Different Mechanism and Efficacy of Dextran-Sodium Sulfate and 2,4,6-Trinitrobenzene Sulphonic Acid in Modeling Ulcerative Colitis in C57BL/6 Mice

Background and Aims: Dextran-sodium sulfate and 2,4,6-trinitrobenzene sulphonic acid are common modeling methods in studying ulcerative colitis. Little attention has been paid to the mechanism differences between the two approaches. Here, we aim to compare the mechanisms and efficacy of these two models and wish to provide fundamental proves for choosing ideal ulcerative colitis models. Methods: Dextran-sodium sulfate and 2,4,6-trinitrobenzene sulphonic acid were applied to induce the colitis in C57BL/6 mice for seven days. Body weight and disease activity index were assessed. Hematology was detected by routine blood test. Histopathology was analyzed by hematoxylin-eosin staining section. Enzyme-linked immunosorbent assay, Western blot and quantitative real-time PCR were used to detect the cytokines protein levels and mRNA levels. Flow cytometry were used to detect the cycles and subsets of splenic cells. Results: Dextran-sodium sulfate induced colitis in C57BL/6 mice showed higher acute immune activities, while 2,4,6-trinitrobenzene sulphonic acid induced colitis showed chronic immune activities with high platelet amounts and activation. Dextran-sodium sulfate is more suitable for modeling acute ulcerative colitis. On the contrary, 2,4,6-trinitrobenzene sulphonic acid is more appropriate for modeling chronic ulcerative colitis. Conclusions: Dextran-sodium sulfate treatment within 7 days in C57BL/6 mice is a suitable experimental model for studying human acute ulcerative colitis with immune response, fecal blood and acute pathogenic damage. Conversely, 2,4,6-trinitrobenzene sulphonic acid treatment within 7 days is more appropriate for studying human chronic ulcerative colitis with hypercoagulable state, IL-2 over-expression state and chronic pathogenic damage.

Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study

Background Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection. Objectives To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme. Design Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later. Setting Thirty-one UK hospitals. Participants Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis. Interventions An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy. Main outcome Identifying ulcerative colitis patients with neoplasia. Results Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09). Limitations Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed. Conclusions Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes. Trial registration Current Controlled Trials ISRCTN81826545. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.

Role of Cancer Stem Cells in Colitis-Associated Colorectal Cancer

Colorectal cancer the third-leading cause of cancer mortality Worldwide; it's a well characterised model at molecular level among various cancera. Chronic ulcerative colitis is one of the causes of colorectal cancer. Recent cancer research focuses on tumor-initiating cells which are the cause of tumor initiation, invasions, drug-resistant, recurrence, and metastasis. Emerging research findings support the presence of colon cancer stem cells in sporadic colorectal cancer and in colitis-associated colorectal cancer. Colitis-associated cancer cells exhibit increased colon cancer stem cell marker expression along with activated developmental signaling pathways. Also, emerging reports exhibit that inhibition stem cell markers in chronic ulcerative colitis cells impedes progression of cancer in genetically engineered animal models and primary samples. This chapter deals of colitis-cancer transition, microenvironment of colitis-associated colorectal cancer, and articulates that cancer stem cells are ideal targets for colorectal cancer.

Sulfated polysaccharide from pacific abalone attenuated DSS-induced acute and chronic ulcerative colitis in mice via regulating intestinal micro-ecology and NF-κB pathway

Due to potential side effects of current drugs in colitis treatment, polysaccharides with anti-inflammatory activity can be considered as an alternative molecule for colitis treatment. Sulfated polysaccharide from pacific abalone...

Myricetin and its derivative M10, myricetin-3-O-β-d-lactose sodium salt, modify the composition of gut microbiota in mice with chronic ulcerative colitis

Background Previous studies revealed that Myricetin and derivative M10, Myricetin-3-O-β-d-lactose sodium salt, prevented chronic ulcerative colitis (UC) in mice. We investigated whether the inhibitory effects of Myricetin and M10 on UC were associated to the modification of intestinal microbiota. Samples of intestinal microbiota were collected from the ileocecum of UC mice which demonstrated response to the treatment of Myricetin and M10. Gut microbiota was analyzed by 16S rDNA sequencing assay. Results UC model mice demonstrated the increases of Firmicutes and Actinobacteria as compared to healthy control mice. Oral M10 and Myricetin normalized the composition of Firmicutes and Actinobacteria. At genus level, the effect of M10 and Myricetin on ulcerative colitis was strongly associated to the increase of probiotics, such as Akkermansia, and the inhibition of pathogenic microorganisms, such as Ruminococcus and Parabacteroides. Myricetin’s derivative M10 significantly increased both biosynthesis and degradation activities, resulting to strong improvements of the metabolism of sulfur, pyruvate, steroid biosynthesis and unsaturated fatty acid biosynthesis in gut microenvironment. Conclusions Natural product Myricetin and its derivative M10 could modify the modification of gut microbiota in UC mice. Combined with pharmacologic effects of Myricetin and M10 in these UC mice, we conclued that the effects of Myricetin and M10 on UC were associated to the modification of intestinal microbiota in the environment of chronic ulcerative colitis.