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Paediatric inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract, comprising of Crohn’s disease (CD), ulcerative colitis (UC), and, where classification is undetermined, inflammatory bowel disease unclassified (IBDU). Paediatric IBD incidence is increasing globally, with prevalence highest in the developed world. Though no specific causative agent has been identified for paediatric IBD, it is believed that a number of factors may contribute to the development of the disease, including genetics and the environment. Another potential component in the development of IBD is the microbiota in the digestive tract, particularly the gut. While the exact role that the microbiome plays in IBD is unclear, many studies acknowledge the complex relationship between the gut bacteria and pathogenesis of IBD. In this review, we look at the increasing number of studies investigating the role the microbiome and other biomes play in paediatric patients with IBD, particularly changes associated with IBD, varying disease states, and therapeutics. The paediatric IBD microbiome is significantly different to that of healthy children, with decreased diversity and differences in bacterial composition (such as a decrease in Firmicutes). Changes in the microbiome relating to various treatments of IBD and disease severity have also been observed in multiple studies. Changes in diversity and composition may also extend to other biomes in paediatric IBD, such as the virome and the mycobiome. Research into biome differences in IBD paediatric patients may help progress our understanding of the aetiology of the disease.

Background Primary non-response (PNR) and secondary loss of response (LoR) to anti-TNF therapy are a significant challenge in up to 45% of patients with IBD. Therapeutic drug monitoring (TDM) refers to the practice of measuring anti-TNF trough level and anti-drug antibody to guide clinical decisions. Reactive TDM is performed in response to a disease flare, whereas proactive TDM consists of periodic TDM to allow treatment optimization and prevention of possible flares. In the main, GI centres recommend the use of TDM as opposed to an empirical management of patients on anti-TNF. However, there are a limited number of studies that have addressed whether proactive TDM leads to improved clinical outcomes in comparison to reactive TDM. Aim The aim of this study was to investigate if proactive TDM improves patient disease management by reducing the risk of treatment failure due to LoR and/or development of anti-drug antibody. Patients and Methods We conducted a single-centre prospective observational study to accrue data on proactive TDM between June 2019 and June 2020. We compared this group to a historical cohort of patients with IBD treated at the same centre using reactive TDM between 2014 and 2017. Results 30 children with IBD (16 M, mean age at diagnosis 11.47 years ± SD 2.93, median 12, range 3–16) started on anti-TNF treatment between June 2019 and June 2020, were prospectively recruited (current follow-up duration: average 7.1 months ± SD 3, median 6.4, range 3.1–13). 10 had ulcerative colitis (UC), 19 had Crohn’s (CD) and one had IBD-U CD-like. 37 children (20 M), 6 with UC and 31 with CD, were included in the retrospective cohort managed with reactive TDM. (Table 1). More patients in the proactive TDM cohort (22/30) were managed by escalating the IFX regime (i.e. 10 mg/Kg 8 – 6 or 4 weekly) compared to the reactive TDM cohort (14/37) (chi-square 8.396, P 0.00376). In the cohort managed with reactive TDM, a higher number of patients developed high titre anti-IFX antibody (> 50 U/ml) post induction (12/37 vs 3/30) (chi-square 4.798, P 0.0285). The need for switching to different biologics was significantly higher in the reactive TDM cohort (22/37) compared to the proactive TDM cohort (1/30) (chi-square 23.15, P Conclusions The introduction of proactive TDM resulted in a significant reduction of patients requiring switch of their primary biologic and saw an increase in mean trough levels due to timely dose escalation. The results of this study are early indicators that proactive TDM offers a better method of managing children with IBD on IFX therapy compared to reactive TDM with the potential of additional clinical benefits such as reducing the risk of developing adverse drug reactions due to high antibody titres.

The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane‐bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3′ end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556‐14A>G and c.491+1G>A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype–phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome., Mutations in the epithelial cell adhesion molecule gene (EPCAM) can result in one of two unrelated diseases, congenital tufting enteropathy or Lynch Syndrome depending on the type and nature of the mutation. We report 13 novel EPCAM mutations from 17 CTE patients, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic mutations. Statistical analyses to evaluate genotype‐phenotype correlations indicate that the c.499dupC frameshift mutation is associated with more severe treatment regimens and greater mortality in CTE.

There has been an explosion in our understanding of the human microbiome (the genome of all our microbes) in the recent years. Advances in genome sequencing technologies and metagenomic analysis (genetic study of genomes taken directly from environmental samples) have enabled scientists to study these microbes and their function and to research microbiome–host interactions both in health and disease. The human microbiome has an estimated 100 trillion microbes, the bulk of which live in our gut. This summary gives an overview about what is known about the microbiota (microbial community) in paediatric practice. This short article is written for the practising paediatrician. For a scientific overview, the reader is referred to reviews.1 ,2 An understanding of this complex ecological community is important as it affects our patients, and manipulation of the gut microbiome has the potential to be used in the treatment of childhood diseases in the future. The human microbiome is composed of communities of bacteria (and viruses and fungi) that have a greater complexity than the human genome itself. Large-scale metagenomic projects (community and environmental genomics), such as the European Metagenomics of the Human Intestinal Tract and the Human Microbiome Project, have reported 3.3 million unique protein-encoding genes as compared with the entire human genome, which has around 23 000 genes. These studies have described the beneficial functions of the normal gut microbiota on health down to the genetic level.3 The human microbiome has extensive functions such as development of immunity, defence against pathogens, host nutrition including production of short-chain fatty acids important in host energy metabolism, synthesis of vitamins and fat storage …

