Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms

From BugSigDB
Needs review
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
Wallen ZD, Demirkan A, Twa G, Cohen G, Dean MN, Standaert DG, Sampson TR, Payami H
Journal
Nature communications
Year
2022
Parkinson's disease (PD) may start in the gut and spread to the brain. To investigate the role of gut microbiome, we conducted a large-scale study, at high taxonomic resolution, using uniform standardized methods from start to end. We enrolled 490 PD and 234 control individuals, conducted deep shotgun sequencing of fecal DNA, followed by metagenome-wide association studies requiring significance by two methods (ANCOM-BC and MaAsLin2) to declare disease association, network analysis to identify polymicrobial clusters, and functional profiling. Here we show that over 30% of species, genes and pathways tested have altered abundances in PD, depicting a widespread dysbiosis. PD-associated species form polymicrobial clusters that grow or shrink together, and some compete. PD microbiome is disease permissive, evidenced by overabundance of pathogens and immunogenic components, dysregulated neuroactive signaling, preponderance of molecules that induce alpha-synuclein pathology, and over-production of toxicants; with the reduction in anti-inflammatory and neuroprotective factors limiting the capacity to recover. We validate, in human PD, findings that were observed in experimental models; reconcile and resolve human PD microbiome literature; and provide a broad foundation with a wealth of concrete testable hypotheses to discern the role of the gut microbiome in PD.

Experiment 1


Needs review

Curated date: 2023/06/03

Curator: Fcuevas3

Revision editor(s): Fcuevas3

Subjects

Location of subjects
United States of America
Host species Species from which microbiome was sampled (if applicable)
Homo sapiens
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Parkinson's disease IDIOPATHIC PARKINSON DIS,Idiopathic Parkinson Disease,Idiopathic Parkinson's Disease,IDIOPATHIC PARKINSONS DIS,Idiopathic PD,LEWY BODY PARKINSON DIS,Lewy Body Parkinson Disease,Lewy Body Parkinson's Disease,Paralysis agitans,paralysis agitans,PARKINSON DIS,PARKINSON DIS IDIOPATHIC,Parkinson disease,Parkinson Disease, Idiopathic,Parkinson syndrome,Parkinson's,Parkinson's disease,Parkinson's disease (disorder),Parkinson's disease NOS,Parkinson's disease NOS (disorder),Parkinson's Disease, Idiopathic,Parkinson's Disease, Lewy Body,Parkinson's syndrome,Parkinsonian disorder,Parkinsonism, Primary,Parkinsons,PARKINSONS DIS,PARKINSONS DIS IDIOPATHIC,PARKINSONS DIS LEWY BODY,Parkinsons disease,Primary Parkinsonism
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Healthy controls.
Group 1 name Corresponds to the case (exposed) group for case-control studies
Parkinson's Disease subjects.
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Potential PD cases for enrollment were identified via systematic pre-screening of electronic medical records (EMR) of patients with an upcoming appointment in the Movement Disorder Clinic at UAB. Subjects were invited to enroll in the study after their clinic visit if the attending specialist confirmed PD diagnosis and the patient was willing to hear about the study.
Group 0 sample size Number of subjects in the control (unexposed) group
234
Group 1 sample size Number of subjects in the case (exposed) group
490
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
N/A

Lab analysis

Sequencing type
WMS
Not specified
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
ANCOM
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.1
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes
Matched on Factors on which subjects have been matched on in a case-control study
Matched on: "Environmental effects" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.Environmental effects
Confounders controlled for Confounding factors that have been accounted for by stratification or model adjustment
Confounders controlled for: "stool sample collection method" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.stool sample collection method, Confounders controlled for: "total sequence count per sample" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.total sequence count per sample


Signature 1

Needs review

Curated date: 2023/06/03

Curator: Fcuevas3

Revision editor(s): Fcuevas3

Source: Supplementary Figure 4. Species correlation networks for PD and neurologically healthy controls.

Description: PD metagenome network with species that emerged from MWAS(ANCOM-BC) as having significantly higher abundance in PD than NHC are colored blue, and those that had significantly lower abundance in PD than NHC colored red.

Abundance in Group 1: increased abundance in Parkinson's Disease subjects.

NCBI Quality ControlLinks
Acidaminococcus intestini
Actinomyces naeslundii
Actinomyces oris
Actinomyces sp. oral taxon 448
Alistipes finegoldii
Alistipes indistinctus
Bacteroides faecis CAG:32
Bifidobacterium bifidum
Bifidobacterium breve
Bifidobacterium dentium
Bifidobacterium longum
Bifidobacterium pullorum
Bifidobacterium pullorum subsp. gallinarum
Bifidobacterium pullorum subsp. saeculare
Candidatus Methanomassiliicoccus intestinalis
Christensenella minuta
Cloacibacillus evryensis
Coprobacillus cateniformis
Eisenbergiella tayi
Enorma massiliensis
Enterococcus avium
Enterococcus faecium
Escherichia coli
Eubacterium callanderi
Eubacterium limosum
Harryflintia acetispora
Hungatella hathewayi
Klebsiella pneumoniae
Klebsiella quasipneumoniae
Lachnoclostridium sp. An131
Lactobacillus gasseri
Lactobacillus paragasseri
Ligilactobacillus salivarius
Limosilactobacillus fermentum
Limosilactobacillus reuteri
Megasphaera sp. DISK 18
Megasphaera sp. MJR8396C
Methanobrevibacter smithii
Parabacteroides distasonis
Porphyromonas asaccharolytica
Pseudoflavonifractor sp. An184
Ruminococcaceae bacterium D5
Ruthenibacterium lactatiformans
Scardovia wiggsiae
Streptococcus anginosus
Streptococcus lutetiensis
Streptococcus mutans
Streptococcus vestibularis
Turicibacter sanguinis
[Clostridium] hylemonae
[Clostridium] innocuum
[Clostridium] leptum
[Collinsella] massiliensis
Lacticaseibacillus rhamnosus
Actinomyces sp. HPA0247

Revision editor(s): Fcuevas3

Signature 2

Needs review

Curated date: 2023/06/03

Curator: Fcuevas3

Revision editor(s): Fcuevas3

Source: Supplementary Figure 4. Species correlation networks for PD and neurologically healthy controls.

Description: PD metagenome network with species that emerged from MWAS as having significantly higher abundance in PD than NHC are colored blue, and those that had significantly lower abundance in PD than NHC colored red.

Abundance in Group 1: decreased abundance in Parkinson's Disease subjects.

NCBI Quality ControlLinks
Roseburia intestinalis
Blautia wexlerae
Fusicatenibacter saccharivorans
Anaerostipes hadrus
Agathobacter rectalis
Roseburia faecis
Faecalibacterium prausnitzii
Eubacterium sp. CAG:38
Ruminococcus bicirculans (ex Wegman et al. 2014)
[Ruminococcus] lactaris
Roseburia inulinivorans
Segatella copri
Clostridium sp. CAG:299
Blautia hansenii
Eubacterium ramulus
Clostridium sp. CAG:58
Monoglobus pectinilyticus
Lachnospira eligens
Dialister invisus
Anaerobutyricum hallii
Rothia mucilaginosa
Actinomyces sp. ICM47
Streptococcus australis
Streptococcus mitis
Butyricicoccus pullicaecorum
Ruminococcus callidus
Streptococcus sp. A12
Veillonella dispar
Streptococcus infantis

Revision editor(s): Fcuevas3