brain-gut axis theory believes that the impairment of intestinal flora is of the reciprocal causation with the cerebral pathological changes in Parkinson's disease. Hence, the theory of xingnao tiaochang (regaining consciousness and regulating intestine) is proposed in combination of the dysfunction of brain mind with the brain-gut axis, based on which, the treating principle and method are determined for regulating the brain and intestine. Separately, in view of traditional Chinese medicine and modern medicine, the treating principle and method of xingnao tiaochang were discussed, as well as the rationality of acupuncture and acupoint selection under its guidance so as to provide a more extensive approach to the clinical treatment of Parkinson's disease.

Aims: Recent studies showed that patients with various bacterial, viral, and fungal infections might be at increased risk of Parkinson's disease (PD). However, the risk of PD in patients with each specific infection varied. This meta-analysis estimated the association between various infections and PD risk., Methods: Literature published from January 1965 to October 2019 in PubMed and EMBASE databases was searched. Data were extracted and pooled using random/fixed effects model. Sensitivity analysis and meta-regression were also performed to analyze the source of heterogeneity. Publication bias was estimated by the trim and fill., Results: Twenty-three out of 6,609 studies were included. Helicobacter pylori (HP; pooled OR = 1.653, 1.426-1.915, p < .001), hepatitis C virus (HCV; pooled OR = 1.195, 1.012-1.410, p = .035), Malassezia (pooled OR = 1.694, 1.367-2.100, p < .001), and pneumoniae (pooled OR = 1.595, 1.020-2.493, p = .041) infection were associated with increased PD risk. Influenza virus, herpes virus, hepatitis B virus, scarlet fever, mumps virus, chicken pox, pertussis, German measles, and measles were not associated with PD risk. After antiviral treatment against HCV reduced the risk of PD in patients with HCV infection (OR = 0.672, 0.571-0.791, p < .001). Significant heterogeneity exists among the included studies., Conclusion: Patients with infection of HP, HCV, Malassezia, pneumoniae might be an increased risk of PD. Antiviral treatment of HCV could reduce the risk of PD., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Following Braak's hypothesis on the infectious pathogenesis of sporadic Parkinson's disease (sPD), several bacteria and viruses have been investigated as likely culprits. Recent research has focused on neuroinvasive influenza A viruses (IAV), whereas a genetic link between sPD and tuberculosis has arisen in LRRK2 - dependent maturation of the phagosome. An integrative, outside - in, multi - hit hypothesis is presented here, where (a) mycobacterial immunomodulation creates a phagocyte niche along with cytokine mediated, site specific (i.e. the gut) alterations of both immunity and the microbiome, (b) copper modulating IAVs gain latency in and control over phagocytes and their phenotypes, (c) gain access to the central nervous system (CNS) via the olfactory and vagus nerves in subsequent infection cycles, (d) induce indolent neuroinflammation characterized by perturbed intraneuronal copper compartmentalization and (e) produce α - synuclein (aSyn) pathology at least in part via copper - induced aggregation and misfolding as well as potential synergy with other underlying, corroborating factors (either genetic or acquired) contributing to dopaminergic neurodegeneration. This hypothesis explores recently arisen evidence for each step of this process, as well as pre-existing, yet unexplored overlapping pathophysiological characteristics of sPD with mycobacterial and IAV infections. The implications of this proposed pathogenic model extend both in sPD research (i.e. determining non - tuberculous mycobacteria as the first hit organism, inactivating IAV - induced copper hijacking), as well as therapeutics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, and in an effort to identify novel therapeutic target for this disease in recent years, human microbiota has attracted much interest. This paper briefly summarizes the main findings concerning the differences of human microbiome across several important mucosal interfaces, including nose, mouth, and gut between PD patients and controls as obtained from a total of 13 studies published since 2015, which covered a total of 943 PD patients and 831 matched controls from 6 countries. Overall, these studies supported the differences of gut microbiota between PD patients and matched controls, while significantly altered bacterial taxa among studies were not identical. Due to relatively limited number of available studies and covered patients, the associations between oral and nasal microbiota and PD remain inconclusive. The therapeutic and diagnostic potentials of gut microbiota for PD are discussed. More well-designed clinical studies recruiting large-scale PD patients are encouraged in future.

