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Concept: Ulcerative colitis

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Crohn’s disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD), are characterized by chronic inflammation of the gastrointestinal tract (1). IBD has been associated with poor quality of life and extensive morbidity and often results in complications requiring hospitalizations and surgical procedures (2-4). Most previous studies of IBD have used administrative claims data or data collected from limited geographic areas to demonstrate increases in estimated prevalence of IBD within the United States (5,6). Few national prevalence estimates of IBD among adults based on large, nationally representative data sources exist, and those that do tend to be based on older data. For example, the most recent national study used 1999 National Health Interview Survey (NHIS) data and estimated that 1.8 million (0.9%) U.S. adults had IBD (7). To examine the prevalence of IBD among the civilian, noninstitutionalized U.S. adult population, data from the 2015 NHIS were analyzed. Overall, an estimated 3.1 million, or 1.3%, of U.S. adults have received a diagnosis of IBD. Within population subgroups, a higher prevalence of IBD was identified among adults aged ≥45 years, Hispanics, non-Hispanic whites, and adults with less than a high school level of education, not currently employed, born in the United States, living in poverty, or living in suburban areas. The use of a nationally representative data source such as the NHIS to estimate the prevalence of IBD overall and by population subgroups is important to understand the burden of IBD on the U.S. health care system.

Concepts: Inflammation, United States, Ulcerative colitis, Crohn's disease, Colonoscopy, Gastroenterology, Inflammatory bowel disease, Suburb

146

Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.

Concepts: Cancer, Ulcerative colitis, Crohn's disease, Colon, Large intestine, Inflammatory bowel disease, Ileostomy, Toxic megacolon

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The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin α4β7, was demonstrated in multicenter, phase 3, randomized, placebo-controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti-tumor necrosis factor (TNF) agents.

Concepts: Monoclonal antibodies, Ulcerative colitis, Crohn's disease, Colon, Colitis, Infliximab, Abdominal pain, Tumor necrosis factor-alpha

138

The Crohn’s and Colitis Knowledge (CCKNOW) score does not reflect updated knowledge relating to inflammatory bowel disease (IBD). The aim of this study was to develop, validate, and apply a novel tool to measure disease-related knowledge in IBD patients.

Concepts: Inflammation, Biopsy, Ulcerative colitis, Crohn's disease, Colonoscopy, Gastroenterology, Inflammatory bowel disease, Helminthic therapy

113

Individuals with colorectal cancer (CRC) have a tendency to intestinal bleeding which may result in mild to severe iron deficiency anemia, but for many colon cancer patients hematological abnormalities are subtle. The fecal occult blood test (FOBT) is used as a pre-screening test whereby those with a positive FOBT are referred to colonscopy. We sought to determine if information contained in the complete blood count (CBC) report coud be processed automatically and used to predict the presence of occult colorectal cancer (CRC) in the setting of a large health services plan. Using the health records of the Maccabi Health Services (MHS) we reviewed CBC reports for 112,584 study subjects of whom 133 were diagnosed with CRC in 2008 and analysed these with the MeScore tool. The odds ratio for being diagnosed with CRC in 2008 was calculated with regards to the MeScore, using cutoff levels of 97% and 99% percentiles. For individuals in the highest one percentile, the odds ratio for CRC was 21.8 (95% CI 13.8 to 34.2). For the majority of the individuals with cancer, CRC was not suspected at the time of the blood draw. Frequent use of anticoagulants, the presence of other gastrointestinal pathologies and non-GI malignancies were assocaitged with false positive MeScores. The MeScore can help identify individuals in the population who would benefit most from CRC screening, including those with no clinical signs or symptoms of CRC.

Concepts: Hemoglobin, Cancer, Colorectal cancer, Anemia, Hematology, Ulcerative colitis, Hematocrit, Fecal occult blood

103

The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1-2 wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.

Concepts: Immune system, Inflammation, Bacteria, Pathology, Infection, Ulcerative colitis, Inflammatory bowel disease, Anti-inflammatory

67

The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

Concepts: Immune system, Inflammation, Bacteria, Gut flora, Nutrition, Ulcerative colitis, Gastroenterology, Inflammatory bowel disease

60

The appendix may modulate colon microbiota and bowel inflammation. We investigated whether appendectomy alters colorectal cancer risk.

Concepts: Cancer, Colorectal cancer, Ulcerative colitis, Crohn's disease, Colon, Constipation, Large intestine, Defecation

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Mucoid structures that coat the epithelium play an essential role in keeping the intestinal microbiota at a safe distance from host cells. Encroachment of bacteria into the normally almost-sterile inner mucus layer has been observed in inflammatory bowel disease and in mouse models of colitis. Moreover, such microbiota encroachment has also been observed in mouse models of metabolic syndrome, which are associated low-grade intestinal inflammation. Hence, we investigated if microbiota encroachment might correlate with indices of metabolic syndrome in humans.

Concepts: Immune system, Inflammation, Bacteria, Ulcerative colitis, Gastroenterology, Inflammatory bowel disease