Gut microbial dysbiosis, IgA, and Enterococcus in common variable immunodeficiency with immune dysregulation
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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
Authors
Berbers RM, Paganelli FL, van Montfrans JM, Ellerbroek PM, Viveen MC, Rogers MRC, Salomons M, Schuurmans J, van Stigt Thans M, Vanmaris RMM, Brosens LAA, van der Wal MM, Dalm VASH, van Hagen PM, van de Ven AAJM, Uh HW, van Wijk F, Willems RJL, Leavis HL
Journal
Microbiome
Year
2025
Keywords:
Common variable immunodeficiency (CVID), Gut microbiota, Immune dysregulation, Pathobionts
BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Significant morbidity and mortality are caused by immune dysregulation complications (CVIDid), which affect around one-third of CVID patients and have a poorly understood etiology. Here, we investigate the hypothesis that gut microbial dysbiosis contributes to the inflammation underlying CVIDid. RESULTS: Bacterial invasion of colonic crypts was observed in CVID (3/15) and X-linked agammaglobulinemia (XLA, 1/3), but not in healthy control (HC, 0/9) biopsies. Fecal gut microbiota was characterized using 16S rRNA-targeted amplicon sequencing. Increased bacterial load, decreased alpha diversity and distinct beta diversity were observed in CVIDid (n = 42) compared to HC (n = 48), and similar results were seen in CVID with IgA deficiency (n = 40) compared to HC. CVIDid and CVID-IgA showed enrichment of the genus Enterococcus, and in vitro studies confirmed the inflammatory potential of Enterococcus gallinarum and Enterococcus hirae in patient monocytes. CONCLUSIONS: This study further supports the hypothesis that a dysregulated gut microbiota, with IgA deficiency as an important driving factor, contributes to systemic inflammation in primary antibody deficiency, and introduces enterococci as potential pathobionts in CVIDid. Video Abstract.
Experiment 1
Needs review
Curated date: 2025/02/11
Curator:
Revision editor(s):
Subjects
- Location of subjects
- Netherlands
- 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
- Common variable immunodeficiency acquired agammaglobulinemia,acquired hypogammaglobulinemia,common variable agammaglobulinemia,common variable hypogamma-globulinemia,common variable immune deficiency,common variable immunodeficiency,CVID,hypogamma-globulinemia, acquired,Idiopathic immunoglobulin deficiency,idiopathic immunoglobulin deficiency,Immunoglobulin deficiency, late-onset,Primary antibody deficiency,primary antibody deficiency,Primary hypogammaglobulinemia,primary hypogammaglobulinemia,secondary hypogammaglobulinemia,sporadic hypogammaglobulinemia,Common variable immunodeficiency
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Healthy Control (HC)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Common Variable Immunodeficiency (CVID)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients living with Common Variable Immunodeficiency.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 48
- Group 1 sample size Number of subjects in the case (exposed) group
- 93
Lab analysis
- Sequencing type
- 16S
- 16S variable region One or more hypervariable region(s) of the bacterial 16S gene
- V3-V4
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Illumina
Statistical Analysis
- Statistical test
- Mann-Whitney (Wilcoxon)
- ANCOM-BC
- 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
Signature 1
Source: Fig. 5A and Supplementary Table 4
Description: Differentially abundant bacteria identified in CVID patients (n=93) vs Healthy Controls (n=48)
Abundance in Group 1: increased abundance in
Signature 2
Source: Fig. 5A and Supplementary Table S4
Description: Differentially abundant bacteria identified in CVID patients (n=93) vs Healthy Controls (n=48)
Abundance in Group 1: decreased abundance in
| NCBI | Quality Control | Links |
|---|---|---|
| Bifidobacteriales | ||
| Bifidobacterium | ||
| Bifidobacteriaceae | ||
| Prevotella 9Prevotella 9 | ||
| Romboutsia | ||
| Selenomonadales | ||
| Actinomycetota |
Experiment 2
Needs review
Curated date: 2025/02/11
Curator:
Revision editor(s):
Differences from previous experiment shown
Subjects
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Common Variable Immunodeficiency (CVID-med)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients living with Common Variable Immunodeficiency without use of antibiotics or immunosuppressive therapy 3 months prior to sampling.
