Metagenome-wide association of gut microbiome features for schizophrenia

From BugSigDB
Reviewed Marked as Reviewed by Atrayees on 2023-7-20
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
Authors
Zhu F, Ju Y, Wang W, Wang Q, Guo R, Ma Q, Sun Q, Fan Y, Xie Y, Yang Z, Jie Z, Zhao B, Xiao L, Yang L, Zhang T, Feng J, Guo L, He X, Chen Y, Chen C, Gao C, Xu X, Yang H, Wang J, Dang Y, Madsen L, Brix S, Kristiansen K, Jia H, Ma X
Journal
Nature communications
Year
2020
Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models.

Experiment 1


Reviewed Marked as Reviewed by Atrayees on 2023-7-20

Curated date: 2021/09/21

Curator: Titas

Revision editor(s): Titas, Aiyshaaaa, WikiWorks, Atrayees

Subjects

Location of subjects
China
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
schizophrenia [X]Schizophrenia, unspecified,[X]Schizophrenia, unspecified (disorder),Dementia Praecox,Disorder, Schizophrenic,Disorders, Schizophrenic,Other specified types of schizophrenia,Other specified types of schizophrenia, chronic state,Other specified types of schizophrenia, chronic state with acute exacerbation,Other specified types of schizophrenia, in remission,Other specified types of schizophrenia, subchronic state,Other specified types of schizophrenia, subchronic state with acute exacerbation,Other specified types of schizophrenia, unspecified state,SCHIZO NEC-CHR/EXACERB,SCHIZO NEC-SUBCHR/EXACER,SCHIZO NOS-CHR/EXACERB,SCHIZO NOS-SUBCHR/EXACER,schizoaffective disorder,schizophrenia,schizophrenia (disease),Schizophrenia (disorder),SCHIZOPHRENIA NEC-CHR,SCHIZOPHRENIA NEC-REMISS,SCHIZOPHRENIA NEC-SUBCHR,SCHIZOPHRENIA NEC-UNSPEC,Schizophrenia NOS,Schizophrenia NOS (disorder),SCHIZOPHRENIA NOS-UNSPEC,schizophrenia with or without an affective disorder,Schizophrenia, NOS,schizophrenia-1,Schizophrenias,SCHIZOPHRENIC DIS,Schizophrenic Disorder,Schizophrenic Disorders,Schizophrenic disorders (disorder),SCZD,Unspecified schizophrenia,Unspecified schizophrenia (disorder),Unspecified schizophrenia, chronic state with acute exacerbation,Unspecified schizophrenia, subchronic state with acute exacerbation,Unspecified schizophrenia, unspecified state
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
Schizophrenic patients (ARSCZ, FESCZ)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Only acutely relapsed schizophrenic (ARSCZ) and first-episode schizophrenic (FESCZ) patients were recruited in this study. The current episode of ARSCZ patients was required to happen in the last three months. ARSCZ patients were free of treatment for at least six months. The current episode of FESCZ patients was required to happen in the last year. FESCZ patients did not take any antipsychotics, or their accumulative dosages of antipsychotics intake were much less than the effective dosage (generally less than 100 mg chlorpromazine equivalents in the last two weeks based on the transformation method).
Group 0 sample size Number of subjects in the control (unexposed) group
81
Group 1 sample size Number of subjects in the case (exposed) group
90

Lab analysis

Sequencing type
WMS
Not specified
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina, BGISEQ-500 Sequencing

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
Spearman Correlation
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
diet, demographics, socioeconomic status, Matched on: "alcohol" 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.alcohol, Matched on: "tobacco use" 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.tobacco use
Confounders controlled for Confounding factors that have been accounted for by stratification or model adjustment
age, body mass index, diet, sex

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
increased
Richness Number of species
increased

Signature 1

Needs review Marked as Needs review by Atrayees on 2023-7-20

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas, Atrayees

Source: Figure 1 + Supplementary Data 5A

Description: The gut microbiota in schizophrenic patients harbored the following facultative anaerobes, which are rare in a healthy gut.