Microbial populations exhibit functional changes in response to different ambient environments. Although whole metagenome sequencing promises enough raw data to study those changes, existing tools are limited in their ability to directly compare microbial metabolic function across samples and studies. We introduce Carnelian, an end-to-end pipeline for metabolic functional profiling uniquely suited to finding functional trends across diverse datasets. Carnelian is able to find shared metabolic pathways, concordant functional dysbioses, and distinguish Enzyme Commission (EC) terms missed by existing methodologies. We demonstrate Carnelian's effectiveness on type 2 diabetes, Crohn's disease, Parkinson's disease, and industrialized and non-industrialized gut microbiome cohorts.

Parkinson's disease (PD) is characterized by motor disorders and the destruction of dopaminergic neurons in the substantia nigra pars compacta. In addition to motor disability, many patients with PD present a spectrum of clinical symptoms, including cognitive decline, psychiatric alterations, loss of smell and bladder dysfunction, among others. Neuroinflammation is one of the most salient features of PD, but the nature of the trigger remains unknown. A plausible mechanism to explain inflammation and the range of clinical symptoms in these patients is the presence of systemic microbial infection. Accordingly, the present study provides extensive evidence for the existence of mixed microbial infections in the central nervous system (CNS) of patients with PD. Assessment of CNS sections by immunohistochemistry using specific antibodies revealed the presence of both fungi and bacteria. Moreover, different regions of the CNS were positive for a variety of microbial morphologies, suggesting infection by a number of microorganisms. Identification of specific fungal and bacterial species in different CNS regions from six PD patients was accomplished using nested PCR analysis and next-generation sequencing, providing compelling evidence of polymicrobial infections in the CNS of PD. Most of the fungal species identified belong to the genera Botrytis, Candida, Fusarium and Malassezia . Some relevant bacterial genera were Streptococcus and Pseudomonas , with most bacterial species belonging to the phyla Actinobacteria and Proteobacteria . Interestingly, we noted similarities and differences between the microbiota present in the CNS of patients with PD and that in other neurodegenerative diseases. Overall, our observations lend strong support to the concept that mixed microbial infections contribute to or are a risk factor for the neuropathology of PD. Importantly, these results provide the basis for effective treatments of this disease using already approved and safe antimicrobial therapeutics., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson's disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae . Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients., Competing Interests: The authors declare no conflict of interest.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative disorders, with an overall global incidence of 40 million. Many studies have revealed the association of intestinal disorders and bacterial infections with PD, but few studies have found such a relationship with AD. In this meta-analysis, related articles published up to September 2018 were searched in PubMed. Of the 2121 related articles screened initially, 56 were found to be eligible. Data on the risks of PD and AD due to five intestinal disorders and infection with Helicobacter pylori , as a representative intestinal microbe, were obtained, and a fixed- or random-effects model was used to pool the odds ratios (ORs) with 95% confidence interval (CIs) from individual studies. The combined OR for all types of intestinal disorders with an increased risk of PD was 3.36 (95% CI: 2.70-4.17). The ORs for each category were as follows: constipation, 4.05 (95% CI, 3.24-5.06); inflammatory bowel disease (IBD), 1.16 (95% CI, 0.89-1.52); irritable bowel syndrome (IBS), 1.75 (95% CI, 0.55-5.56); small intestinal bacterial overgrowth, 5.15 (95% CI, 3.33-7.96); and diarrhea, 1.27 (95% CI, 0.28-5.75). The combined OR of all types of intestinal disorders with an increased risk of AD was 1.52 (95% CI, 1.09-2.13). The ORs for IBS and IBD were 1.42 (95% CI, 1.02-1.99) and 2.40 (95% CI, 1.00-5.76), respectively. The risk estimates of H. pylori infection in PD and AD patients were as follows: OR, 1.65 (95% CI, 1.43-1.91) and OR, 1.40 (95% CI, 1.12-1.76), respectively. These findings suggest that PD and AD are significantly associated with intestinal disorders. The negative roles of H. pylori in the development of PD or AD should be evaluated to shed new light on the diagnosis and treatment of PD and AD. National governments should periodically inspect the intestinal condition of residents and extend health plans to improve intestinal health to prevent potential neurological disorders.

