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Crohn's Disease-Associated Adherent-Invasive Escherichia coli Adhesion Is Enhanced by Exposure to the Ubiquitous Dietary Polysaccharide Maltodextrin <=SEP=> Crohn's disease (CD) is associated with intestinal dysbiosis evidenced by an altered microbiome forming thick biofilms on the epithelium. Additionally, adherent-invasive E. coli (AIEC) strains are frequently isolated from ileal lesions of CD patients indicating a potential role for these strains in disease pathogenesis. The composition and characteristics of the host microbiome are influenced by environmental factors, particularly diet. Polysaccharides added to food as emulsifiers, stabilizers or bulking agents have been linked to bacteria-associated intestinal disorders. The escalating consumption of polysaccharides in Western diets parallels an increased incidence of CD during the latter 20th century. In this study, the effect of a polysaccharide panel on adhesiveness of the CD-associated AIEC strain LF82 was analyzed to determine if these food additives promote disease-associated bacterial phenotypes. Maltodextrin (MDX), a polysaccharide derived from starch hydrolysis, markedly enhanced LF82 specific biofilm formation. Biofilm formation of multiple other E. coli strains was also promoted by MDX. MDX-induced E. coli biofilm formation was independent of polysaccharide chain length indicating a requirement for MDX metabolism. MDX exposure induced type I pili expression, which was required for MDX-enhanced biofilm formation. MDX also increased bacterial adhesion to human intestinal epithelial cell monolayers in a mechanism dependent on type 1 pili and independent of the cellular receptor CEACAM6, suggesting a novel mechanism of epithelial cell adhesion. Analysis of mucosa-associated bacteria from individuals with and without CD showed increased prevalence of malX, a gene essential for MDX metabolism, uniquely in the ileum of CD patients. These findings demonstrate that the ubiquitous dietary component MDX enhances E. coli adhesion and suggests a mechanism by which Western diets rich in specific polysaccharides may promote dysbiosis of gut microbes and contribute to disease susceptibility.

Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease <=SEP=> Background Epithelial barrier function is impaired in Crohn's disease. Aim To define the underlying cellular mechanisms with special attention to tight junctions. Methods Biopsy specimens from the sigmoid colon of patients with mild to moderately active or inactive Crohn's disease were studied in Ussing chambers, and barrier function was determined by impedance analysis and conductance scanning. Tight junction structure was analysed by freeze fracture electron microscopy, and tight junction proteins were investigated immunohistochemically by confocal laser scanning microscopy and quantified in immunoblots. Epithelial apoptosis was analysed in terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick‐end labelling and 4′,6‐diamidino‐2‐phenylindole staining. Results Patients with active Crohn's disease showed an impaired intestinal barrier function as indicated by a distinct reduction in epithelial resistance. As distribution of conductivity was even, focal epithelial lesions (eg, microerosions) did not contribute to barrier dysfunction. Instead, freeze fracture electron microscopy analysis showed reduced and discontinuous tight junction strands. Occludin and the sealing tight junction proteins claudin 5 and claudin 8 were downregulated and redistributed off the tight junction, whereas the pore‐forming tight junctions protein claudin 2 was strongly upregulated, which constitute the molecular basis of tight junction changes. Other claudins were unchanged (claudins 1, 4 and 7) or not detectable in sigmoid colon (claudins 11, 12, 14, 15 and 16). Claudin 2 upregulation was less pronounced in active Crohn's disease compared with active ulcerative colitis and was inducible by tumour necrosis factor α. As a second source of impaired barrier function, epithelial apoptosis was distinctly increased in active Crohn's disease (mean (SD) 5.2 (0.5)% v 1.9 (0.2)% in control). By contrast, barrier function, tight junction proteins and apoptosis were unaffected in Crohn's disease in remission. Conclusion Upregulation of pore‐forming claudin 2 and downregulation and redistribution of sealing claudins 5 and 8 lead to altered tight junction structure and pronounced barrier dysfunction already in mild to moderately active Crohn's disease.

Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. <=SEP=> OBJECTIVES: The incidence of inflammatory bowel disease (IBD) is increasing. Dietary factors such as the spread of the "Western" diet, high in fat and protein but low in fruits and vegetables, may be associated with the increase. Although many studies have evaluated the association between diet and IBD risk, there has been no systematic review. METHODS: We performed a systematic review using guideline-recommended methodology to evaluate the association between pre-illness intake of nutrients (fats, carbohydrates, protein) and food groups (fruits, vegetables, meats) and the risk of subsequent IBD diagnosis. Eligible studies were identified via structured keyword searches in PubMed and Google Scholar and manual searches. RESULTS: Nineteen studies were included, encompassing 2,609 IBD patients (1,269 Crohn's disease (CD) and 1,340 ulcerative colitis (UC) patients) and over 4,000 controls. Studies reported a positive association between high intake of saturated fats, monounsaturated fatty acids, total polyunsaturated fatty acids (PUFAs), total omega-3 fatty acids, omega-6 fatty acids, mono- and disaccharides, and meat and increased subsequent CD risk. Studies reported a negative association between dietary fiber and fruits and subsequent CD risk. High intakes of total fats, total PUFAs, omega-6 fatty acids, and meat were associated with an increased risk of UC. High vegetable intake was associated with a decreased risk of UC. CONCLUSIONS: High dietary intakes of total fats, PUFAs, omega-6 fatty acids, and meat were associated with an increased risk of CD and UC. High fiber and fruit intakes were associated with decreased CD risk, and high vegetable intake was associated with decreased UC risk.

Treatment-related progressive multifocal leukoencephalopathy: current understanding and future steps <=SEP=> Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by a ubiquitous polyomavirus, JC virus. PML is almost always associated with some underlying immunosuppression and acquired immune deficiency syndrome has been the most common predisposing disorder. Recently, different pharmacological agents have been demonstrated to increase the risk of PML. Therapies that predispose people to PML can be classified into three categories: therapies that uniquely increase the risk for the disorder, such as the monoclonal antibodies natalizumab and efalizumab; therapies that appear to increase the risk in individuals already at risk of PML due to pre-existing conditions, such as rituximab and mycophenolate mofetil; and therapies with a mechanism of action that might suggest a potential for increased PML risk and/or with which rare cases of PML have been observed. Unlike the latter two classes, therapeutic agents uniquely increasing the risk of PML are associated with a much greater prevalence of the disorder and a latent interval from the time of drug initiation to the development of PML. PML development with pharmacological agents has provided new insight into the pathogenesis of this devastating disorder. This review focuses on the risks of PML with multiple pharmacological agents, the proposed pathogenesis with these agents, and potential risk mitigation strategies.

Dietary clues to the pathogenesis of Crohn's disease. <=SEP=> Crohn's disease is a complex inherited disorder of unknown pathogenesis with environmental, genetic and microbial factors involved in the development of the disease. A remarkable feature of this disease in childhood is the effective response to exclusive enteral nutrition (EEN) therapy and the need for complete exclusion of normal diet required for success (principle of exclusivity). EEN or dietary interventions might act through removal of dietary components, which affect microbial composition, decrease a proinflammatory response and promote restitution of the epithelial barrier, likewise allowing termination of this vicious disease-forming cycle before a critical threshold is reached. Multiple traditional and nontraditional dietary components may affect the microbiome, mucous layer, intestinal permeability, or adherence and translocation of pathobionts. We review the epidemiological data, as well as data from animal models and cell lines, and propose a model for pathogenesis we have termed the 'bacterial penetration cycle', whereby dietary components such as animal fat, high sugar intake and gliadin, and consumption of emulsifiers, maltodextrin as well as low-fiber diets may be able to cause a localized acquired bacterial clearance defect, leading to bacterial adhesion and penetration, and subsequently inflammation in the gut. © 2014 S. Karger AG, Basel.