- Group 1 sample size Number of subjects in the case (exposed) group
- 50
- 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
Statistical Analysis
Alpha Diversity
- Chao1 Abundance-based estimator of species richness
- unchanged
Signature 1
Source: Supplementary Table 5
Description: Differentially abundant bacteria identified in CVID-med patients (Common Variable Immunodeficiency without medications) (n=50) vs Healthy Controls (n=48)
Abundance in Group 1: increased abundance in
| NCBI | Quality Control | Links |
|---|---|---|
| Anaerotruncus | ||
| Caproiciproducens | ||
| Eubacteriaceae | ||
| Lactococcus | ||
| Sellimonas | ||
| Tyzzerella | ||
| Veillonella |
Experiment 3
Differences from previous experiment shown
Subjects
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Common variable immunodeficiency , Immune dysregulation disease with immunodeficiency acquired agammaglobulinemia,acquired hypogammaglobulinemia,common variable agammaglobulinemia,common variable hypogamma-globulinemia,common variable immune deficiency,common variable immunodeficiency,CVID,hypogamma-globulinemia, acquired,Idiopathic immunoglobulin deficiency,idiopathic immunoglobulin deficiency,Immunoglobulin deficiency, late-onset,Primary antibody deficiency,primary antibody deficiency,Primary hypogammaglobulinemia,primary hypogammaglobulinemia,secondary hypogammaglobulinemia,sporadic hypogammaglobulinemia,Common variable immunodeficiency,immune dysregulation disease with immunodeficiency,Immune dysregulation disease with immunodeficiency
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Common Variable Immunodeficiency with infections only (CVIDio)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Common Variable Immunodeficiency with immune dysregulation (CVIDid)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients living with Common Variable Immunodeficiency with Immune dysregulation.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 51
- Group 1 sample size Number of subjects in the case (exposed) group
- 42
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- Not specified
Lab analysis
Statistical Analysis
Alpha Diversity
- Inverse Simpson Modification of Simpsons index D as 1/D to obtain high values in datasets of high diversity and vice versa
- decreased
Signature 1
Source: Fig. 5B and Supplementary Table 6
Description: Differentially abundant bacteria identified in CVIDid patients (n=42) vs CVIDio (n=51)
Abundance in Group 1: increased abundance in Common Variable Immunodeficiency with immune dysregulation (CVIDid)
| NCBI | Quality Control | Links |
|---|---|---|
| Enterococcaceae | ||
| Enterococcus |
Experiment 4
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Common Variable Immunodeficiency with infections only without medication (CVIDio-med)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Common Variable Immunodeficiency with immune dysregulation without medication (CVIDid-med)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients living with Common Variable Immunodeficiency and Immune dysregulation without use of antibiotics or immunosuppressive therapy 3 months prior to sampling.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 32
- Group 1 sample size Number of subjects in the case (exposed) group
- 18
- 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
Statistical Analysis
Alpha Diversity
- Chao1 Abundance-based estimator of species richness
- unchanged
Signature 1
Source: Supplementary Table 7
Description: Differentially abundant bacteria identified in CVID with immune dysregulation without medication use (CVIDid -med. n=18) versus CVID with infections only without medication use (CVIDio -med. n=32)
Abundance in Group 1: increased abundance in Common Variable Immunodeficiency with immune dysregulation without medication (CVIDid-med)
Experiment 5
Needs review
Curated date: 2025/02/12
Curator:
Revision editor(s):
Differences from previous experiment shown
Subjects
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Common variable immunodeficiency acquired agammaglobulinemia,acquired hypogammaglobulinemia,common variable agammaglobulinemia,common variable hypogamma-globulinemia,common variable immune deficiency,common variable immunodeficiency,CVID,hypogamma-globulinemia, acquired,Idiopathic immunoglobulin deficiency,idiopathic immunoglobulin deficiency,Immunoglobulin deficiency, late-onset,Primary antibody deficiency,primary antibody deficiency,Primary hypogammaglobulinemia,primary hypogammaglobulinemia,secondary hypogammaglobulinemia,sporadic hypogammaglobulinemia,Common variable immunodeficiency
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Common Variable Immunodeficiency with Immunoglobulin A > 0.1g/L (CVID+IgA)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Common Variable Immunodeficiency with Immunoglobulin A < 0.1g/L (CVID+IgA)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients living with CVID with IgA <0.1 g/L
- Group 0 sample size Number of subjects in the control (unexposed) group
- 53
- Group 1 sample size Number of subjects in the case (exposed) group
- 40
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- Not specified
Lab analysis
Statistical Analysis
Alpha Diversity
- Inverse Simpson Modification of Simpsons index D as 1/D to obtain high values in datasets of high diversity and vice versa
- decreased
Signature 1
Source: Supplementary Table 8
Description: Differentially abundant bacteria identified in CVID with Immunoglobulin A < 0.1g/L (CVID-IgA n=40) versus CVID with Immunoglobulin A > 0.1g/L (CVID+IgA n=53)
Abundance in Group 1: increased abundance in
| NCBI | Quality Control | Links |
|---|---|---|
| Enterococcaceae | ||
| Enterococcus | ||
| Eubacterium 2Eubacterium 2 |
Experiment 6
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Common Variable Immunodeficiency with Immunoglobulin A > 0.1g/L without medication use (CVID+IgA-med)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Common Variable Immunodeficiency with Immunoglobulin A < 0.1g/L without medication use (CVID-IgA-med)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients living with Common Variable Immunodeficiency (CVID) with Immunoglobulin A (IgA) <0.1 g/L without use of antibiotics or immunosuppressive therapy 3 months prior to sampling.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 29
- Group 1 sample size Number of subjects in the case (exposed) group
- 21
Lab analysis
Statistical Analysis
Alpha Diversity
- Chao1 Abundance-based estimator of species richness
- unchanged
Signature 1
Source: Supplementary Table 9
Description: Differentially abundant bacteria identified in CVID with Immunoglobulin A < 0.1g/L without medication use (CVID-IgA-med n=21) versus CVID with Immunoglobulin A > 0.1g/L without medication use (CVID+IgA-med n=29).
Abundance in Group 1: increased abundance in Common Variable Immunodeficiency with Immunoglobulin A < 0.1g/L without medication use (CVID-IgA-med)
| NCBI | Quality Control | Links |
|---|---|---|
| Veillonella | ||
| Eubacterium 2Eubacterium 2 | ||
| Haemophilus | ||
| Enterococcus | ||
| Enterococcaceae | ||
| Pasteurellaceae | ||
| Pasteurellales |
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