Suppression of MyD88 disturbs gut microbiota and activates the NLR pathway and hence fails to ameliorate DSS-induced colitis

From BugSigDB
Needs review
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
Authors
Li JH, Chen Y, Ye ZH, Chen LP, Xu JX, Han J, Xie L, Xing S, Tian DA, Seidler U, Liao JZ, Xiao F
Journal
Precision clinical medicine
Year
2024
Keywords:
NOD-like receptor, inflammatory bowel disease, innate immunity, microbiota, myeloid differentiation factor 88, MyD88 inhibitor
BACKGROUND: Myeloid differentiation factor 88 (MyD88) is the core adaptor for Toll-like receptors defending against microbial invasion and initiating a downstream immune response during microbiota-host interaction. However, the role of MyD88 in the pathogenesis of inflammatory bowel disease is controversial. This study aims to investigate the impact of MyD88 on intestinal inflammation and the underlying mechanism. METHODS: MyD88 knockout (MyD88-/-) mice and the MyD88 inhibitor (TJ-M2010-5) were used to investigate the impact of MyD88 on acute dextran sodium sulfate (DSS)-induced colitis. Disease activity index, colon length, histological score, and inflammatory cytokines were examined to evaluate the severity of colitis. RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism. RESULTS: In an acute DSS-colitis model, the severity of colitis was not alleviated in MyD88-/- mice and TJ-M2010-5-treated mice, despite significantly lower levels of NF-κB activation being exhibited compared to control mice. Meanwhile, 16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal Proteobacteria and an up-regulation of the nucleotide oligomerization domain-like receptors (NLRs) signaling pathway in colitis mice following MyD88 suppression. Further blockade of the NLRs signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DSS-induced colitis mice treated with TJ-M2010-5 ameliorated the disease severity, which was not improved solely by MyD88 inhibition. After treatment with broad-spectrum antibiotics, downregulation of the NLR signaling pathway was observed. CONCLUSION: Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota, leading to NLR-mediated immune activation and intestinal inflammation.

Experiment 1


Needs review

Curated date: 2025/05/05

Curator: Tosin

Revision editor(s): Tosin

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
Treatment outcome measurement Treatment outcome measurement,treatment outcome measurement
Group 0 name Corresponds to the control (unexposed) group for case-control studies
DSS + PBS (dextran sodium sulfate + phosphate buffer saline) group
Group 1 name Corresponds to the case (exposed) group for case-control studies
DSS + TJ5 (dextran sodium sulfate + MyD88 inhibitor) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
A treatment group that received DSS (dextran sodium sulfate) and TJ5 (MyD88 inhibitor)

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

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
T-Test
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)?
No

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

Needs review

Curated date: 2025/05/05

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 3F

Description: Relative abundances of indicated bacterial taxa in feces between DSS + PBS (dextran sodium sulfate + phosphate buffer saline) and DSS + TJ5 (dextran sodium sulfate + MyD88 inhibitor) groups

Abundance in Group 1: increased abundance in DSS + TJ5 (dextran sodium sulfate + MyD88 inhibitor) group

NCBI Quality ControlLinks
Enterobacterales
Gammaproteobacteria
Pseudomonadota

Revision editor(s): Tosin

Experiment 2


Needs review

Curated date: 2025/05/05

Curator: Tosin

Revision editor(s): Tosin

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Combination of DSS + TJ5 (dextran sodium sulfate + MyD88 inhibitor), DSS + PBS (dextran sodium sulfate + phosphate buffer saline), H20 + TJ5 (water + MyD88 inhibitor) groups
Group 1 name Corresponds to the case (exposed) group for case-control studies
H20 + PBS( water + Phosphate buffer saline) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
A treatment group that received H20 (water) and PBS (Phosphate buffer saline)

Lab analysis

Statistical Analysis

Statistical test
LEfSe
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
2.5


Signature 1

Needs review

Curated date: 2025/05/05

Curator: Tosin

Revision editor(s): Tosin

Source: Supplementary Figure 3

Description: Significant changes in functional profiles were suggested based on phylogenetic investigations of communities through Lefse analysis.

