Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3

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Citation
PMID PubMed identifier for scientific articles.
38378622
DOI Digital object identifier for electronic documents.
10.1186/s40168-024-01756-6
URI
https://pubmed.ncbi.nlm.nih.gov/38378622/
Authors
Hao W, Ma Q, Wang L, Yuan N, Gan H, He L, Li X, Huang J, Chen J
Journal
Microbiome
Year
2024
Keywords:
Complement C3, Depression, Fecal microbiota transplantation, Gut microbiota, Microglia, Synaptic pruning
BACKGROUND: Remodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown. RESULTS: In the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed. Transplantation of gut microbiota from CUMS-induced depression model mice into specific pathogen-free and germ-free mice induced depression-like behavior and concomitant cognitive impairment in the recipient mice, accompanied by increased activation of the complement C3/CR3 pathway in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal microbiota transplantation from antidepressant-treated donors improved depression-like behaviors and restored gut microbiome disturbances in depressed mice. Concurrently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-mediated synaptic pruning, and increased expression of the synapsin and postsynaptic density protein 95 were observed. Collectively, our results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat depression. CONCLUSIONS: Our findings provide novel insights into the involvement of complement C3/CR3 signaling and aberrant synaptic pruning of chemotactic microglia in gut-brain crosstalk in the pathogenesis of depression. Video Abstract.

Experiment 1


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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine, Scholastica

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled. Contact us to have more species added.
Mus musculus
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
Major depressive disorder major depression,major depressive disorder,recurrent major depression,single major depressive episode,unipolar depression,Major depressive disorder
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Control group
Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks.
Group 0 sample size Number of subjects in the control (unexposed) group
6
Group 1 sample size Number of subjects in the case (exposed) group
6

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V3-V4

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
LEfSe
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
4

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
decreased
Simpson Estimator of species richness and species evenness: more weight on species evenness
decreased
Richness Number of species
decreased

Signature 1

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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: increased abundance in CUMS group

NCBI Quality ControlLinks
Enterobacterales   
Enterobacteriaceae   
Klebsiella   
Gammaproteobacteria   
Pseudomonadota   
Bacteroides   
Bacteroidaceae   
Bacteroidia   
Bacteroidales   
Fusobacteriia   
Verrucomicrobiota   

Revision editor(s): Aleru Divine

Signature 2

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Curated date: 2024/03/22

Curator: Aleru Divine

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Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: decreased abundance in CUMS group

NCBI Quality ControlLinks
Bacillales   
Actinomycetota   
Staphylococcaceae   
Staphylococcus   
Chloroflexia   
Bacillota   
Gemmatimonadia   
ThermiThermi
Armatimonadota   

Revision editor(s): Aleru Divine

Experiment 2


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Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS + XYS group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks, followed by daily oral administration of XYS.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: increased abundance in CUMS + XYS group

NCBI Quality ControlLinks
Bacillota   
Lactobacillus   
Bacilli   
Lactobacillales   
Lactobacillaceae   
Mycoplasmatota   

Revision editor(s): Aleru Divine

Signature 2

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Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: decreased abundance in CUMS + XYS group

NCBI Quality ControlLinks
Actinomycetota   
Armatimonadota   
Bacillales   
Bacillota   
Chloroflexia   
Gemmatimonadia   
Staphylococcaceae   
Staphylococcus   
ThermiThermi

Revision editor(s): Aleru Divine

Experiment 3


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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS + FLX group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks, followed by daily oral administration of FLX.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: increased abundance in CUMS + FLX group

NCBI Quality ControlLinks
Allobaculum   
Erysipelotrichaceae   
Erysipelotrichia   
Erysipelotrichales   
Bacteroidia   
Cyanobacteriota   
Deferribacteres   
Acidobacteriota   
Chlorobiota   
Candidatus Caldatribacterium californiense OP9-cSCG   
Planctomycetia   

Revision editor(s): Aleru Divine

Signature 2

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Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: decreased abundance in CUMS + FLX group

NCBI Quality ControlLinks
Actinomycetota   
Armatimonadota   
Bacillales   
Bacillota   
Chloroflexia   
Gemmatimonadia   
Staphylococcaceae   
Staphylococcus   
ThermiThermi

Revision editor(s): Aleru Divine

Experiment 4


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Curated date: 2024/03/22

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Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
CUMS group
Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS + XYS group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks, followed by daily oral administration of XYS.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
increased
Chao1 Abundance-based estimator of species richness
increased
Simpson Estimator of species richness and species evenness: more weight on species evenness
increased
Richness Number of species
increased

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: increased abundance in CUMS + XYS group

NCBI Quality ControlLinks
Bacillota   
Lactobacillus   
Bacilli   
Lactobacillales   
Lactobacillaceae   
Mycoplasmatota   

Revision editor(s): Aleru Divine

Signature 2

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: decreased abundance in CUMS + XYS group

NCBI Quality ControlLinks
Enterobacterales   
Enterobacteriaceae   
Klebsiella   
Gammaproteobacteria   
Pseudomonadota   
Bacteroides   
Bacteroidaceae   
Bacteroidia   
Bacteroidales   
Fusobacteriia   
Verrucomicrobiota   

Revision editor(s): Aleru Divine

Experiment 5


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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS + FLX group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks, followed by daily oral administration of FLX.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
increased
Chao1 Abundance-based estimator of species richness
increased
Simpson Estimator of species richness and species evenness: more weight on species evenness
increased
Richness Number of species
increased