Introduction 5-aminosalicylate (5-ASA) is efficacious in UC and IBD-unclassified (U). Nephrotoxicity is a rare side-effect. In adults, 5-ASA-induced nephrotoxicity presents at any age with chronic tubulointerstitial nephritis. A delay in diagnosis may result in progressive end-stage renal disease, even after drug discontinuation. However, case reports in children are scant. Aims We examined the hypothesis that renal disease is commoner in children receiving higher doses. We therefore investigated: The usage of all 5ASA brands, orally or rectally in all UC and IBDU diagnosed children 5–ASA dose in mg/kg and other IBD treatment. Serum creatinine (µmmol/l), and calculated eGFR, correlating the maximum dose of 5–ASA with maximum creatinine and lowest eGFR levels respectively. Methods Retrospective collection from a prospectively recorded database (Infloflex), verified with electronic records when full data were available. eGFR was calculated based on heights. Data were analysed using a non-parametric correlation test. Results 117 children with UC and IBDU were treated with 5-ASA drugs. 102 were diagnosed as UC and 15 as IBDU. 62 were male and 55 females. 92 had pancolitis; 21 had left sided colitis; 3 proctitis and 1 right sided colitis only. They received the following other IBD treatments: 79 received prednisolone; 65 azathioprine/6MP; 21 biologics; 14 hydrocortisone; 8 received Methotrexate; 2 ciclosporin and 13 underwent colectomy. 72/117 (62%) had increased creatinine values at some point: 2/72 (3%) had pre-existing renal disease with raised creatinine. A further 3/72 (4%) children with raised creatinine had their 5-ASA drugs discontinued without renal damage. 2/72 (3%) cases were identified with permanent renal damage identified by raised creatinine, and the 5-ASA was discontinued. 3/117 (2.5%) had non-renal intolerance to 5 –ASA, e.g. rash. We correlated the maximum 5- ASA dose against the maximum creatinine (r2=3.6%, p=0.66) and against minimum eGFR (r2=0.6%, p=0.61) respectively using linear regression. Conclusion There was no correlation between maximum 5- ASA vs maximum creatinine or minimum eGFR. Therefore, the effect of 5-ASA on renal function is not dose-related.

INTRODUCTION: \ud Thetanix (gastroresistant capsules containing lyophilized Bacteroides thetaiotaomicron) is a live biotherapeutic, under development for Crohn's disease, that antagonizes transcription factor nuclear factor kappa B, reducing proinflammatory cytokines, particularly tumor necrosis factor alpha. We aimed to assess safety and tolerability in adolescents with Crohn's disease in remission.\ud \ud METHODS: \ud Subjects who were 16–18 years with Crohn's in remission (weighted pediatric Crohn's disease activity index 99% in part B. Two subjects reported adverse events deemed related—one in part A with eructation, flatulence, and reflux; one in part B with dizziness, abdominal pain, and headache. No serious adverse events were reported. There was no significant change in median calprotectin across part B (87.8 [4.4–447] to 50.5 [5.3–572], P = 0.44 by the Fisher exact test in the active group). No significant differences were found in microbiota profiles, but diversity seemed to increase in treated subjects.\ud \ud DISCUSSION: \ud Thetanix, after single and multiple doses, was well tolerated. Although the numbers in this study were small, the safety profile seems good. Future studies should explore efficacy.

IntroductionDiet may modulate immune responses in health and disease. We hypothesised a role for nutrient sensing pathways. Nutrient sensing enteroendocrine cells (EEC) within intestinal epithelium release local neuroendocrine peptides.1 We examined their effects on immune responses in intestinal mu

International audience; Laboratory rats are commonly used in life science research as a model for human biology and disease, but the composition and development of their gut microbiota during life is poorly understood. We determined the fecal microbiota composition of healthy Sprague Dawley laboratory rats from 3 weeks to 2 y of age, kept under controlled environmental and dietary conditions. Additionally, we determined fecal short-chain fatty acid profiles, and we compared the rat fecal microbiota with that of mice and humans. Gut microbiota and to a lesser extent SCFAs profiles separated rats into 3 different clusters according to age: before weaning, first year of life (12- to 26-week-old animals) and second year of life (52- to 104-week-old). A core of 46 bacterial species was present in all rats but its members' relative abundance progressively decreased with age. This was accompanied by an increase of microbiota α-diversity, likely due to the acquisition of environmental microorganisms during the lifespan. Contrastingly, the functional profile of the microbiota across animal species became more similar upon aging. Lastly, the microbiota of rats and mice were most similar to each other but at the same time the microbiota profile of rats was more similar to that of humans than was the microbiota profile of mice. These data offer an explanation as to why germ-free rats are more efficient recipients and retainers of human microbiota than mice. Furthermore, experimental design should take into account dynamic changes in the microbiota of model animals considering that their changing gut microbiota interacts with their physiology.

The microbial pattern-recognizing Toll-like receptors (TLRs) are major signal transducers known to shape and influence the postnatal maturation of host intestinal epithelium. Perturbations in this intricate host-microbe cross-talk have been reported to be associated with uncontrolled epithelial cell growth and thus potential cancer development by mechanisms which are largely unknown. We therefore generated transgenic mice carrying a constitutively active TLR4 (CD4-TLR4) linked to an intestinal epithelial cell-specific promoter. Ex vivo analysis of transgenic crypt-villus organoid cultures revealed an increased proliferative capacity and a lowered cyclooxygenase 2 (Cox-2) expression in these organoids compared with wild-type control cultures. Introducing the CD4-TLR4 transgene into APC(Min/+) mice (CD4-TLR4-APC(Min/+)), a model of colorectal carcinoma, resulted in a dramatic drop in tumor load as compared with control APC(Min/+) mice. Intestinal tumors from CD4-TLR4-APC(Min/+) mice displayed reduced Cox-2 protein, elevated interferon β expression and increased caspase-3 activity, which correlated with increased apoptosis in vivo. Thus, our data reveal that host microbiota-mediated signal transduction via TLR4 in intestinal epithelial cells is far more complex than what is previously reported.