Abundance in Group 1: increased abundance in H20 + PBS( water + Phosphate buffer saline) group

NCBI Quality ControlLinks
Actinomycetota
Allobaculum
Candidatus Saccharimonadota
Coriobacteriaceae
Coriobacteriales
Coriobacteriia
Desulfovibrio
Erysipelotrichaceae
Erysipelotrichales
Erysipelotrichia
Gemmiger
Prevotella
Prevotellaceae
Rikenella
TM7 phylum sp. oral clone CW040
Thermacetogenium
Thermoanaerobacteraceae
Thermoanaerobacterales
CF231CF231
TM73TM73
bacterium F16

Revision editor(s): Tosin

Experiment 3


Needs review

Curated date: 2025/05/05

Curator: Tosin

Revision editor(s): Tosin, PreciousChijioke

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Combination of DSS + TJ5 (Dextran sodium sulfate + MyD88 inhibitor), H20 + PBS ( water + Phosphate buffer saline), H20 + TJ5 (water + MyD88 inhibitor) groups
Group 1 name Corresponds to the case (exposed) group for case-control studies
DSS + PBS(Dextran sodium sulfate + Phosphate buffer saline) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
A treatment group that received DSS (Dextran sodium sulfate) and PBS (Phosphate buffer saline)

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/05/05

Curator: Tosin

Revision editor(s): Tosin

Source: Supplementary Figure 3

Description: Significant changes in functional profiles were suggested based on phylogenetic investigations of communities through Lefse analysis.

Abundance in Group 1: increased abundance in DSS + PBS(Dextran sodium sulfate + Phosphate buffer saline) group

NCBI Quality ControlLinks
Akkermansia
Alcaligenaceae
Anaerotruncus
Bacteroidaceae
Bacteroides
Coprococcus
Exiguobacterium
Macellibacteroides
Nitrobacteraceae
Pseudomonadaceae
Pseudomonadales
Pseudomonas
Sutterella
Verrucomicrobiaceae
Verrucomicrobiales
Verrucomicrobiia
Verrucomicrobiota
(Exiguobacteraceae)(Exiguobacteraceae)

Revision editor(s): Tosin

Experiment 4


Needs review

Curated date: 2025/05/05

Curator: PreciousChijioke

Revision editor(s): PreciousChijioke

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Combination of H20 + PBS ( water + Phosphate buffer saline), DSS + PBS (Dextran sodium sulfate + Phosphate buffer saline) + DSS + TJ5 (Dextran sodium sulfate + MyD88 inhibitor) groups
Group 1 name Corresponds to the case (exposed) group for case-control studies
H20 + TJ5 (water + MyD88 inhibitor) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
A treatment group that received H20 (water) and TJ5 (MyD88 inhibitor)

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/05/05

Curator: PreciousChijioke

Revision editor(s): PreciousChijioke

Source: Supplementary Figure 3

Description: Significant changes in functional profiles were suggested based on phylogenetic investigations of communities through Lefse analysis.

Abundance in Group 1: increased abundance in H20 + TJ5 (water + MyD88 inhibitor) group

NCBI Quality ControlLinks
Adlercreutzia
Bacteroidales
Bacteroidia
Bacteroidota
Clostridiaceae
Cyanobacteriota
Mycoplasmataceae
Mycoplasmatales
Ruminococcus
Streptococcus
Muribaculaceae

Revision editor(s): PreciousChijioke

Experiment 5


Needs review

Curated date: 2025/05/05

Curator: PreciousChijioke

Revision editor(s): PreciousChijioke

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Combination of H20 + PBS ( water + Phosphate buffer saline), DSS + PBS (Dextran sodium sulfate + Phosphate buffer saline) + H20 + TJ5 (water + MyD88 inhibitor) groups
Group 1 name Corresponds to the case (exposed) group for case-control studies
DSS + TJ5 (Dextran sodium sulfate + MyD88 inhibitor) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
A treatment group that received DSS (Dextran sodium sulfate) and TJ5 (MyD88 inhibitor)

Lab analysis

Statistical Analysis

Signature 1

Needs review

Curated date: 2025/05/05

Curator: PreciousChijioke

Revision editor(s): PreciousChijioke

Source: Supplementary Figure 3

Description: Significant changes in functional profiles were suggested based on phylogenetic investigations of communities through Lefse analysis.

Abundance in Group 1: increased abundance in DSS + TJ5 (Dextran sodium sulfate + MyD88 inhibitor) group

NCBI Quality ControlLinks
Pseudomonadota
Gammaproteobacteria
Enterococcaceae

Revision editor(s): PreciousChijioke