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: increased abundance in CUMS + FLX group

NCBI Quality ControlLinks
Allobaculum   
Erysipelotrichaceae   
Erysipelotrichia   
Erysipelotrichales   
Bacteroidia   
Cyanobacteriota   
Deferribacteres   
Acidobacteriota   
Chlorobiota   
Candidatus Caldatribacterium californiense OP9-cSCG   
Planctomycetia   

Revision editor(s): Aleru Divine

Signature 2

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: decreased abundance in CUMS + FLX group

NCBI Quality ControlLinks
Enterobacterales   
Enterobacteriaceae   
Klebsiella   
Gammaproteobacteria   
Pseudomonadota   
Bacteroides   
Bacteroidaceae   
Bacteroidia   
Bacteroidales   
Fusobacteriia   
Verrucomicrobiota   

Revision editor(s): Aleru Divine

Experiment 6


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Mark reviewed
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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
CUMS + XYS group

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: increased abundance in CUMS + FLX group

NCBI Quality ControlLinks
Allobaculum   
Erysipelotrichaceae   
Erysipelotrichia   
Erysipelotrichales   
Bacteroidia   
Cyanobacteriota   
Deferribacteres   
Acidobacteriota   
Chlorobiota   
Candidatus Caldatribacterium californiense OP9-cSCG   
Planctomycetia   

Revision editor(s): Aleru Divine

Signature 2

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 4F and Figure S2d

Description: LEfSe analysis of the differentially abundant taxa in each groups.

Abundance in Group 1: decreased abundance in CUMS + FLX group

NCBI Quality ControlLinks
Bacillota   
Lactobacillus   
Bacilli   
Lactobacillales   
Lactobacillaceae   
Mycoplasmatota   

Revision editor(s): Aleru Divine

Experiment 7


EditHistoryDelete
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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Control group
Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 8G

Description: The representation of the differentially abundant taxa between the CUMS and the control group.

Abundance in Group 1: increased abundance in CUMS

NCBI Quality ControlLinks
Prevotella   
ParaprevotellaceaeParaprevotellaceae

Revision editor(s): Aleru Divine

Signature 2

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Curated date: 2024/03/22

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Source: Figure 8G

Description: The representation of the differentially abundant taxa between CUMS and control.

Abundance in Group 1: decreased abundance in CUMS

NCBI Quality ControlLinks
Bacteria   
Faecalibacterium   

Revision editor(s): Aleru Divine

Experiment 8


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Curated date: 2024/03/22

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Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Control + FMT(CUMS) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group with no stress stimulation for 8 weeks, followed by daily FMT (feces from CUMS group in the first experiment.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine, Scholastica

Source: Figure 8i

Description: The representation of the differentially abundant taxa between the Control + FMT(CUMS) group and the control group.

Abundance in Group 1: increased abundance in Control + FMT(CUMS) group

NCBI Quality ControlLinks
Allobaculum   
Bacteroidales   
Bacteroidia   
Erysipelotrichaceae   
Erysipelotrichales   
Erysipelotrichia   
Parabacteroides   
Porphyromonadaceae   
Prevotella   
ParaprevotellaceaeParaprevotellaceae
Bacteroidota   

Revision editor(s): Aleru Divine, Scholastica

Signature 2

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 8i

Description: The representation of the differentially abundant taxa between the Control + FMT(CUMS) group and the control group.

Abundance in Group 1: decreased abundance in Control + FMT(CUMS) group

NCBI Quality ControlLinks
Bacillota   

Revision editor(s): Aleru Divine

Experiment 9


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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
CUMS + FMT(XYS) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Mice group induced with chronic unpredictable mild stress (CUMS) for 8 weeks, followed by daily FMT (feces from CUMS + XYS group in the first experiment) for 4 weeks.

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
decreased
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Text and Figure S5f

Description: Differential abundance in the Control group and the CUMS + FMT(XYS) group

Abundance in Group 1: increased abundance in CUMS + FMT(XYS) group

NCBI Quality ControlLinks
Lactobacillus   
Akkermansia   

Revision editor(s): Aleru Divine

Experiment 10


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Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
CUMS group

Lab analysis

Statistical Analysis

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness
unchanged
Chao1 Abundance-based estimator of species richness
unchanged
Simpson Estimator of species richness and species evenness: more weight on species evenness
unchanged
Richness Number of species
unchanged

Signature 1

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 8K

Description: The representation of the differentially abundant taxa between the CUMS and the CUMS + FMT(XYS) group.

Abundance in Group 1: increased abundance in CUMS + FMT(XYS) group

NCBI Quality ControlLinks
ParaprevotellaceaeParaprevotellaceae
Prevotella   
Bacteria   

Revision editor(s): Aleru Divine

Signature 2

EditHistoryDelete
Mark reviewed
Your review change was submitted
Needs review

Curated date: 2024/03/22

Curator: Aleru Divine

Revision editor(s): Aleru Divine

Source: Figure 8K

Description: The representation of the differentially abundant taxa between the Control + FMT(CUMS) group and the CUMS group.

Abundance in Group 1: decreased abundance in CUMS + FMT(XYS) group

NCBI Quality ControlLinks
Candidatus Arthromitus   
Dialister   
Ruminococcus   

Revision editor(s): Aleru Divine

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