Background Despite optimal therapy, many children with Crohn’s disease (CD) experience growth retardation. The objectives of the study are to assess the feasibility of a randomised control trial (RCT) of injectable forms of growth-promoting therapy and to survey the attitudes of children with CD and their parents to it. Methods A feasibility study was carried out to determine study arms, sample size and numbers of eligible patients. A face-to-face questionnaire surveyed willingness to consent to future participation in the RCT. Eligibility to the survey was any child under 18 (with their parent/guardian) with CD whose height standard deviation score (HtSDS) was ≤+1. Of 118 questionnaires, 94 (80%) were returned (48 by children and 46 by parents). Results The median age of the patients in the survey was 14.3 years (range 7.0 to 17.7), and 35 (73%) were male. Their median HtSDS was −1.2 (−3.01, 0.23), and it was lower than the median mid-parental HtSDS of −0.6 (−3.1, 1.4). We analysed the willingness of the children whose HtSDS

Subepithelial myofibroblasts are involved in the initiation and coordination of intestinal epithelial repair, but the molecular signaling pathways are largely unknown. The cellular adaptations that occur during repair range from dedifferentiation and migration to proliferation and redifferentiation, in a way that is strongly reminiscent of normal crypt-to-villus epithelial maturation. We therefore hypothesized that Wnt/β-catenin signaling may have a pivotal role in intestinal epithelial wound repair. We used the established scratch wound method in Caco-2 cells and in nontransformed NCM460 cells to monitor the effects of IL-1β-stimulated colonic myofibroblasts (CCD-18co) on intestinal epithelial repair, with immunoblotting and immunodepletion to examine the conditioned media. Conditioned media from IL-1β-stimulated, but not -untreated, myofibroblasts increased Caco-2 wound closure twofold over 24 h. IL-1β-stimulated myofibroblasts downregulated the differentiation marker sucrase-isomaltase in the Caco-2 cells, whereas the proliferation marker c-myc was upregulated. Array expression profiling identified Wnt-5a as the Wnt-related gene that was most upregulated (28-fold) by IL-1β stimulation of CCDs. Recombinant Wnt-5a enhanced proliferation of Caco-2 and NCM460 cells. In scratch assays, it increased migration of the leading edge in both cell lines. Wnt-5a immunodepletion of the IL-1β-CCD conditioned media abrogated the ability to enhance the repair. Wnt-5a often acts through a noncanonical signal transduction pathway. Further experiments supported this pathway in epithelial wound healing: IL-1β-CCD-mediated repair was not affected by the addition of the canonical Wnt antagonist Dickkopf-1. Furthermore, media from stimulated myofibroblasts (but not Wnt-5a-depleted media) increased c-jun in Caco-2 cell nuclear extracts. Myofibroblast-mediated noncanonical Wnt-5a signaling is therefore important in the dedifferentiation and migration stages of epithelial wound repair.

OBJECTIVES We hypothesised that nonadherence to thiopurines is more common in adolescents than in adults with inflammatory bowel disease. METHODS We sought factors associated with thiopurine nonadherence defined by thiopurine metabolite levels. RESULTS Multivariate logistic regression confirmed that adolescents (odds ratio [OR] 4.6 [95% confidence interval [CI] 1.9-11.5]; P < 0.01) compared with adults, patients with Crohn disease (OR 3.3 [CI 1.1-10.5] P = 0.04) compared with ulcerative colitis, and patients living in more socially deprived areas (OR 1.03 [CI 1.0-1.1] P = 0.02) were more likely to be nonadherent to thiopurines. CONCLUSIONS Adolescents are more frequently nonadherent than adults: prospective studies are required to determine the reasons for nonadherence in adolescents.

Background: Children and adolescents with inflammatory bowel disease (IBD) are more likely to have Crohn's 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;)

BACKGROUND AND OBJECTIVES Children and adolescents with inflammatory bowel disease (IBD) have more extensive and severe disease than adults. Despite a lack of comparative studies, thiopurines are frequently cited as being more efficacious in children. To test this assertion, we compared the efficacy of thiopurines in children with IBD with that in adults matched for disease phenotype. PATIENTS AND METHODS Fifty paediatric and adult patients with IBD started on a thiopurine were matched for sex, disease type, and extent. Retrospective data were obtained by electronic case note review, and corticosteroid-free clinical remission and tolerance rates at 6 months as well as relapse rates during the subsequent year were recorded. RESULTS Adverse effects caused discontinuation of thiopurines in 1 of 50 children and 16% (8/50) of adults (P < 0.05). At 6 months, steroid-free remission was achieved in 30% (15/50) of children and 38% (19/50) of adults (P = 0.53). No differences in remission rates were seen according to disease type. At the end of the following year, 73% (11/15) of children and 68% (13/19) of adults remained in remission (P = 1). CONCLUSIONS Thiopurines are tolerated better by children. When phenotype is matched, there is no difference in the therapeutic response to thiopurines between children and adults with IBD.

Because both micronutrients and antimicrobial peptides protect against diarrhea, we looked for an effect on intestinal antimicrobial peptide gene expression during a randomized controlled trial of multiple micronutrient (MM) supplementation.Consenting adults (n=287) in Lusaka, Zambia, were randomized to receive a daily MM supplement or placebo and were followed up for 3.3 years, with a crossover after 2 years. Intestinal biopsy samples were obtained at annual intervals, and messenger RNA of the intestinal antimicrobial peptides human alpha defensin (HD) 5, HD6, human beta-defensin (hBD) 1, hBD2, and LL-37 were quantified by real-time reverse-transcriptase polymerase chain reaction. Samples were also obtained during diarrhea episodes and after convalescence.There was no effect overall of treatment allocation. However, in malnourished adults (body mass indexor =18.5), HD5 mRNA was increased by 0.8 log transcripts/microg total RNA in MM recipients, compared with HD5 mRNA in placebo recipients (P=.007). During diarrhea, HD5 expression was reduced by 0.8 log transcripts in placebo recipients (P=.02) but was not reduced in MM recipients, nor was it reduced after the crossover. Correlations between HD5 and nutritional status were found that were sex-specific but not explained by serum leptin or adiponectin concentrations.Micronutrient supplementation was associated with up-regulation of HD5 only in malnourished adults. Interactions between antimicrobial gene expression and nutritional status may help to explain the increased risk of infection in individuals with malnutrition.

