Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment

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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

Curated date: 2022/05/31

Curator: Jeshudy

Revision editor(s): Jeshudy, Claregrieve1, WikiWorks

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

Curated date: 2022/06/02

Curator: Jeshudy

Revision editor(s): Jeshudy, Claregrieve1

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

Curated date: 2022/06/02

Curator: Jeshudy

Revision editor(s): Jeshudy, Claregrieve1

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


Needs review

Curated date: 2022/06/02

Curator: Jeshudy

Revision editor(s): Jeshudy

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

Needs review

Curated date: 2022/06/04

Curator: Jeshudy

Revision editor(s): Jeshudy

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


Needs review

Curated date: 2022/06/04

Curator: Jeshudy

Revision editor(s): Jeshudy, WikiWorks

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

Lab analysis

Sequencing type
16S
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Roche454

Statistical Analysis

Statistical test
T-Test
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05



Signature 1

Needs review

Curated date: 2022/06/04

Curator: Jeshudy

Revision editor(s): Jeshudy

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