Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review

AIM: To study the clinical efficacy and safety of Fecal microbiota transplantation (FMT). We systematically reviewed FMT used as clinical therapy. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and Conference proceedings from inception to July, 2013. Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category, on an intention-to-treat basis. RESULTS: We included 45 studies; 34 on Clostridium difficile-infection (CDI), 7 on inflammatory bowel disease, 1 on metabolic syndrome, 1 on constipation, 1 on pouchitis and 1 on irritable bowel syndrome (IBS). In CDI 90% resolution of diarrhea in 33 case series (n = 867) was reported, and 94% resolution of diarrhea after repeated FMT in a randomized controlled trial (RCT) (n = 16). In ulcerative colitis (UC) remission rates of 0% to 68% were found (n = 106). In Crohn's disease (CD) (n = 6), no benefit was observed. In IBS, 70% improvement of symptoms was found (n = 13). 100% Reversal of symptoms was observed in constipation (n = 3). In pouchitis, none of the patients (n = 8) achieved remission. One RCT showed significant improvement of insulin sensitivity in metabolic syndrome (n = 10). Serious adverse events were rare. CONCLUSION: FMT is highly effective in CDI, and holds promise in UC. As for CD, chronic constipation, pouchitis and IBS data are too limited to draw conclusions. FMT increases insulin sensitivity in metabolic syndrom

Low interobserver agreement among endoscopists in differentiating dysplastic from non-dysplastic lesions during inflammatory bowel disease colitis surveillance

Item does not contain fulltextOBJECTIVES: During endoscopic surveillance in patients with longstanding colitis, a variety of lesions can be encountered. Differentiation between dysplastic and non-dysplastic lesions can be challenging. The accuracy of visual endoscopic differentiation and interobserver agreement (IOA) has never been objectified. MATERIAL AND METHODS: We assessed the accuracy of expert and nonexpert endoscopists in differentiating (low-grade) dysplastic from non-dysplastic lesions and the IOA among and between them. An online questionnaire was constructed containing 30 cases including a short medical history and an endoscopic image of a lesion found during surveillance employing chromoendoscopy. RESULTS: A total of 17 endoscopists, 8 experts, and 9 nonexperts assessed all 30 cases. The overall sensitivity and specificity for correctly identifying dysplasia were 73.8% (95% confidence interval (CI) 62.1-85.4) and 53.8% (95% CI 42.6-64.7), respectively. Experts showed a sensitivity of 76.0% (95% CI 63.3-88.6) versus 71.8% (95% CI 58.5-85.1, p = 0.434) for nonexperts, the specificity 61.0% (95% CI 49.3-72.7) versus 47.1% (95% CI 34.6-59.5, p = 0.008). The overall IOA in differentiating between dysplastic and non-dysplastic lesions was fair 0.24 (95% CI 0.21-0.27); for experts 0.28 (95% CI 0.21-0.35) and for nonexperts 0.22 (95% CI 0.17-0.28). The overall IOA for differentiating between subtypes was fair 0.21 (95% CI 0.20-0.22); for experts 0.19 (95% CI 0.16-0.22) and nonexpert 0.23 (95% CI 0.20-0.26). CONCLUSION: In this image-based study, both expert and nonexpert endoscopists cannot reliably differentiate between dysplastic and non-dysplastic lesions. This emphasizes that all lesions encountered during colitis surveillance with a slight suspicion of containing dysplasia should be removed and sent for pathological assessment

The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II

BACKGROUND: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that is strongly associated with a particular phenotype of inflammatory bowel disease (IBD) with right-sided colonic involvement. In IBD, several studies demonstrated significant aberrancies in the intestinal microbiota in comparison with healthy controls. We aimed to explore the link between IBD and PSC by studying the intestinal mucosa-adherent microbiota in PSC and ulcerative colitis (UC) patients and noninflammatory controls. METHODS: We included 12 PSC patients, 11 UC patients, and nine noninflammatory controls. The microbiota composition was determined in ileocecal biopsies from each patient by 16S rRNA-based analyses using the human intestinal tract chip. RESULTS: Profiling of the mucosa-adherent microbiota of PSC patients, UC patients, and noninflammatory controls revealed that these groups did not cluster separately based on microbiota composition. At the genus-like level, the relative abundance of uncultured Clostridiales II was significantly lower (almost 2-fold) in PSC (0.26 ± 0.10%) compared with UC (0.41 ± 0.29%) and controls (0.49 ± 0.25%) (p = 0.02). Diversity and richness in the microbiota composition differed across the groups and were significantly lower in PSC patients compared with noninflammatory controls (p = 0.04 and p = 0.02, respectively). No significant differences were found in evenness. CONCLUSIONS: Reduced amounts of uncultured Clostridiales II in PSC biopsies in comparison with UC and healthy controls can be considered a signature of a compromised gut, as we have recently observed that this group of as yet uncultured Firmicutes correlates significantly with health

Findings from a Randomized Controlled Trial of Fecal Transplantation for Patients with Ulcerative Colitis

BACKGROUND: & Aims: Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial. METHODS: Patients with mild to moderately active UC (n=50) were assigned to groups that underwent FMT with feces from healthy donors or were given autologous fecal microbiota (control); each was administered via naso-duodenal tube at the start of the study and 3 weeks later. The study was performed at the Academic Medical Center in Amsterdam from June 2011 through May 2014. The composite primary endpoint was clinical remission (simple clinical colitis activity index scores =2) combined with =1 point decrease in the Mayo endoscopic score at week 12. Secondary endpoints were safety and microbiota composition by phylogenetic microarray in fecal samples. RESULTS: Thirty-seven patients completed the primary endpoint assessment. In the intention-to-treat analysis, 7/23 patients who received fecal transplants from healthy donors (30.4%) and 5/25 controls (20.0%) achieved the primary endpoint (P=.51). In the per protocol analysis, 7/17 patients who received fecal transplants from healthy donors (41.2%) and 5/20 controls (25.0%) achieved the primary endpoint (P=.29). Serious adverse events occurred in 4 patients (2 in the FMT group) but these were not considered to be related to the FMT. At 12 weeks the microbiota of responders in the FMT group was similar to that of their healthy donors; remission was associated with proportions of Clostridium clusters IV and XIVa. CONCLUSIONS: In this phase 2 trial, there was no statistically significant difference in clinical and endoscopic remission between patients with UC who received fecal transplants from healthy donors and those who received their own fecal microbiota, which may be due to limited numbers. However, the microbiota of responders had distinct features from that of nonresponders, warranting further study. ClinicalTrials.gov no: NCT0165003

Anti-Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis

Functional Genomics of Systemic Disorder

Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

Objective Macrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fc gamma-receptor (Fc gamma R) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined.Design We used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rb(high) T-cell transfer model in combination with several genetic mouse models.Results Anti-TNF therapy increased macrophage IL-10 production in an Fc gamma R-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rb(high) T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF.Conclusion The therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.Functional Genomics of Systemic Disorder

Stromal Indian Hedgehog Signaling Is Required for Intestinal Adenoma Formation in Mice

Genome Instability and Cance