Curcumin is the active ingredient of turmeric. It is widely used as a kitchen spice and food colorant throughout India, Asia and the Western world. Curcumin is a major constituent of curry powder, to which it imparts its characteristic yellow colour. For over 4000 years, curcumin has been used in traditional Asian and African medicine to treat a wide variety of ailments. There is a strong current public interest in naturally occurring plant-based remedies and dietary factors related to health and disease. Curcumin is non-toxic to human subjects at high doses. It is a complex molecule with multiple biological targets and different cellular effects. Recently, its molecular mechanisms of action have been extensively investigated. It has anti-inflammatory, antioxidant and anti-cancer properties. Under some circumstances its effects can be contradictory, with uncertain implications for human treatment. While more studies are warranted to further understand these contradictions, curcumin holds promise as a disease-modifying and chemopreventive agent. We review the evidence for the therapeutic potential of curcumin fromin vitrostudies, animal models and human clinical trials.

Inflammatory bowel disease (IBD) is a major source of morbidity in children and adults. Its incidence is rising, particularly in young people. IBD carries a lifelong risk of cancer, which is proportional to disease duration. Drug and surgical treatments rarely offer cure and often carry a high side effect burden. Dietary therapy is highly effective in Crohn's disease. For these reasons, there is much interest in developing novel dietary treatments in IBD. Curcumin, a component of the spice turmeric, and an anti-inflammatory and anti-cancer agent, shows preclinical and clinical potential in IBD. Its mechanisms of action are unknown. Our aim was to assess the effect of curcumin on key disease mediators p38 mitogen-activated protein kinase (MAPK), IL-1β, IL-10 and matrix metalloproteinase-3 (MMP-3) in the gut of children and adults with IBD. Colonic mucosal biopsies and colonic myofibroblasts (CMF) from children and adults with active IBD were culturedex vivowith curcumin. p38 MAPK, NF-κB and MMP-3 were measured by immunoblotting. IL-1β and IL-10 were measured by ELISA. We show reduced p38 MAPK activation in curcumin-treated mucosal biopsies, enhanced IL-10 and reduced IL-1β. We demonstrate dose-dependent suppression of MMP-3 in CMF with curcumin. We conclude that curcumin, a naturally occurring food substance with no known human toxicity, holds promise as a novel therapy in IBD.

Inflammatory bowel disease (IBD) is characterized by an exaggerated immune response that involves pro-inflammatory cytokines including IL-8. Production of these pro-inflammatory cytokines is triggered by pathogen-associated molecular patterns (PAMP). Butyrate, a product of bacterial fermentation of carbohydrates, has been reported to modulate inflammation in IBD, possibly by regulating production of pro-inflammatory cytokines. However, this effect of butyrate is controversial. In this study, we used Pam3CSK4 (Pam3CysSerLys4), the acylated NH2-terminus of the bacterial lipoprotein (a PAMP), to mimic in vivo infection of pathogens. Butyrate transiently down-regulated expression of IL-8 stimulated by Pam3CSK4. Treatment of cells with butyrate before Pam3CSK4, however, enhanced production of IL-8. Furthermore, butyrate induced expression of A20, a negative regulator of the nuclear factor-kappaB pathway. Over-expression of A20 inhibited Pam3CSK4-triggered IL-8 expression. Our data suggest that the inflammatory modulation of butyrate in IBD is mediated by A20 and a short pulse rather than continuous administration of butyrate may provide a protective effect on IBD.

Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a Vγ9Vδ2 T cell receptor (Vδ2 T cells) and mediate host protection against microbial infections and malignancies. Vδ2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed Vδ2 T cell phenotype and function by flow cytometry in blood and intestinal tissue from Crohn’s disease patients (CD patients) and healthy controls. Blood from CD patients included an increased percentage of gut-tropic integrin β7–expressing Vδ2 T cells, while “Th1-committed” CD27-expressing Vδ2 T cells were selectively depleted. A corresponding population of CD27+ Vδ2 T cells was present in mucosal biopsies from CD patients and produced elevated levels of TNFα compared with controls. In colonic mucosa from CD patients, Vδ2 T cell production of TNFα was reduced by pharmacological blockade of retinoic acid receptor-α (RARα) signaling, indicating that dietary vitamin metabolites can influence Vδ2 T cell function in inflamed intestine. Vδ2 T cells were ablated in blood and tissue from CD patients receiving azathioprine (AZA) therapy, and posttreatment Vδ2 T cell recovery correlated with time since drug withdrawal and inversely correlated with patient age. These results indicate that human Vδ2 T cells exert proinflammatory effects in CD that are modified by dietary vitamin metabolites and ablated by AZA therapy, which may help resolve intestinal inflammation but could increase malignancy risk by impairing systemic tumor surveillance.

