Showing papers in "Inflammatory Bowel Diseases in 2009"

Low counts of Faecalibacterium prausnitzii in colitis microbiota.

Abstract: Background: The intestinal microbiota is suspected to play a role in colitis and particularly in inflammatory bowel disease (IBD) pathogenesis. The aim was to compare the fecal microbiota composition of patients with colitis to that of healthy subjects (HS). Methods: fecal samples from 22 active Crohn's disease (A-CD) patients, 10 CD patients in remission (R-CD), 13 active ulcerative colitis (A-UC) patients, 4 UC patients in remission (R-UC), 8 infectious colitis (IC) patients, and 27 HS were analyzed by quantitative real-time polymerase chain reaction (PCR) targeting the 16S rRNA gene. Bacterial counts were transformed to logarithms (Log10 CFU) for statistical analysis. Results: Bacteria of the phylum Firmicutes (Clostridium leptum and Clostridium coccoides groups) were less represented in A-IBD patients (9.7; P = 0.004) and IC (9.4; P = 0.02), compared to HS (10.8). Faecalibacterium prausnitzii species (a major representative of the C. leptum group) had lower counts in A-IBD and IC patients compared to HS (8.8 and 8.3 versus 10.4; P = 0.0004 and P = 0.003). The Firmicutes/Bacteroidetes ratio was lower in A-IBD (1.3; P = 0.0001) and IC patients (0.4; P = 0.002). Compared to HS, Bifidobacteria were less represented in A-IBD and IC (7.9 and 7.7 versus 9.2; P = 0.001 and P = 0.01). Conclusions: The fecal microbiota of patients with IBD differs from that of HS. The phylum Firmicutes and particularly the species F. prausnitzii, are underrepresented in A-IBD patients as well as in IC patients. These bacteria could be crucial to gut homeostasis since lower counts of F. prausnitzii are consistently associated with a reduced protection of the gut mucosa. (Inflamm Bowel Dis 2009)

Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis.

Abstract: The cytokine network in inflammatory bowel disease (IBD) is a complex, dynamic system that plays an important role in regulating mucosal innate and adaptive immune responses. While several studies have been done to evaluate immunomodulatory profiles in murine IBD, they have been limited to a relatively small number of cytokines that do not take into account its dependency of the interplay of multiple factors, and therefore the diagnostic potential of their cytokine profiles have been inconclusive. Herein we demonstrate a novel approach of comprehensive serum multiplex cytokine profiling to describe the modulation of 16 Th1, Th2, Th17 cytokines and chemokines in both acute and chronic murine models of DSS and TNBS-induced colitis. Distinctive disease-specific cytokine profiles were identified with significant correlations to disease activity and duration of disease. TNBS colitis exhibits heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic. In contrast, DSS colitis switches from a Th1-Th17-mediated acute inflammation (increased TNFα, IL6, IL-17 and KC) to a predominant Th2-mediated inflammatory response (increase in IL-4 and IL-10 and concomitant decrease in TNFα, IL6, IL-17 and KC) in the chronic state. Profiles of multiple cytokines seen systemically were also validated locally in colonic mucosa. Moreover, advanced multivariate analyses identified discriminatory cytokine profiles that can be sufficiently used to distinguish unaffected controls from diseases, and one disease type from another. IL-6 and IL-12 stratified gender-associated disease activity in chronic colitis. Our studies provide insight into disease immunopathogenesis and illustrate the significant potential of utilizing multiplex cytokine profiles and bioinformatics as diagnostic tools in IBD.

Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn's disease.

Abstract: Background: Infliximab (IFX) treatment induces mucosal healing (MH) in patients with Crohn's disease (CD) but the impact of MH on the long-term outcome of IFX treatment in CD is still debated. Methods: We studied MH during long-term treatment with IFX in 214 CD patients. A total of 183 patients (85.5%) responded to induction therapy and 31 patients (14.5%) were primary nonresponders. They underwent lower gastrointestinal (GI) endoscopy within a median of 0.7 months (interquartile range [IQR] 0.1–6.8) prior to first IFX and after a median of 6.7 months (IQR 1.4–24.6) after start of IFX and were further analyzed. The relationship between the outcome of IFX treatment long-term and MH was studied. Results: MH was observed in 67.8% of the 183 initial responders (n = 124), with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%). Scheduled IFX treatment from the start resulted in MH more frequently (76.9% MH rate) than episodic treatment (61.0% MH rate; P = 0.0222, odds ratio [OR] 2.14, 95% confidence interval [CI] 1.11–4.12). Concomitant treatment with corticosteroids (CS) had a negative impact on MH (37.9% in patients with CS versus 63.2% in patients without CS; P = 0.021, OR 0.36, 95% CI 0.16–0.80). MH was associated with a significantly lower need for major abdominal surgery (MAS) during long-term follow-up (14.1% of patients with MH needed MAS versus 38.4% of patients without MH; P < 0.0001). Conclusions: MH induced by long-term maintenance IFX treatment is associated with an improved long-term outcome of the disease especially with a lower need for major abdominal surgeries. (Inflamm Bowel Dis 2009;)

