Roles of αsynuclein in gastrointestinal microbiome dysbiosisrelated Parkinson's disease progression (Review).
TL;DR: In this article, the abnormal accumulation of α-synuclein (α-syn) in the intestine caused by changes to the gastrointestinal microbiome (GM) caused misfolding and abnormal aggregation of α−syn in the intestines, leading to the formation of eosinophilic Lewis bodies in the cytoplasm and mitochondrial dysfunction in dopaminergic (DA) neurons.
Abstract: 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.
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TL;DR: The hypothesis that Parkinson’s disease could begin in the gut is supported, with a focus on how food-based therapies might then have an influence on PD and could ameliorate non-motor as well as motor symptoms.
Abstract: Parkinson’s disease is characterized by motor and non-motor symptoms, such as defects in the gut function, which may occur before the motor symptoms. To date, there are therapies that can improve these symptoms, but there is no cure to avoid the development or exacerbation of this disorder. Dysbiosis of gut microbiota could have a crucial role in the gut–brain axis, which is a bidirectional communication between the central nervous system and the enteric nervous system. Diet can affect the microbiota composition, impacting gut–brain axis functionality. Gut microbiome restoration through probiotics, prebiotics, synbiotics or other dietary means could have the potential to slow PD progression. In this review, we will discuss the influence of diet on the bidirectional communication between gut and brain, thus supporting the hypothesis that this disorder could begin in the gut. We also focus on how food-based therapies might then have an influence on PD and could ameliorate non-motor as well as motor symptoms.
16 citations
TL;DR: In this article , the authors discuss how the microbiota-gut-brain axis and environmental influences interact with the immune system to promote a pro-inflammatory state that is involved in the initiation and progression of misfolded α-synuclein proteins and the beginning of the early non-motor symptoms of Parkinson's disease.
6 citations
TL;DR: In this paper , the effects of probiotic Bifidobacterium breve CCFM1067, administered for 5 weeks in a Parkinson's disease (PD) mouse model, were examined.
Abstract: There is mounting evidence that the microbiota–gut–brain axis (MGBA) is critical in the pathogenesis and progression of Parkinson’s disease (PD), suggesting that probiotic therapy restoring gut microecology may slow down disease progression. In this study, we examined the disease-alleviating effects of Bifidobacterium breve CCFM1067, orally administered for 5 weeks in a PD mouse model. Our study shows that supplementation with the probiotic B. breve CCFM1067 protected dopaminergic neurons and suppressed glial cell hyperactivation and neuroinflammation in PD mice. In addition, the antioxidant capacity of the central nervous system was enhanced and oxidative stress was alleviated. Moreover, B. breve CCFM1067 protected the blood–brain and intestinal barriers from damage in the MPTP-induced mouse model. The results of fecal microbiota analysis showed that B. breve CCFM1067 intervention could act on the MPTP-induced microecological imbalance in the intestinal microbiota, suppressing the number of pathogenic bacteria (Escherichia-Shigella) while increasing the number of beneficial bacteria (Bifidobacterium and Akkermansia) in PD mice. In addition, the increase in short chain fatty acids (acetic and butyric acids) may explain the anti-inflammatory action of B. breve CCFM1067 in the gut or brain of the MPTP-induced PD mouse model. In conclusion, we demonstrated that the probiotic B. breve CCFM1067, which can prevent or treat PD by modulating the gut–brain axis, can be utilized as a possible new oral supplement for PD therapy.
4 citations
TL;DR: In this paper , Bacillus amyloliquefaciens-supplemented camel milk (BASY) was used to assess its preventive effect on MS symptoms in a myelin oligodendrocyte glycoprotein (MOG)-immunized C57BL6J mice model.
Abstract: Multiple sclerosis (MS), a distinct autoimmune neuroinflammatory disorder, affects millions of people worldwide, including Saudi Arabia. Changes in the gut microbiome are linked to the development of neuroinflammation via mechanisms that are not fully understood. Prebiotics and probiotics in camel milk that has been fermented have a variety of health benefits. In this study, Bacillus amyloliquefaciens-supplemented camel milk (BASY) was used to assess its preventive effect on MS symptoms in a myelin oligodendrocyte glycoprotein (MOG)-immunized C57BL6J mice model. To this end, MOG-induced experimental autoimmune encephalomyelitis (EAE) was established and the level of disease index, pathological scores, and anti-inflammatory markers of BASY-treated mice using macroscopic and microscopic examinations, qPCR and immunoblot were investigated. The results demonstrate that BASY significantly reduced the EAE disease index, increased total microbial load (2.5 fold), and improved the levels of the short-chain fatty acids propionic, butyric and caproic acids in the diseased mice group. Additionally, myeloperoxidase (MPO) proinflammatory cytokines (IL-1β, IL-6, IL-17, TNF-α) and anti-inflammatory cytokines (TGF-β) were regulated by BASY treatment. Significant suppression of MPO and VCAM levels were noticed in the BASY-treated group (from 168 to 111 µM and from 34 to 27 pg/mL, respectively), in comparison to the EAE group. BASY treatment significantly reduced the expression of inflammatory cytokines, inflammatory progression related transcripts, and inflammatory progression protein markers. In conclusion, BASY significantly reduced the symptoms of EAE mice and may be used to develop a probiotic-based diet to promote host gut health. The cumulative findings of this study confirm the significant neuroprotection of BASY in the MOG-induced mice model. They could also suggest a novel approach to the treatment of MS-associated disorders.
