Nick M. Croft

Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease

TGF-beta1 functions as a negative regulator of T cell immune responses, signaling to target cells using the Smad family of proteins. We show here that Smad7, an inhibitor of TGF-beta1 signaling, is overexpressed in inflammatory bowel disease (IBD) mucosa and purified mucosal T cells. Both whole tissue and isolated cells exhibit defective signaling through this pathway, as measured by phospho-Smad3 immunoreactivity. Specific antisense oligonucleotides for Smad7 reduce Smad7 protein expression in cells isolated from patients with IBD, permitting the cells to respond to exogenous TGF-beta1. TGF-beta1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibition of Smad7 restores TGF-beta1 signaling and enables TGF-beta1 to inhibit cytokine production. In inflamed mucosal tissue explants from patients with CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production, an effect that is partially blocked by anti-TGF-beta1. These results show that Smad7 blockade of TGF-beta1 signaling helps maintain the chronic production of proinflammatory cytokines that drives the inflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF-beta to downregulate this response.

Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease.

Objectives Exclusive enteral feeding reduces inflammation and improves well being, nutrition and growth in children with active Crohn disease. Whether improved growth and increases in growth-related proteins are a consequence of improved nutrition or a reduced inflammation is not known. This study was undertaken to test the hypothesis that changes in growth-related proteins are related to decreased inflammation, rather than improvement in nutritional status. Methods Twelve children with active Crohn disease treated for 6-weeks with exclusive enteral feeding were studied at days 0, 3, 7, 14, 21, 28, and 56. The Paediatric Crohns Disease Activity Index (PCDAI), weight, triceps skinfold thickness, and midupper arm circumference were recorded. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), insulin-like growth factor (IGF-I), IGF-binding protein (IGFBP-3), and leptin were measured at each visit. Wilcoxon matched-pairs signed-rank test was used to compare day 0 with follow-up data. Results Significant improvements (P < 0.05) occurred by day 3 in inflammatory parameters (ESR, IL-6) and by day 7 in PCDAI, CRP, and IGF-I. These changes preceded any significant changes in nutritional parameters (weight-for-age Z score and midupper arm circumference day 14, triceps skinfold thickness day 21). Conclusions Early increases in IGF-I during treatment of Crohn disease are attributable to the anti-inflammatory effect of the enteral feed rather than nutritional restitution.

Intestinal inflammation in cystic fibrosis

BACKGROUND There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, α1 antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1β) were measured. RESULTS Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1β, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.

Prevalence and management of anemia in children, adolescents, and adults with inflammatory bowel disease.

Background: Children and adolescents with inflammatory bowel disease (IBD) are more likely to have Crohns disease (CD) than ulcerative colitis (UC) and their disease tends to be more extensive and severe than in adults. We hypothesized that the prevalence of anemia would therefore be greater in children and adolescents than in adults attending IBD outpatient clinics. Methods: Using the WHO age‐adjusted definitions of anemia we assessed the prevalence, severity, type, and response to treatment of anemia in patients attending pediatric, adolescent, and adult IBD clinics at our hospital. Results: The prevalence of anemia was 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Overall, children (88% [36/41]) and adolescents (83% [20/24]) were more often iron‐deficient than adults (55% [27/49]) (P < 0.01). Multivariate logistic regression showed that both active disease (odds ratio [OR], 4.7 95% confidence interval [CI], 2.5, 8.8) and attending the pediatric clinic (OR 3.7; 95% CI, 1.6, 8.4) but not the adolescent clinic predicted iron deficiency anemia. Fewer iron‐deficient children (13% [5/36]) than adolescents (30% [6/20]) or adults (48% [13/27]) had been given oral iron (P < 0.05); none had received intravenous iron compared with 30% (6/20) adolescents and 41% (11/27) adults (P < 0.0001). Conclusions: Anemia is even more common in children than in older IBD patients. Oral iron was given to half of adolescents and adults but, despite similar tolerance and efficacy, only a quarter of children with iron‐deficient anemia. Reasons for the apparent underutilization of iron therapy include a perceived lack of benefit and concerns about side effects, including worsening of IBD activity. (Inflamm Bowel Dis 2012;)

Adult height in patients with early onset of Crohn's disease

We read with great interest the recently published guidelines on the management of osteoporosis associated with chronic liver disease (Gut 2002;50(suppl I):i1–9). However, we would like to add a few words of comment. Associations between coeliac disease (CD) and primary biliary cirrhosis in particular and other autoimmune liver diseases in general have been reported. In addition, it has been suggested that these individuals should be considered as an at risk group for whom serological testing for CD is indicated. Patients with CD are at high risk of developing low bone mineral density and bone turnover impairment, and it has been shown that adherence to a gluten free diet has a significant positive impact on these parameters. Thus we suggest that physicians caring for patients with the above mentioned liver diseases should screen them for CD in the presence of signs and symptoms suggestive of malabsorption such as osteoporosis. This seems a reasonable strategy as detection of CD will allow for a more rational therapeutic approach to the risks determined by this association. Complications due to the presence of CD, such as malnutrition, anaemia, and osteoporosis, may have a considerable impact on liver disease management and the need/success of transplantation. 6

Technical Report: results of immunological tests on faecal extracts are likely to be extremely misleading

Clinical investigation of gut immunity is difficult because of the need to study intestinal tissues or secretions directly. Others have reported that immunoglobulins, antibodies and cytokines can be detected in saline extracts of faeces. We have assessed the validity of this approach by measuring immunoglobulins, albumin, α1‐antitrypsin and isotype‐specific antibodies in matched samples of faeces and whole gut lavage fluid. Results were compared as estimated output per day, and by using haemoglobin as a common reference substance. Samples were obtained from 10 patients with active inflammatory bowel disease and 10 with other benign GI diseases. For immunoglobulins, albumin and antibodies, the amount detected in faeces varied from < 0.01% to 35.5% (based on estimated daily output) and < 0.01 % to 18.5% (based on haemoglobin) of the amount known to be produced in the gut from results of assays on whole gut lavage fluid (WGLF); there were significantly higher rates of recovery in faecal specimens from patients with active gut inflammation than from other patients. Detection rates and titres of specific antibody in faeces were even lower than those for immunoreactive IgA. These data indicate that immunological tests on saline extracts of faeces do not represent the true status of the gut humoral immune system, and such studies should be strongly discouraged.