Intestinal barrier dysfunction in inflammatory bowel diseases

Abstract: The etiology of human inflammatory bowel diseases (IBDs) is believed to involve inappropriate host responses to the complex commensal microbial flora in the gut, although an altered commensal flora is not completely excluded. A multifunctional cellular and secreted barrier separates the microbial flora from host tissues. Altered function of this barrier remains a major largely unexplored pathway to IBD. Although there is evidence of barrier dysfunction in IBD, it remains unclear whether this is a primary contributor to disease or a consequence of mucosal inflammation. Recent evidence from animal models demonstrating that genetic defects restricted to the epithelium can initiate intestinal inflammation in the presence of normal underlying immunity has refocused attention on epithelial dysfunction in IBD. We review the components of the secreted and cellular barrier, their regulation, including interactions with underlying innate and adaptive immunity, evidence from animal models of the barrier's role in preventing intestinal inflammation, and evidence of barrier dysfunction in both Crohn's disease and ulcerative colitis.

Mechanisms of action of probiotics: Recent advances

Abstract: The intestinal microbiota plays a fundamental role in maintaining immune homeostasis. In controlled clinical trials probiotic bacteria have demonstrated a benefit in treating gastrointestinal diseases, including infectious diarrhea in children, recurrent Clostridium difficile-induced infection, and some inflammatory bowel diseases. This evidence has led to the proof of principle that probiotic bacteria can be used as a therapeutic strategy to ameliorate human diseases. The precise mechanisms influencing the crosstalk between the microbe and the host remain unclear but there is growing evidence to suggest that the functioning of the immune system at both a systemic and a mucosal level can be modulated by bacteria in the gut. Recent compelling evidence has demonstrated that manipulating the microbiota can influence the host. Several new mechanisms by which probiotics exert their beneficial effects have been identified and it is now clear that significant differences exist between different probiotic bacterial species and strains; organisms need to be selected in a more rational manner to treat disease. Mechanisms contributing to altered immune function in vivo induced by probiotic bacteria may include modulation of the microbiota itself, improved barrier function with consequent reduction in immune exposure to microbiota, and direct effects of bacteria on different epithelial and immune cell types. These effects are discussed with an emphasis on those organisms that have been used to treat human inflammatory bowel diseases in controlled clinical trials.

Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management.

Abstract: While there has been a great deal of speculation over the years on the importance of emotional factors in inflammatory bowel disease (IBD), it is only in the last decade or so that studies with stronger designs have been available to clarify the nature of this relationship This review considers recent evidence on the prevalence of anxiety and depressive disorders in IBD, the role of these disorders as a risk factor for IBD onset, the degree to which they affect the course of the IBD, and the contribution of corticosteroid treatment to psychiatric symptom onset There is evidence that anxiety and depression are more common in patients with IBD and that the symptoms of these conditions are more severe during periods of active disease The few studies that address the issue of anxiety and depression as risk factors for IBD do not yet provide enough information to support definite conclusions There is evidence, however, that the course of the disease is worse in depressed patients Treatment with corticosteroids can induce mood disorders or other psychiatric symptoms The second part of the review focuses on patient management issues for those with comorbid anxiety or depression Practical approaches to screening are discussed, and are recommended for routine use in the IBD clinic, especially during periods of active disease We review evidence-based pharmacological and psychological treatments for anxiety and depression and discuss practical considerations in treating these conditions in the context of IBD to facilitate overall management of the IBD patient

Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease

Abstract: BACKGROUND: Large interindividual variation in the composition of the intestinal microbiota between unrelated individuals has made it challenging to identify specific aspects of dysbiosis that lead ...

Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease.

Abstract: Background:Escherichia coli, particularly the adherent-invasive E. coli (AIEC) pathovar, has been increasingly implicated in the ethiopathogenesis of Crohn's disease (CD). We describe the richness, abundance, diversity, and pathogenic features of E. coli and AIEC strains that colonize the intestinal mucosa. Methods: Approximately 100 E. coli colonies per biopsy from 20 CD patients (18 biopsies from colon and 23 from ileum) and 28 healthy controls (C) (25, colon; 27, ileum) were isolated. Repetitive extragenic palindrome-polymerase chain reaction (Rep-PCR) and pulsed field gel electrophoresis (PFGE) were used to analyze the clonality of isolates. For AIEC identification, adhesion and invasion assays were performed over Intestine-407 cells, and the capacity to survive and replicate intracellularly was determined over macrophages J774. The serotypes, phylotypes, and genotypes (19 virulence genes) of strains were also investigated. Results: Mucosa-associated E. coli richness (E. coli subtypes/patient: C = 2.0 ± 1.0; CD = 2.1 ± 1.3) and diversity (Shannon Index: H'C: 2.1 ± 0.6; H'CD: 2.5 ± 0.8) were similar between CD and C, but higher E. coli counts were characteristic of CD patients (P = 0.010), particularly those with Crohn's ileitis (P = 0.001). Host-specific pulsotypes shared virulence features of ExPEC at similar frequencies between CD and C, except for iucD, which was more prevalent in E. coli from controls (C: 75%, CD: 40%, P = 0.027). In contrast, greater AIEC prevalence (% subjects with AIEC: CD = 51.9%; C = 16.7%; P = 0.003), abundance (% AIEC/E. coli: CD = 3.8 ± 5.0%; C = 1.5 ± 3.8%; P = 0.039), and richness (number of AIEC subtypes: CD = 0.8 ± 1.4; C = 0.2 ± 0.4; P = 0.015) of E. coli strains belonging to the AIEC pathovar was observed for CD patients. AIEC subtypes showed a high variability of seropathotypes and pulsotypes, although the B2 phylogroup was the most prevalent (AIEC: 64%, non-AIEC: 38%, P = 0.044). Conclusions: New data about ecological parameters of AIEC reinforces the implication of AIEC in CD. (Inflamm Bowel Dis 2009)