2 citations
TL;DR: In this article , the role of m6A modification and its underlying mechanism in Parkinson's disease was investigated and the potential of METTL14 as a novel diagnostic biomarker for PD was revealed.
Abstract: N6‐methyladenosine (m6A), an emerging modification of messenger RNA, has been implicated in many biological processes. However, its role in Parkinson's disease (PD) remains largely unknown. Here, we investigated the role of m6A modification and its underlying mechanism in PD. First, 86 individuals with PD and 86 healthy controls were recruited from a pilot multicenter cohort. Levels of m6A and its modulators in peripheral blood mononuclear cells of patients with PD and controls were measured using an m6A RNA methylation quantification kit and quantitative real‐time PCR. The underlying mechanism of m6A modification in PD was investigated in vitro through RNA immunoprecipitation assay, RNA stability assay, gene silencing or overexpression, western blot, and confocal immunoassay. The results show that mRNA levels of m6A, METTL3, METTL14, and YTHDF2 in patients with PD were significantly lower than in healthy controls, and METTL14 was the main factor involved in abnormal m6A modification. Area under the curve (AUC) analysis suggests METTL14 may provide excellent diagnostic capability for PD, especially when combined with plasma α‐synuclein (α‐syn). Spearman correlation analysis identified that METTL14 was moderately negatively correlated with plasma α‐syn and the motor function of PD. Mechanistic experiments demonstrated that Mettl14 targets and regulates the expression of the α‐syn gene using its methylation function. Overexpression of Mettl14 dramatically increased m6A modification of α‐syn mRNA and weakened its stability. Further results suggest that α‐syn mRNA was modified by Mettl14 binding of an m6A motif in the coding region of α‐syn mRNA, while the reading protein Ythdf2 was involved in recognizing m6A‐modified α‐syn mRNA. Taken together, our results reveal the potential of METTL14 as a novel diagnostic biomarker for PD and identify modification of pathogenic α‐syn protein by METTL14 via an m6A‐YTHDF2‐dependent mechanism.
1 citations
References
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TL;DR: In this paper, a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level.
Abstract: Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.
9,745 citations
TL;DR: This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
8,452 citations
TL;DR: By combining the rationale of pro- and prebiotics, the concept of synbiotics is proposed to characterize some colonic foods with interesting nutritional properties that make these compounds candidates for classification as health-enhancing functional food ingredients.
Abstract: Because the human gut microbiota can play a major role in host health, there is currently some interest in the manipulation of the composition of the gut flora towards a potentially more remedial community. Attempts have been made to increase bacterial groups such as Bifidobacterium and Lactobacillus that are perceived as exerting health-promoting properties. Probiotics, defined as microbial food supplements that beneficially affect the host by improving its intestinal microbial balance, have been used to change the composition of colonic microbiota. However, such changes may be transient, and the implantation of exogenous bacteria therefore becomes limited. In contrast, prebiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health. Intake of prebiotics can significantly modulate the colonic microbiota by increasing the number of specific bacteria and thus changing the composition of the microbiota. Nondigestible oligosaccharides in general, and fructooligosaccharides in particular, are prebiotics. They have been shown to stimulate the growth of endogenous bifidobacteria, which, after a short feeding period, become predominant in human feces. Moreover, these prebiotics modulate lipid metabolism, most likely via fermentation products. By combining the rationale of pro- and prebiotics, the concept of synbiotics is proposed to characterize some colonic foods with interesting nutritional properties that make these compounds candidates for classification as health-enhancing functional food ingredients.
7,232 citations
TL;DR: A systematic review of studies reporting LEDs yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale.
Abstract: Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.
3,379 citations
TL;DR: The goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category.
Abstract: With the continued interest in the role of the gut microbiota in health, attention has now turned to how to harness the microbiota for the benefit of the host. This Consensus Statement outlines the definition and scope of the term 'prebiotic' as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in December 2016. In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation.
2,863 citations