Research into the role of the gut microbiome in modulating brain function has rapidly increased over the past 10 years, albeit chiefly in animal models. Increasing clinical and preclinical evidence implicates the microbiome as a possible key susceptibility factor for neurological disorders, including Alzheimer's disease, autism spectrum disorder, multiple sclerosis, Parkinson's disease, and stroke. Cross-sectional clinical studies are bolstering the concept of altered microbial composition contributing to the pathophysiology of such diseases. However, the field is nascent, and interpretation of such data is often difficult given that the composition of the microbiome is influenced by various factors such as diet and exercise. Longitudinal studies and randomised controlled trials in humans are needed to find out if targeting the microbiome can yield novel therapeutic strategies. Systems biology approaches will also be important in integrating such data with genomic and metabolomic datasets from clinical cohorts with neurological disease to help guide individual treatment selection., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The gastrointestinal tract is inhabited by trillions of individual microbes, representing hundreds to thousands of distinct species. These indigenous organisms are not simply spectators to host activity, but instead actively modulate critical aspects of host physiology. From digestion and the production of small molecules, to the maturation and tuning of immune responses, the gastrointestinal microbiome influences every organ system in the body. Growing experimental evidence demonstrates microbial influence on neurological function in both health and disease. Furthermore, sequencing of the intestinal microbe population reveals altered community structures in various neurological conditions. Here, we provide a perspective on the potential roles for the intestinal microbiome in modulating Parkinson's disease. While Parkinson's disease has been historically studied as a disease of the central nervous system, there is growing appreciation for the roles of both gastrointestinal function and its resident microbes within this disease state. Recent studies focused on the microbiome during Parkinson's disease may advance our understanding of disease etiology and provide perspective for previously unrecognized therapeutic avenues through modulation of intestinal microbes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.)

Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson's disease patients, weight loss and metabolic disorders such as lipid abnormalities are frequently encountered. This was a prospective investigation of the presence of SIBO using the lactulose breath test, Parkinson's disease symptoms, medications, abdominal symptoms, and blood data involving 39 Parkinson's disease patients. Of the 39 patients, 19 were positive for SIBO, 16 were negative, and 4 were equivocal. SIBO-positive patients had a significantly smaller dopaminergic drug load (dopamine replacement of Parkinson's disease drug potency) (P = 0.009) and significantly lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. No relationship was seen between the presence or absence of SIBO and motor or abdominal symptoms. The following hypothesis was developed with regard to the possibility that intestinal bacterial overgrowth has various effects that are exhibited via bile acid metabolism in Parkinson's disease patients. Serum bilirubin levels become higher as bilirubin metabolism declines with decreases in the intestinal bacteria. At the same time, bile acid is broken down due to increased intestinal bacteria, and lipid absorption decreases. This induces low serum TG levels and leads to weight loss. By a similar mechanism, there is less absorption of vitamin D as bile acid levels decrease, leading to osteoporosis and fractures. The possibility that some of the non-motor manifestations accompanying Parkinson's disease are caused by intestinal dysbiosis needs to be considered., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) and multiple system atrophy (MSA) patients often suffer from gastrointestinal (GI) dysfunction and GI dysbiosis (microbial imbalance). GI dysfunction also occurs in mouse models of PD and MSA., Objectives: To assess gut dysfunction and dysbiosis in PD subjects as compared to controls, identify potential shared microbial taxa in humans and mouse models of PD and MSA, and to assess the effects of potential therapies on mouse GI microbiota., Methods: In this human pilot study, GI function was assessed by fecal consistency/frequency measured using the Bristol Stool Form Scale and GI transit time assessed using Sitzmarks pills and abdominal radiology. Human and mouse microbiota were analyzed by extracting fecal genomic DNA followed by 16S rRNA sequencing., Results: In our PD patients genera Akkermansia significantly increased while a trend toward increased Bifidobacterium and decreased Prevotella was observed. Families Bacteroidaceae and Lachnospiraceae and genera Prevotella and Bacteroides were detected in both humans and PD mice, suggesting potential shared biomarkers. In mice treated with the approved multiple sclerosis drug, FTY720, or with our FTY720-Mitoxy-derivative, we saw that FTY720 had little effect while FTY720-Mitoxy increased beneficial Ruminococcus and decreased Rickenellaceae family., Conclusion: Akkermansia and Prevotellaceae data reported by others were replicated in our human pilot study suggesting the use of those taxa as potential biomarkers for PD diagnosis. The effect of FTY720-Mitoxy on taxa Rikenellaceae and Ruminococcus and the relevance of S24-7 await further evaluation. It also remains to be determined if mouse microbiota have predictive power for human subjects.