Ulcerative colitis: correlation of the Rachmilewitz endoscopic activity index with fecal calprotectin, clinical activity, C-reactive protein, and blood leukocytes.

Abstract: BACKGROUND:: The accuracy of noninvasive markers for the detection of endoscopically active ulcerative colitis (UC) according the Rachmilewitz Score is so far unknown. The aim was to evaluate the correlation between endoscopic disease activity and fecal calprotectin, Clinical Activity Index, C-reactive protein (CRP), and blood leukocytes. METHODS:: UC patients undergoing colonoscopy were prospectively enrolled and scored independently according the endoscopic and clinical part of the Rachmilewitz Index. Patients and controls provided fecal and blood samples for measuring calprotectin, CRP, and leukocytes. RESULTS:: Values in UC patients (n = 134) compared to controls (n = 48): calprotectin: 396 +/- 351 versus 18.1 +/- 5 mug/g, CRP 16 +/- 13 versus 3 +/- 2 mg/L, blood leukocytes 9.9 +/- 3.5 versus 5.4 +/- 1.9 g/L (all P > 0.001). Endoscopic disease activity correlated closest with calprotectin (Spearman's rank correlation coefficient r = 0.834), followed by Clinical Activity Index (r = 0.672), CRP (r = 0.503), and leukocytes (r = 0.461). Calprotectin levels were significantly lower in UC patients with inactive disease (endoscopic score 0-3, calprotectin 42 +/- 38 mug/g), compared to patients with mild (score 4-6, calprotectin 210 +/- 121 mug/g, P > 0.001), moderate (score 7-9, calprotectin 392 +/- 246 mug/g, P = 0.002), and severe disease (score 10-12, calprotectin 730 +/- 291 mug/g, P > 0.001). The overall accuracy for the detection of endoscopically active disease (score

Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse

Abstract: Background: The purpose of the study was to determine the role of fecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohn's disease (CD), in a large, long-term, follow-up study. Methods: The prospective multicenter study included CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow-up was 12 months in patients showing no relapse and until activity flare in relapsing patients. Results: In all, 163 patients (89 CD, 74 UC) were included. Twenty-six patients (16%) relapsed during follow-up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 ± 150 versus 136 ± 158 μg/g; P 150 μg/g) calprotectin concentrations (30% versus 7.8%; P 150 μg/g) sensitivity and specificity to predict relapse were 69% and 69%, respectively. Corresponding values for lactoferrin were 62% and 65%, respectively. The area under the receiver operating characteristic curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months were considered (100% sensitivity). High fecal calprotectin levels or lactoferrin positivity was associated with clinical relapse in Kaplan–Meier survival analysis, and both fecal tests were associated with relapse in the multivariate analysis. Conclusions: Fecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse—especially during the following 3 months—in both CD and UC patients. (Inflamm Bowel Dis 2009)

Interleukin‐23/Th17 pathways and inflammatory bowel disease

Abstract: The IL-23/Th17 pathway has recently been identified to play a critical role in a number of chronic inflammatory diseases including inflammatory bowel disease (IBD). The identification in IBD patients of associations in IL23R and regions that include other genes in the IL-23/Th17 pathway has highlighted the importance of proper IL-23/Th17 pathway regulation in intestinal immune homeostasis. IL-23 plays a role in CD4+ Th17 lineage cells, characterized by IL-17 secretion and the expression of the transcription factor retinoic acid-related orphan receptor (ROR)gamma tau, and in other immune and nonimmune cells. The balance between effector T cell subsets, such as Th17 cells, and CD4+ T regulatory subsets is finely regulated; dysregulation of this balance can lead to inflammation and autoimmunity. As such, the IL-23/Th17 pathway contributes to immune responses that play a role in defenses to microbial infection, as well as in the intestinal inflammation observed in both animal models of colitis and human IBD.

Patients' attitudes to medicines and adherence to maintenance treatment in inflammatory bowel disease.