Abundance in Group 1: decreased abundance in Schizophrenic patients (ARSCZ, FESCZ)

NCBI Quality ControlLinks
Lactobacillus delbrueckii subsp. lactis
Lactobacillus acidophilus
Lactobacillus johnsonii
Paraprevotella xylaniphila
Clostridium perfringens
Leuconostoc gelidum
Butyrivibrio crossotus
Bacteroides finegoldii
Phocaeicola vulgatus
Bacteroides intestinalis

Revision editor(s): Titas, Atrayees

Signature 2

Needs review

Curated date: 2021/09/23

Curator: Titas

Revision editor(s): Titas

Source: Figure 1 + Supplementary Data 5A

Description: Bacteria that are often present in the oral cavity (the following species), were more abundant in patients with schizophrenia than in healthy controls, indicating a close association between the oral and the gut microbiota in schizophrenia.

Abundance in Group 1: increased abundance in Schizophrenic patients (ARSCZ, FESCZ)

NCBI Quality ControlLinks
Veillonella atypica
Veillonella dispar
Bifidobacterium dentium
Dialister invisus
Streptococcus salivarius
Limosilactobacillus oris

Revision editor(s): Titas

Experiment 2


Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas, WikiWorks

Differences from previous experiment shown

Subjects

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

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
Not specified
Statistical test
Mann-Whitney (Wilcoxon)
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Not specified
Matched on Factors on which subjects have been matched on in a case-control study
Not specified
Confounders controlled for Confounding factors that have been accounted for by stratification or model adjustment
Not specified


Signature 1

Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Lwaldron, Titas

Source: Supplementary Figure 2a + 2d

Description: The schizophrenic patients have a significantly lower level of tryptophan in serum (p < 2.2e-16, Two-sided Wilcoxon rank-sum test). The following microbes are abundant in schizophrenic patients and have a negative correlation with serum tryptophan levels (spearman correlation, two-sided P< 0.05).

Abundance in Group 1: increased abundance in Schizophrenic patients (ARSCZ, FESCZ)

NCBI Quality ControlLinks
Acidaminococcus intestini
Akkermansia muciniphila
Alkaliphilus oremlandii
Anaerotruncus colihominis
Bifidobacterium adolescentis
Bifidobacterium angulatum
Bifidobacterium dentium
Bifidobacterium longum
Clostridiales bacterium
Coprobacillus sp.
Cronobacter sakazakii
Dialister invisus
Dorea formicigenerans
Enterococcus faecium
Lachnospiraceae bacterium
Lactobacillus crispatus
Limosilactobacillus fermentum
Limosilactobacillus oris
Megasphaera micronuciformis
Methanobrevibacter smithii
Pseudoflavonifractor capillosus
Streptococcus gallolyticus
Streptococcus mutans
Streptococcus salivarius
Streptococcus vestibularis
Veillonella atypica
Veillonella dispar
Veillonella parvula
[Eubacterium] siraeum
Phocaeicola plebeius

Revision editor(s): Lwaldron, Titas

Signature 2

Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas

Source: Supplementary Figure 2a + 2d

Description: The controls show an abundance of the following species and these species have a positive correlation with tryptophan levels in serum (spearman correlation, two-sidedP< 0.05).

Abundance in Group 1: decreased abundance in Schizophrenic patients (ARSCZ, FESCZ)

NCBI Quality ControlLinks
Clostridium perfringens
Leuconostoc gelidum

Revision editor(s): Titas

Signature 3

Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas

Source: Supplementary Figure 2a + 2d

Description: Schizophrenic patients have a higher level of kynurenic acid (KYNA) and the following microbial species. The species also show a positive correlation with KYNA (spearman correlation, two-sided P< 0.05).

Abundance in Group 1: increased abundance in Schizophrenic patients (ARSCZ, FESCZ)

NCBI Quality ControlLinks
Bifidobacterium angulatum
Bifidobacterium bifidum
Bifidobacterium catenulatum
Bifidobacterium longum
Bifidobacterium pseudocatenulatum
Megasphaera micronuciformis
Streptococcus vestibularis
Veillonella atypica
Veillonella parvula
Limosilactobacillus fermentum

Revision editor(s): Titas

Experiment 3


Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas, WikiWorks

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Schizophrenic patients
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
These new schizophrenic patients were taking antipsychotics.
Group 0 sample size Number of subjects in the control (unexposed) group
45
Group 1 sample size Number of subjects in the case (exposed) group
45


Statistical Analysis

Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
Not specified


Signature 1

Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas

Source: Figure 3b

Description: The following species show significant enrichment in schizophrenic patients.

