Gut microbiota and metabolites of α-synuclein transgenic monkey models with early stage of Parkinson’s disease

AbstractParkinson’s disease (PD) is the second most prevalent neurodegenerative disease. However, it is unclear whether microbiota and metabolites have demonstrated changes at early PD due to the difficulties in diagnosis and identification of early PD in clinical practice. In a previous study, we generated A53T transgenic monkeys with early Parkinson’s symptoms, including anxiety and cognitive impairment. Here we analyzed the gut microbiota by metagenomic sequencing and metabolites by targeted gas chromatography. The gut microbiota analysis showed that the A53T monkeys have higher degree of diversity in gut microbiota with significantly elevated Sybergistetes, Akkermansia, and Eggerthella lenta compared with control monkeys. Prevotella significantly decreased in A53T transgenic monkeys. Glyceric acid, L-Aspartic acid, and p-Hydroxyphenylacetic acid were significantly elevated, whereas Myristic acid and 3-Methylindole were significantly decreased in A53T monkeys. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (KO0131) and the oxidative phosphorylation reaction (KO2147) were significantly increased in metabolic pathways of A53T monkeys. Our study suggested that the transgenic A53T and α-syn aggregation may affect the intestine microbiota and metabolites of rhesus monkeys, and the identified five compositional different metabolites that are mainly associated with mitochondrial dysfunction may be related to the pathogenesis of PD.

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Gut microbiota and metabolites of α-synuclein transgenic monkey models with early stage of Parkinson'sdisease

10.21203/rs.3.rs-54649/v1 ◽

2020 ◽

Author(s):

wei si ◽

yaping yan ◽

shuchao ren ◽

yanchao duan ◽

chenyu lu ◽

...

Keyword(s):

Gut Microbiota ◽

Abc Transporters ◽

Metabolic Pathways ◽

Early Stage ◽

Antibiotic Use ◽

Living Environment ◽

Glyceric Acid ◽

Metagenomic Sequencing ◽

Physiological Processes ◽

Hydroxyphenylacetic Acid

Abstract Background: Parkinson's disease（PD）is the second most prevalent neurodegenerative disease. Gut microbes are susceptible to various external factors (such as living environment, diet, antibiotic use), our research avoids these interferences very well. Gut microbiota affect the physiological processes of the host by regulating metabolites. However, it is unclear whether microbiota and metabolites have demonstrated changes at early stages of PD due to the difficulty to diagnose and identify early stage PD in clinical practice.Methods: In a previous study, we constructed A53T transgenic monkeys with early Parkinson's symptoms. Here we analyzed the gut microbiota by metagenomic sequencing and metabolites by untargeted chromatography, which represent the first effort to identify the association between intestinal microbiota, metabolites and early stage of PD.Results: Compared with control monkeys, the gut microbiota of A53T monkeys is more diverse. Sybergistetes and Eggerthella lenta were significantly elevated in A53T monkeys. In monkeys with early Parkinson's symptoms, Glyceric acid, L-Aspartic acid and p-Hydroxyphenylacetic acid were significantly elevated, but Myristic acid and 3-Methylindole was significantly decreased. ABC transporters are associated with two decreased metabolites. Metabolic pathways are associated with three elevated metabolites. We found KO0131 and KO2147 from metabolic pathways are related to Glycolysis.Conclusion: We identified differential gut microbiota coincides with the microbiota of the currently reported PD patients to some extent. We found these differential metabolites and KOs suggest that A53T monkeys may have Glycolysis problem, and Glycolysis problem may be associated with mitochondrial dysfunction. Our results may be a sign of early Parkinson's screening and diagnosis.