Abstract: Background: Nonadherence has been reported in over 40% of patients taking maintenance therapies (MT) for inflammatory bowel disease (IBD). Studies in other illness groups have shown that nonadherence is related to negative attitudes to treatment. The aim of this study was to assess patients' attitudes to MT for IBD (beliefs about personal need for MT and potential adverse effects) and to identify whether such beliefs are associated with adherence to MT. Methods: A cross-sectional survey was conducted in which 1871 members of the National Association for Colitis and Crohn's Disease (NACC) completed validated questionnaires assessing beliefs about MT and adherence to MT. Results: Low adherence to MT was reported by 29% of participants and was associated with doubts about personal need for MT (odds ratio [OR] = 0.56; 95% confidence interval [CI]: 0.48–0.64; P < 0.001) and concerns about potential adverse effects (OR = 1.66; 95% CI: 1.42–1.94; P < 0.001). Attitudinal analysis showed that while almost half (48%) of the participants were “accepting” of MT (high necessity, low concerns), a large proportion of the sample (42%) were “ambivalent” about MT (high necessity, high concerns), 6% were “sceptical” (low necessity, high concerns) and 4% were “indifferent” (low necessity, low concerns). Compared to those who were “accepting” of MT, participants in all 3 other attitudinal groups were significantly more likely to be nonadherent. Conclusions: The way in which patients judge their personal need for MT relative to their concerns about MT can be a significant barrier to adherence. Interventions to facilitate optimal adherence to MT for IBD should address such perceptual barriers. (Inflamm Bowel Dis 2008)

Appraisal of the pediatric ulcerative colitis activity index (PUCAI)

Abstract: Background: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. Methods: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 ± 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 ± 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. Results: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6–73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30–60]) versus those who did not, (0 points [IQR 0–10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90–0.97). Test–retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84–0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92–0.99]; standardized response mean 2.66). Conclusion: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC. (Inflamm Bowel Dis 2009)

Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: A randomized, double‐blind, placebo‐controlled pilot study

Abstract: Background: Although metronidazole and ciprofloxacin are used to treat perianal Crohn's disease (CD), no placebo-controlled trials have been performed. Methods: We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of metronidazole and ciprofloxacin in patients with perianal CD. Twenty-five patients with CD and actively draining perianal fistulas were randomized to receive ciprofloxacin 500 mg, metronidazole 500 mg, or placebo twice daily for 10 weeks. Remission and response of perianal fistulas were defined as closure of all fistulas and closure of at least 50% of fistulas that were draining at baseline, respectively. The primary endpoint was remission at 10 weeks. Results: Ten patients were randomized to ciprofloxacin, 7 to metronidazole, and 8 to placebo. Remission at week 10 occurred in 3 patients (30%) treated with ciprofloxacin, no patients (0%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.41). Response at week 10 occurred in 4 patients (40%) treated with ciprofloxacin, 1 patient (14.3%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.43). Termination of the trial prior to week 10 occurred in 1 patient (10%) treated with ciprofloxacin, 5 patients (71.4%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P < 0.02). No serious adverse events occurred. Conclusion: Remission and response occurred more frequently in patients treated with ciprofloxacin but the differences were not significant in this pilot study. Ciprofloxacin was well tolerated. (Inflamm Bowel Dis 2008)

Corticosteroids but not infliximab increase short-term postoperative infectious complications in patients with ulcerative colitis.

Abstract: Background: Recent reports suggest that the preoperative use of infliximab (IFX) increases postoperative infectious complications in patients with ulcerative colitis (UC). Therefore, we determined the impact of IFX on postoperative infectious complications. Methods: A consecutive group of 141 UC patients (41% female, median age 39.8 years) undergoing (procto)colectomy was studied. Postoperative infectious complications were compared between 22 patients who received IFX within 12 weeks prior to (procto)colectomy (IFX group) and 119 patients who did not (control group). Short-term infectious complications, consisting of anastomotic leaks, pelvic abscesses, wound infections, and nonsurgical site infections, were recorded within 30 days after primary surgery. Results: At primary surgery there was no significant difference in gender, disease extent, smoking behavior, body mass index, and concomitant medication (including corticosteroids) between the groups. Patients in the IFX group less often underwent restorative proctocolectomy without defunctioning ileostomy (9% versus 34%, P = 0.022), had a significantly shorter median (interquartile range, IQR) disease duration (2.7 [1.2–8.6] versus 5.9 [2.6–13.0] years, P < 0.036) and a significantly higher C-reactive protein level at primary surgery (51.7 [9.9–103.6] versus 19.1 [7.5–42.6] mg/L, P = 0.023). There was no short-term mortality. A moderate-to-high dose of corticosteroids (≥20 mg methylprednisolone for ≥2 months, odds ratio 5.19 [95% confidence interval [CI]: 1.72–15.66], P = 0.003) and a restorative proctocolectomy without defunctioning ileostomy (odds ratio 6.45 [95% CI: 2.12–19.64], P = 0.001) were independent predictors of short-term postoperative infectious complications. Conclusion: Corticosteroids and a restorative proctocolectomy without defunctioning ileostomy, but not IFX, are associated with an increased risk of short-term postoperative infectious complications in UC. (Inflamm Bowel Dis 2009)

Pain and inflammatory bowel disease

Abstract: Abdominal pain is a common symptom of inflammatory bowel disease (IBD: Crohn's disease, ulcerative colitis). Pain may arise from different mechanisms, which can include partial blockage and gut distention as well as severe intestinal inflammation. A majority of patients suffering from acute flares of IBD will experience pain, which will typically improve as disease activity decreases. However, a significant percentage of IBD patients continue experiencing symptoms of pain despite resolving inflammation and achieving what appears to be clinical remission. Current evidence suggests that sensory pathways sensitize during inflammation, leading to persistent changes in afferent neurons and central nervous system pain processing. Such persistent pain is not only a simple result of sensory input. Pain processing and even the activation of sensory pathways is modulated by arousal, emotion, and cognitive factors. Considering the high prevalence of iatrogenic as well as essential neuropsychiatric comorbidities including anxiety and depression in IBD patients, these central modulating factors may significantly contribute to the clinical manifestation of chronic pain. The improved understanding of peripheral and central pain mechanisms is leading to new treatment strategies that view pain as a biopsychosocial problem. Thus, improving the underlying inflammation, decreasing the excitability of sensitized afferent pathways, and altering emotional and/or cognitive functions may be required to more effectively address the difficult and disabling disease manifestations.