Crohn's disease: a review of treatment options and current research. <=SEP=> Crohn's disease is an autoimmune disorder that affects nearly 1.4 million Americans. The etiology of Crohn's disease is not completely understood, however, research has suggested a genetic link. There is currently no known cure for Crohn's disease and, as a result, most government-funded research is being conducted to increase the quality of life of afflicted patients (i.e. reducing chronic inflammation and alleviating growth impairment in pediatric patients). A number of treatment options are available including an alpha-4 integrin inhibitor and several TNF-alpha inhibitors. Furthermore, research is being conducted on several alternative treatment options to help understand exactly which cellular mechanisms (i.e. inducing apoptosis in leukocytes) are required for clinical efficacy. This review seeks to chronicle the current available treatment options for patients affected by Crohn's disease to aid in understanding potential cellular mechanistic requirements for an efficacious drug, and shed light on potential options for future treatment. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers <=SEP=> Background Crohn's disease is common in developed nations where the typical diet is low in fibre and high in processed food. Primary lesions overlie Peyer's patches and colonic lymphoid follicles where bacterial invasion through M-cells occurs. We have assessed the effect of soluble non-starch polysaccharide (NSP) and food emulsifiers on translocation of Escherichia coli across M-cells. Methods To assess effects of soluble plant fibres and food emulsifiers on translocation of mucosa-associated E coli isolates from Crohn's disease patients and from non-Crohn's controls, we used M-cell monolayers, generated by co-culture of Caco2-cl1 and Raji B cells, and human Peyer's patches mounted in Ussing chambers. Results E coli translocation increased across M-cells compared to parent Caco2-cl1 monocultures; 15.8-fold (IQR 6.2–32.0) for Crohn's disease E coli (N=8) and 6.7-fold (IQR 3.7–21.0) for control isolates (N=5). Electron microscopy confirmed E coli within M-cells. Plantain and broccoli NSP markedly reduced E coli translocation across M-cells at 5 mg/ml (range 45.3–82.6% inhibition, p<0.01); apple and leek NSP had no significant effect. Polysorbate-80, 0.01% vol/vol, increased E coli translocation through Caco2-cl1 monolayers 59-fold (p<0.05) and, at higher concentrations, increased translocation across M-cells. Similarly, E coli translocation across human Peyer's patches was reduced 45±7% by soluble plantain NSP (5 mg/ml) and increased 2-fold by polysorbate-80 (0.1% vol/vol). Conclusions Translocation of E coli across M-cells is reduced by soluble plant fibres, particularly plantain and broccoli, but increased by the emulsifier Polysorbate-80. These effects occur at relevant concentrations and may contribute to the impact of dietary factors on Crohn's disease pathogenesis.

When can we cure Crohn's? <=SEP=> Crohn's disease is a life-long idiopathic inflammatory disease which affects the entire gastrointestinal tract and occasionally extra-intestinal organs. CD is thought to result from complex interactions between environmental factors, the gut microbes, and the genetic background and the immune system of the host. In the last decades research on these pathogenetic components, and especially on mucosal immunity, has led to the development of biologic agents and therapeutic strategies that have improved dramatically the treatment of CD but we are still far away from curing the disease. If there is a treatment for CD that will probably evolve through methodical steps towards integrating research on all the components involved in the pathogenesis of CD. This holistic and global approach may aid at unravelling the mysteries of CD and developing novel agents and therapeutic strategies which by targeting multiple pathogenetic pathways and at different stages of disease may lead hopefully to cure. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Prospective Study of Long-term Intake of Dietary Fiber and Risk of Crohn’s Disease and Ulcerative Colitis <=SEP=> Background & Aims Increased intake of dietary fiber has been proposed to reduce risk of inflammatory bowel diseases (Crohn’s disease [CD], ulcerative colitis [UC]). However, few prospective studies have examined associations between long-term intake of dietary fiber and risk of incident CD or UC. Methods We collected and analyzed data from 170,776 women, followed over 26 y, who participated in the Nurses’ Health Study, followed for 3,317,425 person-y. Dietary information was prospectively ascertained via administration of a validated semi-quantitative food frequency questionnaire every 4 y. Self-reported CD and UC were confirmed through review of medical records. Cox proportional hazards models, adjusting for potential confounders, were used to calculate hazard ratios (HRs). Results We confirmed 269 incident cases of CD (incidence 8/100,000 person-y) and 338 cases of UC (incidence 10/100,000 person-y). Compared to the lowest quintile of energy-adjusted cumulative average intake of dietary fiber, intake of the highest quintile (median of 24.3 g/day) was associated with a 40% reduction in risk of CD (multivariate HR for CD, 0.59; 95% confidence interval [CI], 0.39–0.90). This apparent reduction appeared to be greatest for fiber derived from fruits; fiber from cereals, whole grains, or legumes did not modify risk. In contrast, neither total intake of dietary fiber (multivariate HR, 0.82; 95% CI 0.58–1.17) nor intake of fiber from specific sources appeared to be significantly associated with risk of UC. Conclusion Based on data from the Nurses’ Health Study, long-term intake of dietary fiber, particularly from fruit, is associated with lower risk of CD but not UC. Further studies are needed to determine the mechanisms that mediate this association.