Recent data suggest gut microbiota dysbiosis as a contributing factor in neurodegenerative diseases, such as Parkinson's Disease (PD) and Alzheimer's Disease (AD), and these pathologies may manifest via the microbiota-gut-brain-axis, which comprises bidirectional communication through neuroimmune, neuroendocrine, and direct neural pathways such as the vagus nerve. Preclinical and human clinical trial data reveal exciting potential for novel treatment targets and therapeutic modulation with prebiotics, medicinal herbs, probiotics, and synbiotics in health, aging, and neurodegeneration and are reviewed here. While greater insights and characterization of the microbiota-gut-brain axis have been revealed over the past decade, salient questions related to the pathology, pathogenesis and clinical treatment of the axis in the context of both health and neurodegenerative disease remain and are discussed in this review. Future directions such as additional well-controlled, large scale, longitudinal human clinical trials are urgently needed to further elucidate both mechanism and therapeutic opportunity in health, neurological disease, and disease subpopulations to ensure that the next decade ushers the dawn of targeted therapeutic modulation of the microbiota-gut-brain axis.

Parkinson's disease (PD) is a common progressive neurodegenerative disease. PD produces a pathological state in the intestine and disordered gut microbiota (GM), which may be important for the pathogenesis and progression of PD, but it is not clear. To explore the conditions and characteristics of intestinal pathology and GM disorders when PD-related injuries occur, we used twice 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute administration with an interval of 3 weeks (each was an intraperitoneal injection of 25 mg/kg MPTP for 5 consecutive days). We observed the changes in intestinal and brain immune status, intestinal barrier function and GM in different injury states one day, one week, and three weeks after the first stimulus and one day and one week after the second stimulus. Our study found that two subacute administrations of MPTP induced dopaminergic (DAergic) neuron injury and inflammation in the midbrain and ileum, impaired intestinal barrier function and GM disorders closely related to administration. These changes recovered after the first administration, but after repeated administration, some indicators showed more dramatic changes than during the first administration. Our results suggest that the intestinal tract is sensitive to PD-related injury, and the GM is susceptible to disturbances caused by intestinal function, which may be concerned in local immune disorders of the intestine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The gut microbiome was extensively researched for its biological variety and its potential role in propagating diseases outside of the gastrointestinal (GI) tract. Recently, a lot of effort was focused on comprehending the gut-brain axis and the bizarre communication between the GI system and the nervous system. Ample amount of studies being carried out also revealed the involvement of the gut microbiome in enhancing the degree of many neurological disorders, including neurodegenerative diseases. It was widely observed that there were distinct microbiome profiles and dysbiosis within patients suffering from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Various approaches to re-establish the balance of the gut microbiome, from antibiotic therapy, fecal microbiota transplant, or ingestion of psychobiotics, are discussed within this review within the specific context of combating neurodegenerative diseases. Present studies and clinical trials indicate that although there is an immense potential of gut microbiome modification to be preventive or therapeutic, there are still many intercalated components of the gut-brain axis at play and thus, more research needs to be carried out to delineate microbiome factors that may potentially alleviate symptoms of neurodegeneration.