Helminths and the IBD hygiene hypothesis

Abstract: Helminths are parasitic animals that have evolved over 100,000,000 years to live in the intestinal track or other locations of their hosts. Colonization of humans with these organisms was nearly universal until the early 20th century. More than 1,000,000,000 people in less developed countries carry helminths even today. Helminths must quell their host's immune system to successfully colonize. It is likely that helminths sense hostile changes in the local host environment and take action to control such responses. Inflammatory bowel disease (IBD) probably results from an inappropriately vigorous immune response to contents of the intestinal lumen. Environmental factors strongly affect the risk for IBD. People living in less developed countries are protected from IBD. The “IBD hygiene hypothesis” states that raising children in extremely hygienic environments negatively affects immune development, which predisposes them to immunological diseases like IBD later in life. Modern day absence of exposure to intestinal helminths appears to be an important environmental factor contributing to development of these illnesses. Helminths interact with both host innate and adoptive immunity to stimulate immune regulatory circuitry and to dampen effector pathways that drive aberrant inflammation. The first prototype worm therapies directed against immunological diseases are now under study in the United States and various countries around the world. Additional studies are in the advanced planning stage. (Inflamm Bowel Dis 2008)

Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions.

Abstract: BACKGROUND: Smaller family size and voluntary childlessness has been reported in IBD; however the disease-related reasons for this from a patient viewpoint are not described. The aims were to 1) determine whether IBD patients perceptions of the issues surrounding IBD pregnancy and childbearing influence their reproductive behavior and 2) describe these specific perceptions and concerns related to fertility and pregnancy. METHODS: All contactable subjects between 18-50 years of age from a hospital-based IBD database were surveyed by postal questionnaire. Data were obtained regarding age gender IBD diagnosis and treatment body image and sexual relationships as well as both objective and subjective data regarding fertility and pregnancy. Comparisons were made to community norms where data were available. Contingency tables with Fishers exact test were used. RESULTS: Of 365 subjects 255 responded (70%). The mean age was 35.5 years overall 34.7 years for women. In all 34% of participants were male 127 had Crohns disease (CD) 85 ulcerative colitis (UC) and 5 indeterminate colitis (IC). The average fertility rate was no different between women with CD and UC (1.0 and 1.2 births/woman respectively; P = 0.553) compared with 1.81 for all Australian women. Although 42.7% of IBD patients reported a fear of infertility patients only sought medical fertility advice at the same rate as the general population. Fear of infertility was most evident in women those with CD and those reporting previous surgery. Specific patient concerns which appear to have decreased patients family size included IBD heritability the risk of congenital abnormalities and medication teratogenicity. CONCLUSIONS: The unusually high response rate indicates the centrality of reproductive issues to IBD patients. "Voluntary" childlessness in this group appears to result from concerns about adverse reproductive outcomes that may not be justified. Patients require accurate counseling addressing fertility and pregnancy outcomes in IBD to assist in their decision making.

Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease.

Abstract: Background Extraintestinal manifestations (EIMs) in pediatric patients with inflammatory bowel disease (IBD) are poorly characterized We examined the prevalence of EIMs at diagnosis, subsequent incidence, and risk factors for EIMs

Long-term outcome of maintenance infliximab therapy in children with Crohn's disease.

Abstract: Background: Infliximab therapy has short-term benefits in children with moderate-to-severe Crohn's disease (CD). We assessed the long-term outcome of infliximab maintenance therapy in children with CD. Methods: We performed a multicenter cohort study of 729 pediatric patients with CD enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Children younger than 16 years and newly diagnosed with CD were eligible for this study. Disease and medication information were collected prospectively from the treating physician at diagnosis, 30 days, and quarterly thereafter. No interventions were specified, per protocol. Results: In all, 202 of 729 patients received infliximab: 62%, 23%, and 15% within 1, 1–2, and >2 years of diagnosis, respectively. The mean age at infliximab initiation was 12.7 years. A total of 158 infliximab-treated patients received maintenance therapy, 29 episodic (8 converted to maintenance), and 15 had incomplete follow-up. Among 128 patients administered maintenance infliximab and followed for ≥1 year, concomitant medications at infliximab initiation included corticosteroids (52%) and immunomodulators (90%). By 1, 2, and 3 years, <10% of patients continuing on maintenance infliximab were receiving corticosteroids (P < 0.001). Following maintenance therapy initiation, 26%, 44%, and 33% of patients continuing on maintenance infliximab over 0–1, 1–2, and 2–3 years, respectively, had clinically inactive disease not requiring corticosteroids or surgery. The likelihood of continuing maintenance infliximab at 1, 2, and 3 years was 93%, 78%, and 67%, respectively. Conclusions: Infliximab maintenance therapy was a durable and effective treatment that was associated with prolonged corticosteroid withdrawal over a 3-year period in children with CD. (Inflamm Bowel Dis 2008)

Patient trust‐in‐physician and race are predictors of adherence to medical management in inflammatory bowel disease

Abstract: BACKGROUND Adherence plays an important role in the therapeutic effectiveness of medical therapy in IBD. We assessed whether trust-in-physician and Black race were predictors of adherence.

