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      The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder

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          ABSTRACT

          Background

          Increasing evidence connects the gut microbiota and the onset and/or phenotype of Parkinson's disease (PD). Differences in the abundances of specific bacterial taxa have been reported in PD patients. It is, however, unknown whether these differences can be observed in individuals at high risk, for example, with idiopathic rapid eye movement sleep behavior disorder, a prodromal condition of α‐synuclein aggregation disorders including PD.

          Objectives

          To compare microbiota in carefully preserved nasal wash and stool samples of subjects with idiopathic rapid eye movement sleep behavior disorder, manifest PD, and healthy individuals.

          Methods

          Microbiota of flash‐frozen stool and nasal wash samples from 76 PD patients, 21 idiopathic rapid eye movement sleep behavior disorder patients, and 78 healthy controls were assessed by 16S and 18S ribosomal RNA amplicon sequencing. Seventy variables, related to demographics, clinical parameters including nonmotor symptoms, and sample processing, were analyzed in relation to microbiome variability and controlled differential analyses were performed.

          Results

          Differentially abundant gut microbes, such as Akkermansia, were observed in PD, but no strong differences in nasal microbiota. Eighty percent of the differential gut microbes in PD versus healthy controls showed similar trends in idiopathic rapid eye movement sleep behavior disorder, for example, Anaerotruncus and several Bacteroides spp., and correlated with nonmotor symptoms. Metagenomic sequencing of select samples enabled the reconstruction of genomes of so far uncharacterized differentially abundant organisms.

          Conclusion

          Our study reveals differential abundances of gut microbial taxa in PD and its prodrome idiopathic rapid eye movement sleep behavior disorder in comparison to the healthy controls, and highlights the potential of metagenomics to identify and characterize microbial taxa, which are enriched or depleted in PD and/or idiopathic rapid eye movement sleep behavior disorder. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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          Most cited references38

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          Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals

          ABSTRACT No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways.
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            Parkinson's disease: a dual‐hit hypothesis

            Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non‐motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose – hence the term ‘dual‐hit’.
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              Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

              Background Parkinson’s disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker. Methods We performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls. Results We found increased Verrucomicrobiaceae (Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae (Prevotella copri) and Erysipelotrichaceae (Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions. Conclusions Our data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0428-y) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                brit.mollenhauer@paracelsus-kliniken.de
                paul.wilmes@uni.lu
                Journal
                Mov Disord
                Mov. Disord
                10.1002/(ISSN)1531-8257
                MDS
                Movement Disorders
                John Wiley and Sons Inc. (Hoboken )
                0885-3185
                1531-8257
                26 August 2017
                January 2018
                : 33
                : 1 ( doiID: 10.1002/mds.v33.1 )
                : 88-98
                Affiliations
                [ 1 ] Eco‐Systems Biology Research Group, Luxembourg Centre for Systems Biomedicine (LCSB) University of Luxembourg Esch‐sur‐Alzette Luxembourg
                [ 2 ] Paracelsus‐Elena‐Klinik Kassel Germany
                [ 3 ] Department of Neurology Philipps University Marburg Germany
                [ 4 ] University Medical Center Goettingen, Department of Neurosurgery Goettingen Germany
                [ 5 ] University Medical Center Goettingen, Department of Neurology Goettingen Germany
                Author notes
                [*] [* ] Correspondence to: Dr. Paul Wilmes, Eco‐Systems Biology Research Group, Luxembourg Centre for Systems Biomedicine, 6, avenue des Hauts‐Fourneaux, 4362 Esch‐sur‐Alzette, Luxembourg; E‐mail: paul.wilmes@ 123456uni.lu ; or Dr. Brit Mollenhauer, Paracelsus‐Elena‐Klinik, Klinikstraße 16, 34128 Kassel, Germany; E‐mail: brit.mollenhauer@ 123456paracelsus-kliniken.de
                [†]

                Drs. Mollenhauer and Wilmes made equal contributions.

                Author information
                http://orcid.org/0000-0002-9780-1933
                Article
                MDS27105
                10.1002/mds.27105
                5811909
                28843021
                7ef4ea4b-ae41-440f-8eff-64a3f630be59
                © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 April 2017
                : 22 June 2017
                : 23 June 2017
                Page count
                Figures: 3, Tables: 1, Pages: 12, Words: 8021
                Funding
                Funded by: BIOMARKAPD
                Funded by: EU Joint Programme on Neurodegenerative Diseases (JPND) co‐funded by the Luxembourg National Research Fund (FNR)
                Funded by: FNR CORE grant
                Award ID: BM/10404093
                Funded by: “Espoir en tête” grant from the Rotary Club Luxembourg
                Funded by: University Medical Center Göttingen, Paracelsus‐Elena‐Klinik
                Funded by: Michael J. Fox Foundation for Parkinson's Research (MJFF)
                Funded by: Parkinson Fond Deutschland
                Funded by: Deutsche Parkinson Vereinigung
                Funded by: Charitable Hertie‐Foundation
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                mds27105
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:14.02.2018

                Medicine
                pd,rbd,nonmotor phenotype,16s rrna gene amplicon sequencing,genome reconstructions
                Medicine
                pd, rbd, nonmotor phenotype, 16s rrna gene amplicon sequencing, genome reconstructions

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