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

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Reviewed Marked as Reviewed by Peace Sandy on 2024-2-11
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


Reviewed Marked as Reviewed by Peace Sandy on 2024-2-11

Curated date: 2023/06/03

Curator: Fcuevas3

Revision editor(s): Fcuevas3, Peace Sandy, Victoria

Subjects

Location of subjects
United States of America
Host species Species from which microbiome was sampled. Contact us to have more species added.
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,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,parkinson's disease
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)
3 Months

Lab analysis

Sequencing type
WMS
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
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).
centered log-ratio
Statistical test
ANCOM
MaAsLin2
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
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

Reviewed Marked as Reviewed by Peace Sandy on 2024-2-11

Curated date: 2023/06/03

Curator: Fcuevas3

Revision editor(s): Fcuevas3, Peace Sandy

Source: Fig. 3

Description: Differential abundances and effect sizes of PD-associated species. Analysis included N = 724 biologically independent samples from 490 PD and 234 neurologically healthy control (NHC) subjects. Forty-six species that had at least 75% (and up to 750%) change in abundance in PD are shown here; for all 84 PD-associated species see Supplementary Fig. 3. a Distribution of relative abundances. Log2 transformed relative abundance values, as used in MaAsLin2, were used to generate the boxplots. Untransformed relative abundances, shown in parenthesis, are provided on the X-axis for easier interpretation of data. Boxplots show distribution of the data for PD (blue green) and NHC (orange). Each sample was plotted according to its abundance of the species. The left, middle, and right vertical boundaries of each box represents the first, second (median), and third quartiles of the data; that is, 25% of samples have abundance lower than the left border of the box, 25% of samples have abundances that are higher than the right border of the box. Absence of a box indicates 75% of samples had zero abundance. The lines extending from the two ends of each box represent 1.5x outside the interquartile range (range = (abundance value at 75% minus abundance value at 25%) x 1.5). Points beyond the lines are outlier samples.

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

NCBI Quality ControlLinks
Bifidobacterium dentium
Actinomyces oris
Streptococcus mutans
[Clostridium] leptum
Acidaminococcus intestini
Eisenbergiella tayi
Methanobrevibacter smithii
Alistipes indistinctus
Bifidobacterium bifidum
Escherichia coli
Ruminococcaceae bacterium D16
Bifidobacterium longum
Hungatella hathewayi
Ruthenibacterium lactatiformans
Parabacteroides distasonis
Alistipes finegoldii
Klebsiella pneumoniae
Actinomyces
[Clostridium] innocuum

Revision editor(s): Fcuevas3, Peace Sandy

Signature 2

Reviewed Marked as Reviewed by Peace Sandy on 2024-2-11

Curated date: 2023/06/03

Curator: Fcuevas3

Revision editor(s): Fcuevas3, Peace Sandy

Source: Fig. 3

Description: Differential abundances and effect sizes of PD-associated species. Analysis included N = 724 biologically independent samples from 490 PD and 234 neurologically healthy control (NHC) subjects. Forty-six species that had at least 75% (and up to 750%) change in abundance in PD are shown here; for all 84 PD-associated species see Supplementary Fig. 3. a Distribution of relative abundances. Log2 transformed relative abundance values, as used in MaAsLin2, were used to generate the boxplots. Untransformed relative abundances, shown in parenthesis, are provided on the X-axis for easier interpretation of data. Boxplots show distribution of the data for PD (blue green) and NHC (orange). Each sample was plotted according to its abundance of the species. The left, middle, and right vertical boundaries of each box represents the first, second (median), and third quartiles of the data; that is, 25% of samples have abundance lower than the left border of the box, 25% of samples have abundances that are higher than the right border of the box. Absence of a box indicates 75% of samples had zero abundance. The lines extending from the two ends of each box represent 1.5x outside the interquartile range (range = (abundance value at 75% minus abundance value at 25%) x 1.5). Points beyond the lines are outlier samples.

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

NCBI Quality ControlLinks
Roseburia intestinalis
Blautia wexlerae
Fusicatenibacter saccharivorans
Anaerostipes hadrus
Roseburia faecis
Faecalibacterium prausnitzii
Ruminococcus bicirculans (ex Wegman et al. 2014)
[Ruminococcus] lactaris
Roseburia inulinivorans
Prevotella corporis
Blautia hansenii
Eubacterium ramulus
Clostridium sp.
Monoglobus pectinilyticus
Dialister invisus
Lachnospira eligens

Revision editor(s): Fcuevas3, Peace Sandy