Therapeutic potential of helminth soluble proteins in TNBS-induced colitis in mice.

Abstract: Background: The hygiene hypothesis suggests an inverse relationship between the incidence of parasitic infections and chronic inflammatory bowel diseases (IBD). We investigated the therapeutic potential of Schistosoma mansoni and Ancylostoma caninum soluble proteins on experimental colitis in mice. Methods: Colitis was induced by intrarectal administration of 10 mg trinitrobenzene sulfonic acid (TNBS) in 30% ethanol. Six hours after TNBS injection, mice were treated intraperitoneally with helminth proteins. Three days later, colonic inflammation was scored based on 5 inflammatory parameters: clinical disease activity, macroscopic and microscopic inflammation score, extent of inflammation, and myeloperoxidase (MPO) activity. To determine immunological pathways induced by S. mansoni proteins we measured cytokine profiles of T-lymphocytes from colon, mesenteric lymph nodes (MLN), and spleen by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Results: Control mice showed no signs of inflammation, whereas all inflammatory parameters were significantly increased in mice with colitis. Treatment of mice with colitis with S. mansoni or A. caninum proteins decreased the macroscopic inflammation score, extent of inflammation, and MPO activity. Immunologically, induction of colitis significantly increased expression of IFN-γ mRNA in the inflamed colon. Treatment with S. mansoni proteins caused a decrease of proinflammatory cytokines (IFN-γ, IL-17) in colon and MLN, whereas the production of regulatory cytokines (IL-10, TGF-β) increased significantly in colon tissue. Conclusions: Treatment with proteins of S. mansoni and A. caninum ameliorated TNBS-induced colitis in mice. S. mansoni proteins increased mRNA expression of regulatory cytokines while suppressing expression of proinflammatory cytokines. Therefore, we suggest a therapeutic potential for helminth proteins in the treatment of IBD.

Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis

Abstract: Background: Activation of cannabinoid (CB)1 receptors results in attenuation of experimental colitis. Our aim was to examine the role of CB2 receptors in experimental colitis using agonists (JWH133, AM1241) and an antagonist (AM630) in trinitrobenzene sulfonic acid (TNBS)-induced colitis in wildtype and CB2 receptor-deficient (CB mice. Methods: Mice were treated with TNBS to induce colitis and then given intraperitoneal injections of the CB2 receptor agonists JWH133, AM1241, or the CB2 receptor antagonist AM630. Additionally, CB mice were treated with TNBS and injected with JWH133 or AM1241. Animals were examined 3 days after the induction of colitis. The colons were removed for macroscopic and microscopic evaluation, as well as the determination of myeloperoxidase activity. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for CB2 receptor was also performed in animals with TNBS and dextran sodium sulfate colitis. Results: Intracolonic installation of TNBS caused severe colitis. CB2 mRNA expression was significantly increased during the course of experimental colitis. Three-day treatment with JWH133 or AM1241 significantly reduced colitis; AM630 exacerbated colitis. The effect of JWH133 was abolished when animals were pretreated with AM630. Neither JWH133 nor AM1241 had effects in CB mice. Conclusions: We show that activation of the CB2 receptor protects against experimental colitis in mice. Increased expression of CB2 receptor mRNA and aggravation of colitis by AM630 suggests a role for this receptor in normally limiting the development of colitis. These results support the idea that the CB2 receptor may be a possible novel therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2009)

Effects of active and passive smoking on disease course of Crohn's disease and ulcerative colitis

Abstract: Background: Smoking is a remarkable risk factor for inflammatory bowel disease (IBD). aggravating Crohn's disease (CD) while having beneficial effects On Ulcerative colitis (UC). We Studied the effects of active and passive smoking in Dutch IBD patients. Methods: A questionnaire focusing Oil cigarette smoke exposure was sent to 820 IBD patients. Returned questionnaries were incorporated into a retrospective chart review, containing details about disease behavior and received therapy. Results: In all, 675 IBD patients (380 [56%] CD and 295 [44%] UC) responded. At diagnosis there were 52% smokers in CD, 41% it) the general Population, and 28% in UC. The number of present smokers in CD is lower than in the general population (26% versus 35%). No detrimental effects of active smoking oil CD were observed, but passive smokers needed immunosuppressants and infliximab more frequently than nonpassive smokers. Active smoking had beneficial effects oil UC, indicated by reduced rates of colectomy, primary sclerosing cholangitis, and backwash-ileitis in active smokers compared to never smokers, and higher daily cigarette dose correlated with less extensive colitis and a lower need for therapy. Furthermore, smoking cessation after diagnosis was, detrimental for UC patients, indicated by increased needs for steroids and hospitalizations for patients that stopped smoking after compared to before the diagnosis. Conclusions: Active smoking is a risk factor for CD, but does not affect the outcome passive smoking is detrimental for the outcome of CD patients. In UC, active smoking shows dose-dependent beneficial effects. Our data suggest that passive smoking is a novel risk factor for CD.

