Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment
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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
Yu YN, Yu TC, Zhao HJ, Sun TT, Chen HM, Chen HY, An HF, Weng YR, Yu J, Li M, Qin WX, Ma X, Shen N, Hong J, Fang JY
Journal
Oncotarget
Year
2015
BACKGROUND: Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated. METHODS: 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting. RESULTS: The levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone. CONCLUSIONS: F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.
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
- colorectal cancer cancer of colorectum,cancer of large bowel,cancer of large intestine,cancer of the large bowel,colon cancer,colorectal cancer,colorectum cancer,CRC,large intestine cancer,malignant colorectal neoplasm,malignant colorectal tumor,malignant colorectum neoplasm,malignant large bowel neoplasm,malignant large bowel tumor,malignant large intestine neoplasm,malignant large intestine tumor,malignant neoplasm of colorectum,malignant neoplasm of large bowel,malignant neoplasm of large intestine,malignant neoplasm of the large bowel,malignant neoplasm of the large intestine,malignant tumor of large bowel,malignant tumor of large intestine,malignant tumor of the large bowel,malignant tumor of the large intestine
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Negative control group
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- CRA and CRC groups
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- Patients with CRA (colorectal adenoma) or CRC (colorectal carcinoma) confirmed by colonoscopy and pathological examination
- Group 0 sample size Number of subjects in the control (unexposed) group
- 52
- Group 1 sample size Number of subjects in the case (exposed) group
- 89
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- 6 months
Lab analysis
- Sequencing type
- 16S
- 16S variable region One or more hypervariable region(s) of the bacterial 16S gene
- V1-V3
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Roche454
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)?
- 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
Signature 1
Needs review
Source: Table 1
Description: Differential microbial abundance between the control group and the CRA+CRC patients
Abundance in Group 1: decreased abundance in CRA and CRC groups
| NCBI | Links |
|---|---|
| Actinomyces | |
| Bifidobacterium | |
| Blautia | |
| Clostridium | |
| Dorea | |
| Eubacterium | |
| Lactobacillus | |
| Roseburia |
Revision editor(s): Jeshudy, Claregrieve1
Signature 2
Needs review
Source: Table 1
Description: Differential microbial abundance between the control group and the CRA+CRC patients
Abundance in Group 1: increased abundance in CRA and CRC groups
| NCBI | Links |
|---|---|
| Coprococcus | |
| Enterococcus | |
| Escherichia/Shigella sp. | |
| Fusobacterium | |
| Streptococcus |
Revision editor(s): Jeshudy, Claregrieve1
Experiment 2
Subjects
- Location of subjects
- China
- 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
- Intestine Bowel,Intestinal tract,Intestine
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Control (male C57BL/6-APCMin/+ and male wild-type C57BL/6)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- C57BL/6-APCMin/+: F. nucleatum (Fn), E. coli (Ec); wild-type C57BL/6: DMH, Fn, Fn+DMH, Ec, Ec+DMH
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- DMH was injected subcutaneous at a dose of 20 mg/kg once weekly.
All treatments were performed for 8 weeks to ensure aberrant crypt foci (ACF) formation or 20 weeks to ensure tumor formation.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 20
- Group 1 sample size Number of subjects in the case (exposed) group
- 70
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- None
Lab analysis
- Sequencing type
- 16S
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Roche454
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: Figure 3
Description: Lumen microbiota distribution at the phylum level in mice treated with A. bacteria or B. BBR. The relative contribution of a phylum was calculated as the percentage of the sequences of this phylum to all sequences in this population. Mean ± SEM (standard error of mean) was calculated according to percentage of the sequences of this phylum to all sequences in each individual. The differences in relative abundances were calculated using Mann-Whitney U test. Two-sided P-values < 0.05 were considered statistically significant.
Abundance in Group 1: increased abundance in C57BL/6-APCMin/+: F. nucleatum (Fn), E. coli (Ec); wild-type C57BL/6: DMH, Fn, Fn+DMH, Ec, Ec+DMH
| NCBI | Links |
|---|---|
| Bacteroidota | |
| Bacillota | |
| Pseudomonadota | |
| Verrucomicrobiota | |
| Cyanobacteriota | |
| Mycoplasmatota |
Revision editor(s): Jeshudy
Experiment 3
Subjects
- Location of subjects
- China
- 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
- Intestine Bowel,Intestinal tract,Intestine
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- colorectal cancer cancer of colorectum,cancer of large bowel,cancer of large intestine,cancer of the large bowel,colon cancer,colorectal cancer,colorectum cancer,CRC,large intestine cancer,malignant colorectal neoplasm,malignant colorectal tumor,malignant colorectum neoplasm,malignant large bowel neoplasm,malignant large bowel tumor,malignant large intestine neoplasm,malignant large intestine tumor,malignant neoplasm of colorectum,malignant neoplasm of large bowel,malignant neoplasm of large intestine,malignant neoplasm of the large bowel,malignant neoplasm of the large intestine,malignant tumor of large bowel,malignant tumor of large intestine,malignant tumor of the large bowel,malignant tumor of the large intestine
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- male C57BL/6-APCMin/+: Ctrl, F. nucleatum (Fn), E. coli (Ec); male wild-type C57BL/6): Ctrl, DMH, Fn, Fn+DMH, Ec, Ec+DMH
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- C57BL/6-APCMin/+: BBR and Fn+BBR; wild-type C57BL/6: BBR, BBR+DMH and BBR+Fn+DMH
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- DMH was injected subcutaneous at a dose of 20 mg/kg once weekly. BBR was administrated by gavage at a dose of 100 mg/kg two hours after bacterial feeding.
All treatments were performed for 8 weeks to ensure aberrant crypt foci (ACF) formation or 20 weeks to ensure tumor formation.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 90
- 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)
- None
Signature 1
Source: Figure 3
Description: Lumen microbiota distribution at the phylum level in mice treated with A. bacteria or B. BBR. The relative contribution of a phylum was calculated as the percentage of the sequences of this phylum to all sequences in this population. Mean ± SEM (standard error of mean) was calculated according to percentage of the sequences of this phylum to all sequences in each individual. The differences in relative abundances were calculated using Mann-Whitney U test.
Abundance in Group 1: decreased abundance in C57BL/6-APCMin/+: BBR and Fn+BBR; wild-type C57BL/6: BBR, BBR+DMH and BBR+Fn+DMH
| NCBI | Links |
|---|---|
| Mycoplasmatota | |
| Verrucomicrobiota |
Revision editor(s): Jeshudy
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