Parkinson's disease (PD) exhibits systemic effects on the human metabolism, with emerging roles for the gut microbiome. Here, we integrate longitudinal metabolome data from 30 drug-naive, de novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naive PD cohort, and prospective data from the general population. Our key results are (1) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls; (2) dopaminergic medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population; and (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, which is consistent with the changed metabolome. The multi-omics integration reveals PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder, affecting 3.7% of the population over 65 years of age. PD involves degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNPC) with deficiency of dopamine. Genetic factors like SNCA, PARK-2, PARK-7, PINK-1 and LRRK-2 as well as environmental toxins enhance alpha-synuclein, amyloid β (beta) and τ (tau) proteins aggregation. Moreover, oxidative stress, mitochondrial dysfunctioning, neuroinflammation, prion like phenomena, excitotoxicity, mutations etc are known to cause pathological insult in PD. Recently, facts indicates strong correlation between gut-brain axis and PD. The communication between the gastrointestinal system (GIT) and central nervous system is bidirectional and it is hypothesized that PD arises in the gut and spreads to brain via vagus nerve that helps to propagate the alpha-synuclein that target brain. The Lewy bodies are found in olfactory bulb, dorsal motor vagal nerve and the ENS of the gut indicate peripheral and central correlation. The alteration of gut microbial flora leads to GIT disturbance which cause neuroinflammation by prion alpha-synuclein expression and produces PD like symptoms. Persistent gut inflammation with spontaneous neuroinflammation is yet need to confirm but increased intestinal permeability and disrupt function of GIT is known to produce non-motor symptoms of PD. The present review is aimed to explore mechanistic approach for gut associated PD symptoms as well as use of probiotics and prebiotics as therapeutic approach to retain gut microbial flora and prevent PD like symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

There is growing awareness within the scientific community of the strong connection between the inflammation in the intestine and the pathogenesis of Parkinson's disease (PD). In previous studies we developed a PD animal model exposing pup rats to permethrin (PERM) pesticide. Here, we intended to explore whether in our animal model there were changes in gut permeability, fecal microbiota and hepatic injury. Moreover, we tested if the co-treatment with an electrolyzed reduced (ERW) was effective to protect against alterations induced by PERM. Rats (from postnatal day 6 to 21) were gavaged daily with PERM, PERM+ERW or vehicle and gut, liver and feces were analyzed in 2-months-old rats. Increased gut permeability, measured by FITC-dextran assay, was detected in PERM group compared to control and PERM+ERW groups. In duodenum and ileum, concentration of occludin was higher in control group than those measured in PERM group, whereas only in duodenum ZO-1 was higher in control than those measured in PERM and PERM+ERW groups. Number of inflammatory focis and neutrophils as well as iNOS protein levels were higher in livers of PERM-treated rats than in those of PERM+ERW and control rats. Fecal microbiota analysis revealed that Lachnospira was less abundant and Defluviitaleaceae more abundant in the PERM group, whereas the co-treatment with ERW was protective against PERM treatment since the abundances in Lachnospira and Defluviitaleaceae were similar to those in the control group. Higher abundances of butyrate- producing bacteria such as Blautia, U.m. of Lachnospiraceae family, U.m. of Ruminococcaceae family, Papillibacter, Roseburia, Intestinimonas, Shuttleworthia together with higher butyric acid levels were detected in PERM+ERW group compared to the other groups. In conclusion, the PD animal model showed increased intestinal permeability together with hepatic inflammation correlated with altered gut microbiota. The positive effects of ERW co-treatment observed in gut, liver and brain of rats were linked to changes on gut microbiota., Competing Interests: The authors have declared that no competing interests exist.

Although the brain-gut axis appears to play a role in the pathogenesis of Parkinson's disease, the precise mechanisms underlying the actions of gut microbiota in this disease are unknown. This study was undertaken to investigate whether antibiotic-induced microbiome depletion affects dopaminergic neurotoxicity in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP significantly decreased dopamine transporter (DAT) immunoreactivity in the striatum and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra of water-treated mice. However, MPTP did not decrease DAT or TH immunoreactivity in the brains of mice treated with an antibiotic cocktail. Furthermore, antibiotic treatment significantly decreased the diversity and altered the composition of the host gut microbiota at the genus and species levels. Interestingly, MPTP also altered microbiome composition in antibiotic-treated mice. These findings suggest that antibiotic-induced microbiome depletion might protect against MPTP-induced dopaminergic neurotoxicity in the brain via the brain-gut axis.

