Metagenome-wide association of gut microbiome features for schizophrenia
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Study information
-
Quality control
- Retracted paper
- Contamination issues suspected
- Batch effect issues suspected
- Uncontrolled confounding suspected
- Results are suspect (various reasons)
- Tags applied
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
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
Needs review
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
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Illumina, BGISEQ-500 Sequencing
Statistical Analysis
- Statistical test
- Mann-Whitney (Wilcoxon)
- 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
- 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
Reviewed Marked as Reviewed by Lwaldron on 2021/09/23
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: increased abundance in Schizophrenic patients (ARSCZ, FESCZ)
| NCBI | Links |
|---|---|
| Alkaliphilus oremlandii | |
| Cronobacter sakazakii | |
| Enterococcus faecium | |
| Limosilactobacillus fermentum |
Revision editor(s): Titas
Signature 2
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 | Links |
|---|---|
| Veillonella atypica | |
| Veillonella dispar | |
| Bifidobacterium dentium | |
| Dialister invisus | |
| Streptococcus salivarius | |
| Limosilactobacillus oris |
Revision editor(s): Titas
Experiment 2
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
Statistical Analysis
- Statistical test
- Mann-Whitney (Wilcoxon)
- Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
- 0.05
Signature 1
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)
Signature 2
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 | Links |
|---|---|
| Clostridium perfringens | |
| Leuconostoc gelidum ⚠ |
Revision editor(s): Titas
Signature 3
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)
Revision editor(s): Titas
Experiment 3
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
- 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
Signature 1
Source: Figure 3b
Description: The following species show significant enrichment in schizophrenic patients.
Abundance in Group 1: increased abundance in Schizophrenic patients
Revision editor(s): Titas
Signature 2
Source: Figure 3b
Description: The following species show enrichment in healthy controls.
Abundance in Group 1: decreased abundance in Schizophrenic patients
| NCBI | Links |
|---|---|
| Bacteroides finegoldii | |
| Bacteroides intestinalis | |
| Phocaeicola dorei |
Revision editor(s): Titas
Experiment 4
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
- 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
- Statistical test
- Mann-Whitney (Wilcoxon)
- 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
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:Revision editor(s): Titas
Experiment 5
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
- Baseline schizophrenic patients
- 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).
- 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
- Statistical test
- Mann-Whitney (Wilcoxon)
- 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
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:Revision editor(s): Titas
Experiment 6
incomplete
Subjects
- Host species Species from which microbiome was sampled (if applicable)
- Mus musculus
- 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.
Statistical Analysis
- Statistical test
- ANOVA
- Kruskall-Wallis
- 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
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