Abundance in Group 1: increased abundance in Schizophrenic patients

NCBI Quality ControlLinks
Akkermansia muciniphila
Alkaliphilus oremlandii
Bifidobacterium adolescentis
Bifidobacterium longum
Cronobacter sakazakii
Enterococcus faecium
Streptococcus vestibularis
Veillonella parvula
[Clostridium] symbiosum
[Eubacterium] siraeum
Phocaeicola plebeius

Revision editor(s): Titas

Signature 2

Needs review

Curated date: 2021/09/22

Curator: Titas

Revision editor(s): Titas

Source: Figure 3b

Description: The following species show enrichment in healthy controls.

Abundance in Group 1: decreased abundance in Schizophrenic patients

NCBI Quality ControlLinks
Bacteroides finegoldii
Bacteroides intestinalis
Phocaeicola dorei

Revision editor(s): Titas

Experiment 4


Needs review

Curated date: 2021/09/23

Curator: Titas

Revision editor(s): Titas, WikiWorks

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Baseline schizophrenic patients
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
These schizophrenic patients were selected from the 90 medication-free patients of experiment 1.
Group 0 sample size Number of subjects in the control (unexposed) group
81
Group 1 sample size Number of subjects in the case (exposed) group
38


Statistical Analysis

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
age, body mass index, diet, sex


Signature 1

Needs review

Curated date: 2021/09/23

Curator: Titas

Revision editor(s): Titas

Source: Figure 3d + Supplementary data 10

Description: Of the 26 identified microbial species, 20 species remained significantly changed between 81 controls and 38 baseline patients (P < 0.1, FDR = 0.44, Benjamini and Hochberg method).

Abundance in Group 1:
NCBI Quality ControlLinks
Akkermansia muciniphila
Alkaliphilus oremlandii
Bacillus anthracis
Bacteroides finegoldii
Bacteroides intestinalis
Bifidobacterium adolescentis
Bifidobacterium longum
Cronobacter sakazakii
Enterococcus faecium
Streptococcus vestibularis
Veillonella parvula
[Eubacterium] siraeum
Phocaeicola plebeius

Revision editor(s): Titas

Experiment 5


Needs review

Curated date: 2021/09/23

Curator: Titas

Revision editor(s): Titas, WikiWorks

Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
38 of the 90 patients had 3-months of treatment (27 with risperidone and 11 with other antipsychotics).


Statistical Analysis

Signature 1

Needs review

Curated date: 2021/09/23

Curator: Titas

Revision editor(s): Titas

Source: Figure 3d + Supplementary data 10

Description: After 3-months of treatment, the abundances of 12 of these 26 mOTUs remained significantly changed compared with the 81 controls (P < 0.1, FDR = 0.33, Benjamini and Hochberg method, Supplementary Data 10).

Abundance in Group 1:
NCBI Quality ControlLinks
Akkermansia muciniphila
Alkaliphilus oremlandii
Bacillus anthracis
Bacteroides intestinalis
Bifidobacterium adolescentis
Bifidobacterium longum
Cronobacter sakazakii
Enterococcus faecium
Streptococcus vestibularis
Veillonella parvula
[Eubacterium] siraeum
Phocaeicola plebeius

Revision editor(s): Titas

Experiment 6


incomplete

Curated date: 2021/09/23

Curator: Titas

Revision editor(s): LGeistlinger, Titas

Differences from previous experiment shown

Subjects

Location of subjects
Not specified
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Not specified
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Not specified
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Saline-treated and Streptococcus thermophilus ST12 - treated mice
Group 1 name Corresponds to the case (exposed) group for case-control studies
Streptococcus vestibularis - treated mice
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
S. vestibularis ATCC 49124 was transplanted, using oral gavage and drinking water, into C57BL/6 mice after antibiotics-based microbiota depletion.
Group 0 sample size Number of subjects in the control (unexposed) group
Not specified
Group 1 sample size Number of subjects in the case (exposed) group
Not specified


Statistical Analysis

Statistical test
ANOVA
Kruskall-Wallis
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
Matched on Factors on which subjects have been matched on in a case-control study
Not specified