The Inflammatory Bowel Diseases and Ambient Air Pollution: A Novel Association

OBJECTIVES: The inflammatory bowel diseases (IBDs) emerged after industrialization. We studied whether ambient air pollution levels were associated with the incidence of IBD. METHODS: The health improvement network (THIN) database in the United Kingdom was used to identify incident cases of Crohn's disease (n=367) or ulcerative colitis (n=591), and age- and sex-matched controls. Conditional logistic regression analyses assessed whether IBD patients were more likely to live in areas of higher ambient concentrations of nitrogen dioxide (NO(2)), sulfur dioxide (SO(2)), and particulate matter <10 μm (PM(10)), as determined by using quintiles of concentrations, after adjusting for smoking, socioeconomic status, non-steroidal anti-inflammatory drugs (NSAIDs), and appendectomy. Stratified analyses investigated effects by age. RESULTS: Overall, NO(2), SO(2), and PM(10) were not associated with the risk of IBD. However, individuals ≤23 years were more likely to be diagnosed with Crohn's disease if they lived in regions with NO(2) concentrations within the upper three quintiles (odds ratio (OR)=2.31; 95% confidence interval (CI)=1.25-4.28), after adjusting for confounders. Among these Crohn's disease patients, the adjusted OR increased linearly across quintile levels for NO(2) (P=0.02). Crohn's disease patients aged 44-57 years were less likely to live in regions of higher NO(2) (OR=0.56; 95% CI=0.33-0.95) and PM(10) (OR=0.48; 95% CI=0.29-0.80). Ulcerative colitis patients ≤25 years (OR=2.00; 95% CI=1.08-3.72) were more likely to live in regions of higher SO(2); however, a dose-response effect was not observed. CONCLUSIONS: On the whole, air pollution exposure was not associated with the incidence of IBD. However, residential exposures to SO(2) and NO(2) may increase the risk of early-onset ulcerative colitis and Crohn's disease, respectively. Future studies are needed to explore the age-specific effects of air pollution exposure on IBD risk

Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles

Background: The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI. Aim: To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes. Methods: Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels. Results: Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups. Conclusions: Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence.American College of Gastroenterology (Clinical Research Award ACGJR-017-2015

An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD

A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes

Peer reviewedPublisher PD

A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes

Background: Randomised controlled trials (RCTs) are perceived as the gold-standard method for evaluating healthcare interventions, and increasingly include quality of life (QoL) measures. The observed results are susceptible to bias if a substantial proportion of outcome data are missing. The review aimed to determine whether imputation was used to deal with missing QoL outcomes. Methods: A random selection of 285 RCTs published during 2005/6 in the British Medical Journal, Lancet, New England Journal of Medicine and Journal of American Medical Association were identified. Results: QoL outcomes were reported in 61 (21%) trials. Six (10%) reported having no missing data, 20 (33%) reported ≤ 10% missing, eleven (18%) 11%–20% missing, and eleven (18%) reported >20% missing. Missingness was unclear in 13 (21%). Missing data were imputed in 19 (31%) of the 61 trials. Imputation was part of the primary analysis in 13 trials, but a sensitivity analysis in six. Last value carried forward was used in 12 trials and multiple imputation in two. Following imputation, the most common analysis method was analysis of covariance (10 trials). Conclusion: The majority of studies did not impute missing data and carried out a complete-case analysis. For those studies that did impute missing data, researchers tended to prefer simpler methods of imputation, despite more sophisticated methods being available.The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorate. Shona Fielding is also currently funded by the Chief Scientist Office on a Research Training Fellowship (CZF/1/31)

Inflammatory bowel disease: past, present, and future

Crohn’s disease and ulcerative colitis, collectively known as the inflammatory bowel diseases (IBD), are largely diseases of the twentieth century, and are associated with the rise of modern, Westernized industrial society. Although the causes of these diseases remain incompletely understood, the prevailing model is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in the genetically susceptible host. A review of the past and present of these diseases shows that detailed description preceded more fundamental elucidation of the disease processes. Working out the details of disease pathogenesis, in turn, has yielded dividends in more focused and effective therapy for IBD. This article highlights the key descriptions of the past, and the pivotal findings of current studies in disease pathogenesis and its connection to medical therapy. Future directions in the IBD will likely explicate the inhomogeneous causes of these diseases, with implications for individualized therapy

Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants

BACKGROUND:Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants. METHODOLOGY/PRINCIPAL FINDINGS:By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes. CONCLUSIONS/SIGNIFICANCE:These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing

The association between environmental exposures during childhood and the subsequent development of Crohn's Disease: A score analysis approach

Background Environmental factors during childhood are thought to play a role in the aetiology of Crohn's Disease (CD). In South Africa, recently published work based on an investigation of 14 childhood environmental exposures during 3 age intervals (0-5, 6-10 and 11-18 years) has provided insight into the role of timing of exposure in the future development of CD. The 'overlapping' contribution of the investigated variables however, remains unclear. The aim of this study was to perform a post hoc analysis using this data and investigate the extent to which each variable contributes to the subsequent development of CD relative to each aforementioned age interval, based on a score analysis approach. Methods Three methods were used for the score analysis. Two methods employed the subgrouping of one or more (similar) variables (methods A and B), with each subgroup assigned a score value weighting equal to one. For comparison, the third approach (method 0) involved no grouping of the 14 variables. Thus, each variable held a score value of one. Results Results of the score analysis (Method 0) for the environmental exposures during 3 age intervals (0-5, 6-10 and 11-18 years) revealed no significant difference between the case and control groups. By contrast, results from Method A and Method B revealed a significant difference during all 3 age intervals between the case and control groups, with cases having significantly lower exposure scores (approximately 30% and 40% lower, respectively). Conclusion Results from the score analysis provide insight into the 'compound' effects from multiple environmental exposures in the aetiology of CD.IS

Galectin-4 Controls Intestinal Inflammation by Selective Regulation of Peripheral and Mucosal T Cell Apoptosis and Cell Cycle

Galectin-4 is a carbohydrate-binding protein belonging to the galectin family. Here we provide novel evidence that galectin-4 is selectively expressed and secreted by intestinal epithelial cells and binds potently to activated peripheral and mucosal lamina propria T-cells at the CD3 epitope. The carbohydrate-dependent binding of galectin-4 at the CD3 epitope is fully functional and inhibited T cell activation, cycling and expansion. Galectin-4 induced apoptosis of activated peripheral and mucosal lamina propria T cells via calpain-, but not caspase-dependent, pathways. Providing further evidence for its important role in regulating T cell function, galectin-4 blockade by antisense oligonucleotides reduced TNF-alpha inhibitor induced T cell death. Furthermore, in T cells, galectin-4 reduced pro-inflammatory cytokine secretion including IL-17. In a model of experimental colitis, galectin-4 ameliorated mucosal inflammation, induced apoptosis of mucosal T-cells and decreased the secretion of pro-inflammatory cytokines. Our results show that galectin-4 plays a unique role in the intestine and assign a novel role of this protein in controlling intestinal inflammation by a selective induction of T cell apoptosis and cell cycle restriction. Conclusively, after defining its biological role, we propose Galectin-4 is a novel anti-inflammatory agent that could be therapeutically effective in diseases with a disturbed T cell expansion and apoptosis such as inflammatory bowel disease