BACKGROUND. Growth failure is a recognized complication of pediatric-onset Crohn's disease, but there are few data on final adult height. OBJECTIVE. Our purpose with this work was to determine adult height and the clinical features that influence long-term growth impairment. METHODS. We retrospectively studied 123 patients with Crohn's disease (65 male and 58 female) who had reached adult height. All of the case subjects were diagnosed before age 16.0 years. Heights were converted to SD scores and univariate analysis performed of factors postulated to influence final height, that is, interval from onset of symptoms to diagnosis, prepubertal onset of symptoms, gender, jejunal disease present at diagnosis, systemic steroid therapy, intestinal surgery, and midparental height SD scores. Significant univariate factors were additional analyzed in regression models. RESULTS. Mean height deficit at diagnosis was −0.50 SD scores, which improved to −0.29 SD scores at final height. Mean final height compared with target height, calculated from parental height, was −2.4 cm (range: −20.0 to 9.0 cm). Nineteen percent of the case subjects achieved a final height >8.0 cm below target height. The length of the interval between symptom onset and diagnosis correlated negatively with height SD scores at diagnosis. Height SD scores at diagnosis were related to final height SD scores, independent of midparental height. The presence of jejunal disease was negatively related to final height. CONCLUSIONS. Mean final adult height showed a modest deficit compared with target height, but in one fifth of patients, final height was significantly less than target height. Earlier diagnosis and improved treatment of jejunal disease would be likely to improve final height.

Objectives: Butyrate concentrations in the gastrointestinal tract vary greatly with age. In intestinal epithelial cells, butyrate enhances gene transcription by increasing histone acetylation, rendering the nucleosome open to transcription factors. However, it inhibits human insulin-like growth factor binding protein (hIGFBP)-3 expression. We therefore hypothesized that butyrate also acts by regulating transcription factor acetylation. Methods: Gene regulation was examined in Caco-2 cells. RNA stability was measured after interruption of transcription. The activity of deletion mutations of the hIGFBP-3 promoter was examined in reporter assays. Transcription factor binding to promoter DNA was analyzed. Results: Butyrate did not increase the transcription of a repressor because it inhibited hIGFBP-3 mRNA in the absence of protein synthesis. Nor did butyrate decrease the stability of hIGFBP-3 mRNA. Analysis of the hIGFBP-3 promoter demonstrated a butyrate-response element that included the binding sites for p300 and Sp1/Sp3. Transfection of Caco-2 cells with E1A, an inhibitor of p300 acetyltransferase activity, reversed the butyrate-induced repression of hIGFBP-3. Because Sp3 represses the initiation of transcription, we studied whether butyrate induced Sp3 acetylation. Electrophoretic mobility shift assays of nuclei extracted from Caco-2 cells treated with 5 mmol/L butyrate demonstrated an extra, heavier band in addition to the Sp3-DNA binding in untreated cells. This corresponded to a protein, detected only in butyrate treated cells, that was identified both by an anti-Sp3 antibody and by an anti-acetyl lysine antibody. Conclusions: This study demonstrates that butyrate increases the acetylation of a nonhistone protein, Sp3, catalyzed by p300 acetyltransferase activity.

Background & Aims: The up-regulation of matrix metalloproteinases (MMPs) in the inflamed gut has mainly been associated with mucosal degradation and ulceration. However, their in vitro capacity to specifically cleave inflammatory mediators indicates that MMPs may have a profound immunoregulatory impact. We hypothesized that MMPs proteolytically modify intestinal epithelial chemokine signaling. Methods: Interleukin-1β–stimulated Caco-2 cells were exposed basolaterally to nanomolar concentrations of activated MMP-3 or cocultured with interleukin-1β–stimulated, MMP-producing, colonic myofibroblasts (CCD-18co). The conditioned media were subjected to chemotaxis assays. In addition, epithelial cells from patients with colitis were examined by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Results: MMP-3 dose-dependently induced the neutrophil (up to 5-fold) but not monocyte chemoattractant capacity of Caco-2 cells. A similar Caco-2 chemotactic response was obtained in the Caco-2/CCD-18co cocultures. The principal mediator of these protease-related effects was identified as the potent neutrophil chemokine CXCL7 (neutrophil activating peptide 2), a proteolytic cleavage product of chemotactically inert platelet basic protein (PBP), not previously identified in the intestine. Antibodies against CXCL7 inhibited the MMP-induced chemotactic response by 84%, and PBP mRNA and protein were detected in stimulated Caco-2 but not in CCD-18co cells. Furthermore, PBP transcript and protein levels were low in the mucosa and in isolated epithelial cells from patients with Crohn's disease and from normal intestine but increased up to 13-fold in patients with ulcerative colitis. Conclusions: These findings identify a novel proinflammatory action of MMPs in inflammation and suggest that lamina propria myofibroblasts are required to achieve maximal intestinal epithelial immune activation.

Enteral nutrition has a positive effect on growth in children with active Crohn's disease. The question arises: is this is due only to improved nutrition? Enteral formulas may also directly reduce inflammation, lowering the expression of cytokines like interleukin (IL)-6 that inhibit growth. Four lines of evidence support the hypothesis that enteral formulas directly lessen inflammation: enteral nutrition directly affects the inflamed intestine; changes in inflammatory markers precede repletion of nutrition status; molecular pathways exist linking changes in luminal contents to the expression of class II MHC genes in intestinal epithelium in animal studies; and enteral formulas have a direct effect on cytokine expression by intestinal epithelial cells.

Changes in diet greatly affect the mucosal immune system, particularly in diseases such as Crohn's disease and necrotizing enterocolitis. This review examines the hypothesis that alterations in the luminal environment of the intestine regulate the expression of genes in the epithelium responsible for signaling to immune cells. Increasing chemokine expression in the mouse intestinal epithelium using transgenic techniques enhances the recruitment of neutrophils and lymphocytes into the intestine. Furthermore, SCFA concentrations in the intestinal lumen vary markedly with diet. SCFAs alter chemokine expression by inhibiting histone deacetylase activity in the enterocyte. The review therefore describes a molecular pathway explaining how changes in diet may alter leukocyte recruitment by regulating enterocyte gene expression. It is likely that other similar pathways remain to be discovered.