Alterations of phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: A clue to pathogenesis

Abstract: Background: Phospholipids are essential for the normal function of the intestinal mucus barrier. The objective of this study was to systematically investigate phospholipids in the intestinal mucus of humans suffering from inflammatory bowel diseases, where a barrier defect is strongly supposed to be pathogenetic. Methods: Optimal mucus recovery was first validated in healthy mice and the method was then transferred to the endoscopic acquisition of ileal and colonic mucus from 21 patients with ulcerative colitis (UC), 10 patients with Crohn's disease (CD), and 29 healthy controls. Nano-electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to determine phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) in lipid extracts of mucus specimens. Results: Human and rodent mucus contained very similar phospholipid species. In the ileal and colonic mucus from patients suffering from UC, the concentration of PC was highly significantly lower (607 ± 147 pmol/100 μg protein and 745 ± 148 pmol/100 μg protein) compared to that of patients with CD (3223 ± 1519 pmol/100 μg protein and 2450 ± 431 pmol/100 μg protein) and to controls (3870 ± 760 pmol/100 μg protein and 2790 ± 354 pmol/100 μg protein); overall, P = 0.0002 for ileal specimens and P < 0.0001 for colonic specimens. Independent of disease activity, patients suffering from UC showed an increased saturation grade of PC fatty acid residues and a higher LPC-to-PC ratio. Conclusions: The intestinal mucus barrier of patients with UC is significantly altered concerning its phospholipid concentration and species composition. These alterations may be very important for the pathogenesis of this disease and underline new therapeutic strategies. Inflamm Bowel Dis 2009

Prebiotics in chronic intestinal inflammation

Abstract: Prebiotics are nondigestible fermentable fibers that are reported to have health benefits for the host. Older as well as more recent studies show beneficial effects in experimental colitis and lately also in human inflammatory bowel diseases (IBD), such as Crohn's disease, ulcerative colitis, and chronic pouchitis. In this review we give an overview of the benefits of prebiotics in rodent IBD models and in IBD patients and discuss their possible protective mechanisms. Commensal intestinal bacteria induce and perpetuate chronic intestinal inflammation, whereas others are protective. However, most of the current medications are directed against the exaggerated proinflammatory immune response of the host, some of them toxic and costly. Feeding prebiotics changes the composition of the intestinal microflora toward more protective intestinal bacteria and alters systemic and mucosal immune responses of the host. Therapy for IBD targeting intestinal bacteria and their function is just emerging. Prebiotics have the promise to be relatively safe, inexpensive, and easy to administer. Unraveling their protective mechanisms will help to develop rational applications of prebiotics. However, the initial promising results with dietary prebiotics in preclinical trials as well as small studies in human IBD will need to be confirmed in large randomized controlled clinical trials.

Inflammatory bowel disease in the setting of autoimmune pancreatitis.

Abstract: Background: Despite scattered case reports, the prevalence of inflammatory bowel disease (IBD) in patients with autoimmune pancreatitis (AIP) is unknown. We sought to better characterize the putative association between the conditions. Methods: Medical records of 71 patients meeting accepted criteria for AIP were reviewed to identify those with endoscopic and histological evidence of IBD. Colon samples in patients with both AIP and IBD were immunostained to identify IgG4-positive cells. Results: Four patients with AIP (5.6%) had a diagnosis of IBD: 3 had ulcerative colitis (UC) and 1 had Crohn’s disease (CD). The diagnosis of IBD preceded or was simultaneous to that of AIP. Two AIP-UC patients treated for AIP with prednisone had a recurrence of AIP, and 1 required 6-mercaptopurine for long-term corticosteroidsparing treatment. Two AIP-IBD patients underwent Whipple resections, and 1 had recurrent AIP. All 3 patients with UC presented with pancolitis, and 2 required colectomy. Colon samples from 1 patient with UC and 1 patient with CD were available for review. Increased numbers of IgG4-positive cells (10 per high-power field) were noted on the colon sample from the patient with UC. Conclusions: Almost 6% of patients with proven AIP had a diagnosis of IBD, compared to a prevalence of 0.4%– 0.5% in the general population, potentially implying a 12–15-fold increase in risk. Patients with both AIP and IBD may have increased extent and severity of IBD. The finding of IgG4-positive cells on colon biopsy suggests that IBD may represent an extrapancreatic manifestation of AIP. (Inflamm Bowel Dis 2009;15:1326 –1330)

Azathioprine is superior to budesonide in achieving and maintaining mucosal healing and histologic remission in steroid-dependent Crohn's disease.

