Project description:PROTECT is a multicenter pediatric inception cohort study of response to standardized colitis therapy. In order to more explicitly model progression to colectomy within one year of diagnosis, we performed differential expression analysis between baseline rectal RNAseq biopsies of 21 patients who progressed to colectomy, and 310 who did not. We report rectal gene expression of pediatric patients with ulcerative colitis at diagnosis and at one year follow-up.
Project description:Ulcerative Colitis fecal samples were transplanted into IL10 deficient gnotobiotic mice. Half of the mice received a protease inhibitor cocktail in their drinking water. After 8-weeks colonization the animals were studied for colonic inflammation, and fecal samples were collected and analyzed by LC-MS3 based quantitative metaproteomics. Data from mice transplanted with two UC patients were analyzed in this dataset.
Project description:Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) that predisposes to colorectal cancer (CRC) and is modeled in mice by administration of dextran sodium sulfate (DSS) in drinking water. There are two isoforms of STAT3, STAT3α is pro-inflammatory and anti-apoptotic, while STAT3β has opposing effects on STAT3α. We examined the severity of DSS-induced colitis in transgenic-mice expressing only STAT3α ( / ) and in wild-type (WT) mice administered C188-9, a small molecule direct-inhibitor of STAT3. While manifestations of DSS-induced UC, such as mortality, weight-loss, rectal-bleeding, diarrhea, and colon-shortening, were exacerbated in / transgenic versus cage-control WT mice, all were prevented by C188-9 treatment of WT mice. C188-9 treatment also increased apoptosis of pathogenic CD4+T-cells, reduced colon-levels of IL17-positive cells, down-modulated mRNA-levels of STAT3-genes involved in inflammation, apoptosis-prevention, and colorectal-cancer-metastases. These are the only studies showing efficacy of Thus small-molecule targeting of STAT3 may be a useful novel approach in treating UC and preventing UC-associated colorectal-cancer. We performed genome-wide microarray expression profiling to gain greater understanding of the mechanisms involved in the protective effect of C188-9 in DSS-induced colitis, we examined mRNA levels in the colon of mice receiving DSS or plain water, without or with C188-9 treatment.
Project description:Ulcerative colitis is heritable disorder with variable clinical outcome but to date only less than 10% of the disease susceptibility and the disease outcome is explained by IBD (inflammatory bowel disease) associated genetic loci. This missing heritability lay fertile grounds for investigating epigenetics as possible explanation. The aims of the study were to investigate genome-wide DNA methylation of the rectal tissue in an inception cohort of UC at two time points, once at baseline (treatment naïve) and at follow-up to explore how longitudinal DNA methylation influences the disease onset, disease progression and outcome. For this purpose, we profiled DNA methylation within rectal mucosal biopsies of pediatric UC (n=211) and non-IBD control patients (n=85) to perform epigenome-wide association studies (EWAS) of specific cell types (i.e epithelial, immune, and fibroblast), to identify UC specific differences. We have also performed longitudinal analysis on follow-up samples (n =73), and also additional comparisons were made between patients eventually undergoing colectomy versus those who did not.
Project description:To seek effects of inflammatory status and 5-aminosalicylic acid (5-ASA, mesalazine) exposure ex vivo on mRNA levels within rectal mucosal biopsies from patients with ulcerative colitis.
Project description:The epithelial expression of the insulin receptor in the colon is previously reported to correlate with the extent of colonic inflammation. Here, we investigated the effect of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer. We report increased susceptibility to chemically-induced colitis together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we show that topically administered insulin in inflamed colons of wildtype mice reduces inflammation-induced weight loss and improves remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores and developed significantly fewer and smaller tumors compared with the control group receiving phosphate-buffered saline only. Rectal insulin therapy can potentially be a novel treatment targeting the epithelial layer to enhance mucosal healing in the ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.
Project description:To seek effects of inflammatory status and 5-aminosalicylic acid (5-ASA, mesalazine) exposure ex vivo on mRNA levels within rectal mucosal biopsies from patients with ulcerative colitis. A total of 12 biopsies were analysed, 3 biological replicates in each of 4 categories (inflamed with or without 5-ASA, non-inflamed with or without 5-ASA).
Project description:RNAseq analysis of laser capture microdissected ileal epithelial cells from stopFlox(control) and stopdIEC (epithelium-specific vitamin A signaling knockdown) mice