The requirements and barriers to successful transition of adolescents with inflammatory bowel disease: Differing perceptions from a survey of adult and paediatric gastroenterologists

BACKGROUND AND AIM Preliminary data highlight the importance of appropriate transition for successful transfer of adolescents with IBD from paediatric to adult care. The aim of this study was to identify both the perceived needs of adolescent IBD patients and the barriers to successful transition from the perspective of professionals involved in their care. METHODS A postal questionnaire was distributed to UK adult and paediatric gastroenterologists with an interest in IBD. The questionnaire utilised closed questions as well as ranked items on the importance of the various competencies of adolescents with IBD required for successful transition. RESULTS Response rate of 62% and 49% for paediatric and adult gastroenterologists respectively was achieved. A structured transition service was perceived as very important by 80% paediatric compared to 47% adult gastroenterologists (p=0.001). A higher proportion of adult than paediatric gastroenterologists identified inadequacies in the preparation of adolescents for transfer (79% and 42%, p=0.001). The main areas of perceived deficiency in preparation identified were patient lack of knowledge about the condition and treatment, lack of self advocacy and co-ordination of care. Lack of resources, clinical time, and a critical mass of patients were the factors ranked highest by both groups as barriers to transition care. Both adult (65%) and paediatric gastroenterologists (62%) highlighted suboptimal training in adolescent medicine for adult gastroenterologists. CONCLUSIONS This survey highlights differences in the perception of adult and paediatric gastroenterologists in the management of transition care and perceived competencies for adolescents with IBD. Lack of training and inadequate resources are the main barriers identified for development of a successful transition service.

Inhibition of NF-κB Signaling in Human Dendritic Cells by the Enteropathogenic Escherichia coli Effector Protein NleE

Intestinal dendritic cells (DCs) send processes between epithelial cells into the gut lumen to sample pathogens. Noninvasive enteropathogenic Escherichia coli (EPEC) colonize the gut using a type three secretion system (T3SS) to inject effector proteins into epithelial cells. We hypothesized that EPEC might also inject proteins into DC processes to dampen immune recognition. Using a T3SS-linked fluorescence resonance energy transfer-based system we show that EPEC injects effectors into in vitro grown human myeloid DCs. Injected cells emit a blue signal due to cleavage of the green fluorescence resonance energy transfer-based substrate CCF2/AM by β-lactamase. When cultured with a mutant EPEC unable to translocate effector proteins, myeloid DCs show rapid activation of NF-κB, secrete large amounts of proinflammatory cytokines and increase expression of CD80, CD83, and CD86, whereas wild-type EPEC barely elicits cytokine production and shuts off nuclear translocation of NF-κB p65. By deleting effector protein genes, we identified NleE as being critical for this effect. Expression of NleE in HeLa cells completely prevented nuclear p65 accumulation in response to IL1-β, and luciferase production in an NF-κB reporter cell line. DCs cocultured with wild-type EPEC or NleE-complemented strains were less potent at inducing MLR. EPEC was also able to inject effectors into DCs sending processes through model gut epithelium in a transwell system and into Peyer’s patch myeloid DCs. Thus, EPEC translocate effectors into human DCs to dampen the inflammatory response elicited by its own pathogen-associated molecular patterns.

Inflammatory bowel disease in young people: the case for transitional clinics.

Background: The incidence of inflammatory bowel disease (IBD) is increasing among adolescents. In all, 25% of patients are diagnosed before the age of 16, when they are traditionally transferred from the pediatric to the adult service. Methods: We conducted a retrospective case‐controlled study to characterize patients treated in a novel transitional adolescent–young adult IBD clinic. This compared disease extent, radiation exposure, therapeutic strategy, and requirement for surgery in 100 adolescents with controls from our adult IBD clinic matched for disease duration. Results: The median (range) ages for the adolescent and adult population was 19 (16–28) and 43 (24–84), with a median age at diagnosis of 15 (3–26) and 39 (13–82) respectively (P < 0.001). Crohns disease was significantly more common in the adolescents. Disease distribution was ileocolonic in 69% of adolescents and 28% of adults, restricted to the ileum in 20% of adolescents and 47% of adults, and colonic only in 11% and 22%, respectively. Upper gastrointestinal involvement occurred in 23% of adolescents, but was not seen in adults (P < 0.01). Total ulcerative colitis was seen in 67% of adolescents and 44% of adults (P < 0.01). Contrary to previous data adolescents did not receive more ionizing radiation than adults. Requirement for immunosuppressive therapy was higher in the adolescent group (53% versus 31%, respectively, P < 0.01). Likewise, 20% of adolescents had required biological therapy compared to only 8% in the adult cohort (P < 0.05). Conclusions: Gastroenterologists should recognize that IBD is more complex when presenting in adolescence and our data support the creation of specific adolescent transitional clinics. Inflamm Bowel Dis 2009

Systematic Review of the Evidence Base for the Medical Treatment of Paediatric Inflammatory Bowel Disease

Objective: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. Methods: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. Results: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. Conclusions: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.