The cell-to-cell transmission of the major pathogenic proteins of Parkinson's disease and Alzheimer's disease is reminiscent of the prion protein, which is defined as a proteinaceous infectious particle that causes human and animal transmissible spongiform encephalopathies. The possibility has raised that the pathogenic proteins of Parkinson's and Alzheimer's disease are infectious, i.e. that they can transmit disease from human to human. In this review, we address this question by comparing the similarities and differences between Alzheimer's disease/Parkinson's disease pathological proteins and prions and by discussing the possible consequences for disease transmission risk., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Parkinson's disease (PD) is a frequent neurodegenerative disease among elderly people. Genetic and underlying environmental factors seem to be involved in the pathogenesis of PD related to degeneration of dopaminergic neurons in the striatum. In previous experimental researches oxidative stress, mitochondrial dysfunction, homocysteine, and neuroinflammation have been reported as potential mechanisms. Among environmental factors, nutrition is one of the most investigated areas as it is a potentially modifiable factor. The purpose of this review is to provide current knowledge regarding the relation between diet and PD risk. We performed a comprehensive review including the most relevant studies from the year 2000 onwards including prospective studies, nested case-control studies, and meta-analysis. Among dietary factors we focused on specific nutrients and food groups, alcoholic beverages, uric acid, and dietary patterns. Furthermore, we included studies on microbiota as recent findings have shown a possible impact on neurodegeneration. As a conclusion, there are still many controversies regarding the relationship between PD and diet which, beside methodological differences among studies, may be due to underlying genetic and gender-specific factors. However, some evidence exists regarding a potential protective effect of uric acid, poly-unsaturated fatty acids, coffee, and tea but mainly in men, whereas dairy products, particularly milk, might increase PD risk through contaminant mediated effect.

Studies have confirmed that the gut microbiota may be involved in the pathogenesis of Parkinson's disease(PD). However, the alterations in fecal microbiome in North-eastern Han sporadic PD patients remains unknown. This case control study was conducted to explore fecal microbiota compositions in North-eastern Han sporadic PD patients. The gut microbiota composition of 10 patients with sporadic PD and over 65 age and 10 matched controls was analyzed in this study. Microbiota communities in the feces were investigated using high-throughput Illumina Miseq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene. The structure and richness of the fecal microbiota differed between PD patients and healthy controls. We had observed that the overall composition of gut microbiota in North-eastern Han Chinese healthy and PD patients was slightly different. The abundance of the family of Bacteroides and Prevotellaceae were significantly increased in heathy controls while the abundance of Ruminococcaceae, Verrucomicrobiaceae, Porphyromondaceae, Hydrogenoanaerobacterium and Lachnospiraceae NK4A were significantly enriched in North-eastern Han Chinese patients with PD. Sporadic PD patients North-eastern Han China is accompanied by alterations in the abundance of specific gut microbes. Our findings will provide a foundation to improve our understanding the pathogenesis of PD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: In recent years the hypothesis that gut microbiota associates with Parkinson's disease (PD) has gained importance, although it has not been possible to define a specific microbiota composition as a predictive biomarker of this disease. We have investigated dysbiosis of gut microbiota in a selected population of PD patients from Central Italy, and examined the weight of specific confounders and predictors, in order to identify potential correlations with clinical phenotypes., Methods: 152 fecal samples were collected from 80 patients and 72 healthy controls. Patients were enrolled according to tight inclusion criteria. Microbiota composition was studied through 16s ribosomal RNA gene amplicon sequencing analysis in combination with data on dietary/life habits. Age, loss of weight, and sex were recognized as confounding factors, whereas PD-status, age, Body Mass Index, "eat cereals", "gain of weigth" and "physical activity" as predictors. The presence of Lactobacillaceae, Enterobacteriaceae and Enterococcaceae families was significantly higher in feces from PD patients compared to healthy controls, while Lachnospiraceae were significantly reduced. Lower levels of Lachnospiraceae and higher levels of Enterobacteriaceae families also correlated with increased disease severity and motor impairment (Hoehn & Yahr stage, MDS-UPDRS Part III). Predictive metagenomics indicated a significant variation of genes involved in the metabolism of short chain fatty acids and amino acids, and in lipopolysaccharide biosynthesis., Conclusions: PD showed a distinctive microbiota composition. Functional predictions suggest changes in pathways favoring a pro-inflammatory environment in the gastrointestinal tract, and a reduction in the biosynthesis of amino acids acting as precursors of physiological transmitters., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles 1,2 . An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes 3 . PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells 4 , but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo 5-8 . It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens 9 , which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1 -/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8 + T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that 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, which highlights the relevance of the gut-brain axis in the disease 10 .