Purpose: Cyclooxygenase (COX)-2 has been causally implicated in carcinogenesis. The evidence for increased COX-2 in the malignant progression of Barrett’s esophagus is contradictory. We hypothesize that COX-2 expression may be causally affected by the gastrin status via the cholecystokinin 2 (CCK2) receptor. Experimental Design: COX-2 and prostaglandin E2 expression were evaluated by Western blotting and enzyme-linked immune assay in samples of squamous esophagus, Barrett’s esophagus with varying degrees of dysplasia to adenocarcinoma, and normal duodenum. Differentiation status was evaluated by histopathology and villin expression. A longitudinal case-control study compared COX-2 in patients who progressed to adenocarcinoma with nonprogressors matched for age and length of follow-up. Messenger RNA levels of gastrin and CCK2 receptor in biopsies and cell lines were evaluated by reverse transcription-PCR, and in vitro gastrin stimulation was conducted with and without inhibitors for CCK2 (YM022) and COX-2 (NS-398). Cell proliferation was evaluated using minichromosome maintenance protein 2 (Mcm2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Results: COX-2 expression is significantly increased in Barrett’s esophagus before dysplasia development. Expression is highly variable within Barrett’s dysplasia and adenocarcinoma samples independent of differentiation status. In a longitudinal case-control study, the expression levels within patients increased over time, regardless of the degree of malignant progression. Biopsies from nondysplastic Barrett’s esophagus expressed increased gastrin mRNA levels compared with other biopsies. Gastrin significantly induced COX-2, prostaglandin E2, and cell proliferation in biopsies and cell lines. Gastrin-induced proliferation can be inhibited by YM022 and NS-398. Conclusions: COX-2 is up-regulated early in the Barrett’s metaplasia sequence. During carcinogenesis, gastrin is a significant determinant of COX-2 activity levels via the CCK2 receptor.

Background & Aims: Normal weaning induces class II major histocompatibility complex(Ia) and invariant chain (Ii) expression in the mouse intestinal epithelium. Because the class II transactivator protein (CIITA) induces Ia and Ii in most cell types, we hypothesized that diet-induced expression of these genes was through CIITA. Methods: Mouse litters were split and weaned onto an elemental diet or a normal (complex) chow diet. On days 24, 31, and 45, epithelial cells were isolated from small intestine with EDTA, and the RNA was extracted from both wild-type and interferon (IFN)- receptor knockout mice. Messenger RNA (mRNA) was measured by Northern blotting, RNase protection assay, and real-time polymerase chain reaction and Ia localized by immunohistochemistry. Results: By day 31, CIITA mRNA was induced in the intestinal epithelium of normally weaned wild-type mice, and this mirrored the expression of Ii chain mRNA. Mice weaned onto an elemental diet did not exhibit Ii mRNA or increased CIITA mRNA in the intestinal epithelium by day 31, but low levels of Ii mRNA were detectable by day 45. Of the 3 isoforms of CIITA, weaning onto a complexdiet induced only CIITA IV by day 31. Mice deficient in the IFN- receptor expressed Ia in the epithelium and they also accumulated Ii mRNA (at low levels) by day 45, irrespective of diet. CIITA III mRNA accumulation mirrored the dietary-independent changes of Ii mRNA. Conclusions: Two mechanisms regulate Ii in the mouse intestinal epithelium: a rapid one, which is diet-induced acting through CIITA IV; and a slower, dietary-independent pathway, acting through CIITA III.

Despite much progress in the understanding of pathogenesis and of management, diarrhoeal illnesses remain one of the most important causes of global childhood mortality and morbidity. Infections account for most illnesses, with pathogens employing ingenious mechanisms to establish disease. In the developed world, an upsurge in immune-mediated gut disorders might have resulted from a disruption of normal bacterial-epithelial cross-talk and impaired maturation of the gut's immune system. Oral rehydration therapies are the mainstay of management of gastroenteritis, and their composition continues to improve. Malnutrition remains the major adverse prognostic indicator for diarrhoea-related mortality, emphasising the importance of nutrition in early management. Drugs are of little use, except for specific indications although new agents that target mechanisms of secretory diarrhoea show promise, as do probiotics. However, preventive strategies on a global scale might ultimately hold the greatest potential to reduce the burden of diarrhoeal disease. These strategies include vaccines and, most importantly, policies to address persisting inequalities between the developed and developing worlds with respect to nutrition, sanitation, and access to safe drinking water.

Chronic inflammation is characterised by modifications in cytokine concentrations, whereas growth is mainly dependent on the GH-IGF axis. IGF-I bioavailability is modulated by a family of IGF-binding proteins (IGFBPs). The aim of the present study was to evaluate the interactions among interleukin-1beta (IL-1beta), IL-6 and IGFBP secretion by intestinal cells to assess whether cytokines modulate IGFBP secretion, and in turn IGF-I and IGF-II bioavailability. The human colon carcinoma derived cell line Caco-2 was used as an in vitro model for its capacity to differentiate spontaneously. Experiments were carried out on day 4 (undifferentiated state) and day 14 (differentiated state) after plating. Carcinoembryonic antigen (CEA) was used as a marker of differentiation and increased in the conditioned media (CM) from days 4 to 14 (0.2+/-0.01 ng/ml per 10(5) cells vs 3.3+/-0.2 ng/ml per 10(5) cells, P