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Changes in the Gut Microbiome and Predicted Functional Metabolic Effects in an Australian Parkinson’s Disease Cohort

Frontiers in Neuroscience ◽

10.3389/fnins.2021.756951 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jade E. Kenna ◽

Eng Guan Chua ◽

Megan Bakeberg ◽

Alfred Tay ◽

Sarah McGregor ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gut Microbiota ◽

Gut Microbiome ◽

Metabolic Pathways ◽

Metabolic Effects ◽

Rrna Gene ◽

Microbial Composition ◽

Kegg Analysis ◽

Cohort Differences

Background: There has been increasing recognition of the importance of the gut microbiome in Parkinson’s disease (PD), but the influence of geographic location has received little attention. The present study characterized the gut microbiota and associated changes in host metabolic pathways in an Australian cohort of people with PD (PwP).Methods: The study involved recruitment and assessment of 87 PwP from multiple Movement Disorders Clinics in Australia and 47 healthy controls. Illumina sequencing of the V3 and V4 regions of the 16S rRNA gene was used to distinguish inter-cohort differences in gut microbiota; KEGG analysis was subsequently performed to predict functional changes in host metabolic pathways.Results: The current findings identified significant differences in relative abundance and diversity of microbial operational taxonomic units (OTUs), and specific bacterial taxa between PwP and control groups. Alpha diversity was significantly reduced in PwP when compared to controls. Differences were found in two phyla (Synergistetes and Proteobacteria; both increased in PwP), and five genera (Colidextribacter, Intestinibacter, Kineothrix, Agathobaculum, and Roseburia; all decreased in PwP). Within the PD cohort, there was no association identified between microbial composition and gender, constipation or use of gastrointestinal medication. Furthermore, KEGG analysis identified 15 upregulated and 11 downregulated metabolic pathways which were predicted to be significantly altered in PwP.Conclusion: This study provides the first comprehensive characterization of the gut microbiome and predicted functional metabolic effects in a southern hemisphere PD population, further exploring the possible mechanisms whereby the gut microbiota may exert their influence on this disease, and providing evidence for the incorporation of such data in future individualized therapeutic strategies.

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Development of a stable, early stage unilateral model of Parkinson's disease in middle-aged rhesus monkeys

Experimental Neurology ◽

10.1016/j.expneurol.2008.04.027 ◽

2008 ◽

Vol 212 (2) ◽

pp. 431-439 ◽

Cited By ~ 19

Author(s):

Feng Ding ◽

Liming Luan ◽

Yi Ai ◽

Ashley Walton ◽

Greg A. Gerhardt ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rhesus Monkeys ◽

Early Stage ◽

Middle Aged

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Gut Status in Parkinson’s Disease: The GutSPark Protocol

Medical Sciences Forum ◽

10.3390/msf2021005031 ◽

2021 ◽

Vol 5 (1) ◽

pp. 31

Author(s):

Miguel Grunho ◽

Catarina Godinho ◽

António Alves de Matos ◽

Helena Barroso ◽

Ricardo Carregosa ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Oral Health ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Early Stage ◽

Alpha Synuclein ◽

Inflammatory Conditions ◽

Biopsy Specimens ◽

Digestive Disorders

The neuropathological hallmark of Parkinson’s disease (PD) is the accumulation of alpha–synuclein (AS) aggregates. The identification of AS aggregates in gut biopsy specimens from people with PD may provide an opportunity to identify PD at a very early stage, prior to symptom onset. Changes in gut microbiota and inflammatory conditions (such as periodontitis) may be linked with PD onset/evolution. This project aims to explore the concept of microbiota–gut–brain axis in PD, studying gut biopsy specimens for AS aggregates, oral and intestinal microbiota, associated digestive disorders and oral health, of both patients with PD and controls.

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Gut Microbiota and Metabolome Alterations Associated with Parkinson’s Disease

mSystems ◽

10.1128/msystems.00561-20 ◽

2020 ◽

Vol 5 (5) ◽

Cited By ~ 5

Author(s):

Sarah Vascellari ◽

Vanessa Palmas ◽

Marta Melis ◽

Silvia Pisanu ◽

Roberto Cusano ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gut Microbiota ◽