Abstract: Background: The effects of azathioprine (AZA) and budesonide (BUD) on mucosal healing and histologic remission of Crohn's disease (CD) are insufficiently studied. In this prospective study we evaluated the comparative effects of AZA and BUD on endoscopic and histologic activity in patients with steroid-dependent Crohn's ileocolitis or proximal colitis who had achieved clinical remission on conventional steroids. Methods: Patients were randomized to AZA (2.0–2.5 mg/kg a day) or BUD (6–9 mg a day) for 1 year. The study protocol included clinical examination, laboratory tests, calculation of the Crohn's Disease Activity Index (CDAI), completion of the Inflammatory Bowel Disease Questionnaire (IBDQ), at baseline and then every 2 months for 1 year. Ileocolonoscopy with regional biopsies was performed at baseline and then at the end of the study to assess mucosal healing and the histologic activity of CD. Results: Thirty-eight patients were randomized to AZA and 39 to BUD. At the end of the study 32 and 25 patients in the AZA and BUD groups, respectively, were in clinical remission (P = 0.07). The Crohn's Disease Endoscopic Index of Severity (CDEIS) score fell significantly only in the AZA group (P < 0.0001). Complete or near complete healing was achieved in 83% of AZA-treated patients compared with only 24% of BUD-treated patients (P < 0.0001). Histologic activity as assessed by an average histology score (AHS) fell significantly only in the AZA group (P < 0.001 versus baseline) and was significantly lower than in the BUD group at the end of the study (P < 0.001). Eight patients in the AZA group were withdrawn for adverse events (n = 6) or relapse of disease compared with 14 patients in the BUD group who were withdrawn for relapse of disease. Conclusions: In patients with steroid-dependent inflammatory Crohn's ileocolitis or proximal colitis who achieve clinical remission with conventional steroids, a 1-year treatment with AZA was superior to BUD in achieving and maintaining mucosal healing and histologic remission. (Inflamm Bowel Dis 2008)

Lactobacillus casei downregulates commensals' inflammatory signals in Crohn's disease mucosa.

Abstract: Background: The interaction of commensal bacteria with the intestinal immune system is an essential factor in the development of inflammatory bowel disease (IBD). The study of isolated commensal bacteria's effects on the mucosal immune response might be relevant for a better understanding of pathophysiological mechanisms in IBD. Methods: We investigated the immune responses to signals from the commensal Escherichia coli ATCC 35345 and the probiotic Lactobacillus casei DN-114 001 in Crohn's disease (CD) mucosa. Ileal specimens were obtained during surgery from CD patients. Mucosal explants were incubated with L. casei or its genomic DNA; TNF-α, IFN-γ, IL-2, IL-6, IL-8, and CXCL1 were measured in the supernatant. Second, tissue expression of key proinflammatory cytokines (IL-6, TGF-β, IL-23p19, IL-12p35, IL-17F), and chemokines (IL-8, CXCL1, CXCL2) was evaluated after incubation with L. casei or E. coli. Finally, combination experiments were carried out by incubating both strains with mucosal explants at different timepoints. Results: Live L. casei significantly decreased secretion of TNF-α, IFN-γ, IL-2, IL-6, IL-8, and CXCL1 by CD mucosa, but the effect was not reproduced by L. casei DNA. Second, live L. casei downregulated expression of IL-8, IL-6, and CXCL1 and did not modify expression of IL-23p19, IL-12p35, and IL-17F. In contrast, E. coli significantly upregulated expression of all these cytokines. Interestingly, combination experiments revealed the ability of L. casei to prevent and counteract the proinflammatory effects of E. coli. Conclusions: Live L. casei can counteract the proinflammatory effects of E. coli on CD inflamed mucosa by specific downregulation of key proinflammatory mediators. (Inflamm Bowel Dis 2008)

Probiotic preparation VSL#3 induces remission in children with mild to moderate acute ulcerative colitis: a pilot study.

Abstract: Background: Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) that has periods of exacerbated symptoms and periods that are symptom-free. The treatment of active UC with probiotic bacteria could possibly induce remission. We evaluated the clinical efficacy and safety profile of probiotic preparation VSL#3 in the treatment of mild to moderate acute UC in the pediatric population. Methods: Eighteen eligible patients between the ages of 3–17 with mild to moderate acute UC received open-label VSL#3 daily in 2 divided doses for 8 weeks. The disease activity pre- and post-VSL#3 therapy was assessed by the simple clinical colitis activity index (SCCAI); Mayo ulcerative colitis endoscopic score; inflammatory markers: erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); serum cytokine profiling; and rectal tissue microbial profiling done at baseline and at week 8. Results: Thirteen patients completed 8 weeks of VSL#3 treatment and 5 patients were withdrawn due to lack of improvement. Remission (defined as SCCAI ≤3) was achieved in 56% of children (n = 10); response (decrease in SCCAI ≥2, but final score ≤5) in 6% (n = 1); and no change or worsening in 39% (n = 7). Post-VSL#3 treatments demonstrated a bacterial taxonomy change in rectal biopsy. The VSL#3 was well tolerated in clinical trials and no biochemical and clinical adverse effects attributed to VSL#3 were identified. Conclusions: Treatment of pediatric patients diagnosed with mild to moderate UC with VSL#3 resulted in a remission rate of 56% and a combined remission/response rate of 61%. (Inflamm Bowel Dis 2008)