After completing this article, readers should be able to: 1. Describe how changes in chemokine expression affect lymphocyte and neutrophil function in the intestine. 2. Describe the effects of butyrate on interleukin-8 and monocyte chemotactic protein-1 expression. 3. Delineate the process by which butyrate alters the expression of chemokines. The intestinal epithelium acts as a barrier to the external environment contained within the gut lumen. (1) The barrier is not complete, with the intestine allowing sampling of macromolecules (2) and active absorption of nutrients. It has become increasingly apparent that the enterocyte itself acts as an immune cell, as evidenced by the existence of receptors for bacterial products (3) and its ability to express a wide variety of molecules on its surface that contain immunoglobulin domains. The epithelial cell also expresses proteins that may interact with immunocytes within the intestine. These include surface molecules such as class II major histocompatibility complex (MHC) and cytokines that are released from the epithelium such as chemokines or interleukin (IL)-6. These signaling proteins enable the epithelial cell to orchestrate events in the intestine. We have hypothesized that changes in the intestinal lumen regulate the expression of signaling molecules by the epithelial cell. Thus, dietary effects on the intestinal lumen can act through the epithelium to alter indirectly events in the intestine, particularly those of the mucosal immune system. This review presents evidence that altering the expression of signaling genes in the epithelium affects the mucosal immune system. In addition, it describes how changes in the intestinal lumen (influenced by diet) alter the expression of these genes. The effects of the lumen on epithelial cell gene expression, therefore, can be considered as an afferent limb in this process, and the effects of the epithelial cell on the mucosal immune system can be considered the efferent limb. Evidence for …

After completing this article, readers should be able to: 1. List the three primary components from which the intestinal environment is derived. 2. Delineate the specific regions between the bulk phase of the intestine and the epithelial cell apex. 3. Discuss the effect of mucus on the acid microclimate of the intestine. The intestinal lumen is topologically outside the living organism. The physicochemical environment of the intestine determines how nutrients are absorbed and controls potential pathogens. The body regulates the composition of the lumen, and the ability of the intestine to dominate this space is critical to life. The key evolutionary event in the development of multiorgan animals was containment of this external environment into a tube to gain effective control over it. This allowed the intestine to select from this area those factors that were beneficial while leaving behind those that were of no benefit or even harmful. Unicellular organisms, sponges, and other collections of cells cannot regulate their absorptive surfaces. They, therefore, have not solved the essential problem of allowing other cells in the body to specialize into organs whose environment is bathed in more consistent surroundings than are found in nature. The evolution of the intestine led to the appearance of many different organ types, including muscles and nerves, which ultimately resulted in intelligent life. This review examines how the intestinal environment is regulated, with particular reference to neonates. The environment of the intestine is derived from three primary components: dietary intake, bacterial ecology, and factors such as peristalsis and glandular secretions that are intrinsic to the intestine. Regulation of the physicochemical environment, therefore, depends on the body’s ability to control each of these areas effectively. Dietary intake is controlled by active ingestion. As gut development led to the evolution of complex organisms, so also the appearance of coordination in …

Delayed puberty frequently complicates the clinical course of young patients with inflammatory bowel disease, more often in Crohn's disease than ulcerative colitis. Undernutrition has been thought to be the main reason for delayed puberty in these patients. However, puberty may be delayed despite a normal nutritional status. Observations in patients with inflammatory bowel disease and in rats with experimental colitis suggest that inflammatory mediators may have a direct adverse influence, independent of undernutrition, on the onset and progression of puberty. Serum androgens are consistently reported to be reduced in patients with delayed puberty and inflammatory bowel disease. This reduction is not necessarily secondary to a reduction in gonadotrophins as serum concentrations of gonadotrophins have been reported to be normal or even increased in some studies. Management of delayed puberty involves calorie supplements to correct undernutrition and treatment of inflammation. Observations in boys with delayed puberty and controlled studies in experimental models of intestinal inflammation suggest that testosterone therapy can accelerate puberty.

Copyright: © 2014 Li, Symonds, Miao, Sanderson and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This article has been made available through the Brunel Open Access Publishing Fund. T-cell responses are induced by antigen presenting cells (APC) and signals from the microenvironment. Antigen persistence and inflammatory microenvironments in chronic infections and cancer can induce a tolerant state in T-cells resulting in hyporesponsiveness, loss of effector function, and weak biochemical signaling patterns in response to antigen stimulation. Although the mechanisms of T-cell tolerance induced in chronic infection and cancer may differ from those involved in tolerance to self-antigen, the impaired proliferation and production of IL-2 in response to antigen stimulation are hallmarks of all tolerant T cells. In this review, we will summarize the evidence that the immune responses change from non-self to “self”-like in chronic infection and cancer, and will provide an overview of strategies for re-balancing the immune response of antigen-specific T cells in chronic infection and cancer without affecting the homeostasis of the immune system. Arthritis Research UK and Medical Research Council UK.

The Toll protein in Drosophila regulates dorsal ventral patterning during embryogenesis, and participates in antibacterial and antifungal host defense. Mammalian homologues are termed Toll-like receptors and, to date, nine have been cloned (TLRI-9) in humans. They are characterized by extracellular leucine-rich repeats and a cytoplasmic domain similar to the interleukin 1 receptor. Both TLR2 and TLR4 recognize various bacterial cell wall components including lipopolysaccharide (LPS). This results in the activation of the NFkappaB pathway. Peripheral blood mononuclear cells (PBMCs) express both TLR2 and TLR4. The authors hypothesized that the expression of TLR 2 and TLR4 in human intestinal epithelial cells differs from PBMCs because of the abundance of LPS in the intestinal lumen.Epithelial cells were isolated from Caco-2 cells, fetal gut explants, and small bowel resection specimens using Hanks/ethylenediamine tetraacetic acid solution. PBMCs were used as positive controls. Ribonucleic acid (RNA) was isolated using the TRIzol method. Standard reverse transcription-polymerase chain reaction examined TLR2 and TLR4 messenger RNA (mRNA) expression. NFkappaB expression was determined using a luciferase reporter assay.TLR2 mRNA was highly expressed in PBMCs and was present in all human intestinal epithelial cells. TLR4 mRNA was detected only in PBMCs. TLR4 is not present in epithelium from children with inflammatory bowel disease. In Caco-2 cells, significant NFkappaB activation in response to LPS occurred only in the presence of TLR4 introduced by complementary deoxyribonucleic acid transfection.Absence of TLR4 is associated with endotoxin hyporesponsiveness of intestinal epithelial cells. TLR4 is not directly involved in inflammation of the intestinal epithelium. Although TLR2 is normally present in the epithelial cell, it plays a limited role in inflammation. It may be activated during conditions in which bacterial cell wall concentrations within the intestine are pathologically high.