Metabolic Pathways ◽

Short Chain Fatty Acid ◽

Direct Analysis ◽

Chain Fatty Acid ◽

Protective Effects ◽

Intestinal Dysbiosis ◽

Synergistic Relationship

To our knowledge, this is one of the few studies thus far that correlates the composition of the gut microbiota with the direct analysis of fecal metabolites in patients with Parkinson’s disease. Overall, our data highlight microbiota modifications correlated with numerous fecal metabolites. This suggests that Parkinson’s disease is associated with gut dysregulation that involves a synergistic relationship between gut microbes and several bacterial metabolites favoring altered homeostasis. Interestingly, a reduction of short-chain fatty acid (SCFA)-producing bacteria influenced the shape of the metabolomics profile, affecting several metabolites with potential protective effects in the Parkinson group. On the other hand, the extensive impact that intestinal dysbiosis has at the level of numerous metabolic pathways could encourage the identification of specific biomarkers for the diagnosis and treatment of Parkinson’s disease, also in light of the effect that specific drugs have on the composition of the intestinal microbiota.

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Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202127 ◽

2020 ◽

Vol 10 (4) ◽

pp. 1541-1549

Author(s):

Seok Jong Chung ◽

Sangwon Lee ◽

Han Soo Yoo ◽

Yang Hyun Lee ◽

Hye Sun Lee ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Early Stage ◽

Striatal Dopamine ◽

Motor Deficits ◽

Dopamine Depletion ◽

Severe Motor ◽

Severe Group ◽

Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

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Gene expression analysis in modeling Parkinson’s disease

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.04.103-104 ◽

2020 ◽

pp. 103-104

Author(s):

М.М. Руденок ◽

А.Х. Алиева ◽

А.А. Колачева ◽

М.В. Угрюмов ◽

П.А. Сломинский ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Stage ◽

Systemic Disease ◽

Molecular Genetic ◽

Presymptomatic Stage ◽

Whole Transcriptome Analysis ◽

Whole Transcriptome ◽

The Brain ◽

Transcriptome Level

Несмотря на очевидный прогресс, достигнутый в изучении молекулярно-генетических факторов и механизмов патогенеза болезни Паркинсона (БП), в настоящее время стало ясно, что нарушения в структуре ДНК не описывают весь спектр патологических изменений, наблюдаемых при развитии заболевания. В настоящее время показано, что существенное влияние на патогенез БП могут оказывать изменения на уровне транскриптома. В работе были использованы мышиные модели досимптомной стадии БП, поздней досимптомной и ранней симптомной (РСС) стадиями БП. Для полнотранскриптомного анализа пулов РНК тканей черной субстанции и стриатума мозга мышей использовались микрочипы MouseRef-8 v2.0 Expression BeadChip Kit («Illumina», США). Полученные данные указывают на последовательное вовлечение транскриптома в патогенез БП, а также на то, что изменения на транскриптомном уровне процессов транспорта и митохондриального биогенеза могут играть важную роль в нейродегенерации при БП уже на самых ранних этапах. Parkinson’s disease (PD) is a complex systemic disease, mainly associated with the death of dopaminergic neurons. Despite the obvious progress made in the study of molecular genetic factors and mechanisms of PD pathogenesis, it has now become clear that violations in the DNA structure do not describe the entire spectrum of pathological changes observed during the development of the disease. It has now been shown that changes at the transcriptome level can have a significant effect on the pathogenesis of PD. The authors used models of the presymptomatic stage of PD with mice decapitation after 6 hours (6 h-PSS), presymptomatic stage with decapitation after 24 hours (24 h-PSS), advanced presymptomatic (Adv-PSS) and early symptomatic (ESS) stages of PD. For whole transcriptome analysis of RNA pools of the substantia nigra and mouse striatum, the MouseRef-8 v2.0 Expression BeadChip Kit microchips (Illumina, USA) were used. As a result of the analysis of whole transcriptome data, it was shown that, there are a greater number of statistically significant changes in the tissues of the brain and peripheral blood of mice with Adv-PSS and ESS models of PD compared to 6 h-PSS and 24 h-PSS models. In general, the obtained data indicate the sequential involvement of the transcriptome in the pathogenesis of PD, as well as the fact that changes at the transcriptome level of the processes of transport and mitochondrial biogenesis can play an important role in neurodegeneration in PD at an early stage.

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