Artificial sweetener consumption and urinary tract tumors in Cordoba, Argentina. <=SEP=> OBJECTIVE: To determine the role of the habitual use of the most common artificial sweeteners (AS) in the development of urinary tract tumors (UTT) in Argentina. METHODS: Case-control study of 197 patients with histologically confirmed UTT of transitional varieties, and 397 controls with acute, non-neoplastic, and non-urinary tract diseases, admitted to the same hospitals in Córdoba (Argentina) between 1999 and 2006. All subjects were interviewed about their use of AS and their exposure to other known or suspected risk factors for UTT. RESULTS: Fifty-one UTT patients (26%) and 87 controls (22%) used AS. The risk of UTT was significantly increased in long-term (> or =10 years) AS users compared with none-AS users. The OR (95% CI) for long-term consumers was 2.18 (1.22-3.89) and for short-term users was 1.10 (0.61-2.00) after adjustment for age, gender, BMI, social status. and years of tobacco use. CONCLUSION: Regular use of AS for 10 years or more was positively associated with UTT.

The potential toxicity of artificial sweeteners. <=SEP=> Since their discovery, the safety of artificial sweeteners has been controversial. Artificial sweeteners provide the sweetness of sugar without the calories. As public health attention has turned to reversing the obesity epidemic in the United States, more individuals of all ages are choosing to use these products. These choices may be beneficial for those who cannot tolerate sugar in their diets (e.g., diabetics). However, scientists disagree about the relationships between sweeteners and lymphomas, leukemias, cancers of the bladder and brain, chronic fatigue syndrome, Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism, and systemic lupus. Recently these substances have received increased attention due to their effects on glucose regulation. Occupational health nurses need accurate and timely information to counsel individuals regarding the use of these substances. This article provides an overview of types of artificial sweeteners, sweetener history, chemical structure, biological fate, physiological effects, published animal and human studies, and current standards and regulations.

A critical review of the genetic toxicity of steviol and steviol glycosides. <=SEP=> Extracts of the leaves of the stevia plant (Stevia rebaudiana Bertoni) are used to sweeten food and beverages in South America, Japan and China. The components responsible for the sweet properties of the plant are glycosides of steviol, primary stevioside (ent-13-hydroxykaur-16-en-18-oic acid), which is 250-300 times sweeter than sucrose and rebaudiosides A and C. Stevioside and steviol have been subjected to extensive genetic testing. The majority of the findings show no evidence of genotoxic activity. Neither stevioside nor its aglycone steviol have been shown to react directly with DNA or demonstrate genotoxic damage in assays relevant to human risk. The mutagenic activity of steviol and some of its derivatives, exhibited in strain TM677, was not reproduced in the same bacteria having normal DNA repair processes. The single positive in vivo study measuring single-strand DNA breaks in Wistar rat tissues by stevioside, was not confirmed in experiments in mice and appears to be measuring processes other than direct DNA damage. Neither stevioside nor steviol-induced clastogenic effects at extremely high dose levels in vivo. Application of a Weight-of-Evidence approach to assess the genetic toxicology database concludes that these substances do not pose a risk of genetic damage following human consumption.