Background & Aims: Interferon (IFN)-γ plays an important role in the immunologic control of infection by the protozoan enteropathogen Cryptosporidium parvum . We tested the hypothesis that IFN-γ may directly inhibit infection of enterocytes by this pathogen. Methods: HT-29, Caco-2, and H4 human enterocyte cell lines were grown in monolayers and incubated with IFN-γ before exposure with C. parvum . IFN-γ receptor expression in the cell lines was determined by Western blot analysis. Results: IFN-γ inhibited C. parvum infection of both HT-29 and Caco-2 cells but not H4 cells. Response to IFN-γ was related to the expression of the IFN-γ receptor in the respective cell lines. The effect of IFN-γ was partially reversed by inhibition of the JAK/STAT signaling pathway. IFN-γ mediated its action by at least 2 mechanisms: (1) inhibition of parasite invasion and (2) by modification of intracellular Fe 2+ concentration. No role for tryptophan starvation or nitric oxide synthase activity was found. TNF-α and IL-1β also had anti– C. parvum activity but had no synergistic effect with IFN-γ. Conclusions: IFN-γ directly induces enterocyte resistance against C. parvum infection; this observation may have important consequences for our understanding of the mucosal immune response to invasive pathogens. GASTROENTEROLOGY 2001;120:99-107

Butyrate, a fermentation product of intestinal bacteria, modifies chromatin structure through histone acetylation, thereby altering gene transcription. EL-8 and MCP-1 are chemokines, expressed by intestinal epithelial cells, which attract neutrophils and monocytes, respectively. We hypothesized that butyrate may alter IL-8 and MCP-1 expression by intestinal epithelial cells through histone acetylation. IL-8 and MCP-1 expression was measured by ELISA and RNA transfer blots. Acetylated histones were separated on acetic acid-urea-triton gels. Butyrate was compared to Trichostatin-A, a specific inhibitor of histone deacetylase and to other short chain fatty acids. Caco-2 cells constitutively secreted MCP-1 but not IL-8. Butyrate reversibly decreased MCP-1 secretion. In contrast, butyrate increased IL-8 production. The effects of butyrate and Trichostatin-A were greater when cells were stimulated with EL-1β. Butyrate and Trichostatin-A both increased histone acetylation. Trichostatin-A and other short chain fatty acids altered chemokine secretion according to their effect on histone acetylation. Butyrate reversibly switches chemokine secretion by epithelial cells through histone acetylation. We speculate that butyrate carries information from resident bacteria to epithelial cells. Epithelial cells transduce this signal through histone acetylation, modulating the secretion of chemokines.

This review examines recent advances in the dietary modulation of gene expression in the gastrointestinal tract. We have chosen to concentrate on individual genes and examine what is known about their regulation, attempting to link different studies together.

VEGF (vascular endothelial growth factor) is a multifunctional cytokine active on blood vessel cells. The present study measured VEGF in the aqueous phase of human milk and examined how the concentration varied with gestational age and the duration of lactation after birth. We hypothesized that VEGF-specific receptors were present on the apical surface of intestinal epithelial cells. The concentration of monomeric VEGF (containing 165 residues) measured by ELISA in the breast milk was 2 orders of magnitude greater than that measured in the serum of normal adults. The VEGF165 concentration in the first week of lactation was greater in the breast milk of mothers of full-term than in preterm babies (p < 0.05). The concentration in the breast milk of mothers of full-term infants decreased (p < 0.01) after the first week of lactation. Scatchard analysis of radioligand-receptor binding showed the presence of specific receptors for 125I-VEGF165 on the surface of Caco-2, an intestinal epithelial cell line, with a kd of 2.85 to 4 nM. Reverse transcriptase PCR of Caco-2 cell RNA showed mRNA for the VEGF receptor flt-1. In conclusion, VEGF is present in high concentrations in breast milk and binds to specific receptors on cells derived from intestinal epithelium.

The final composition of leukocytes present in a site of inflammation in response to chemokine stimulation and activation may depend on both the nature of the secreted chemokines as well as the relative expression of the multitude of specific chemokine cell surface receptors on many different cell types. Because related receptors with different affinities and cross-reactive binding capabilities are present on each type of leukocyte, relative differences in receptor distribution and receptor affinity for specific chemokines may significantly influence which cells are ultimately attracted to and activated by each individual chemokine. Production of IL-8, MCP-1, and ENA-78 by endothelial cells, LPMNC, and epithelial cells in IBD could establish a chemotactic gradient capable of influencing the increased migration of monocytes/macrophages, granulocytes, and lymphocytes from the blood stream through the endothelium into both the mucosa and submucosa during chronic IBD. The ability of chemokines to induce chemotaxis, leukocyte activation, granule exocytosis, increased production of metalloenzymes, and up-regulation of respiratory burst activity indicates that there may be a variety of different mechanisms by which chemokines could markedly increase chronic inflammation and chronic intestinal tissue destruction in IBD.

Intestinal epithelial (Caco-2) cells secrete the chemokine, IL-8, after stimulation with IL-1beta, but not after lipopolysaccharide. Butyrate is a short chain fatty acid derived from the metabolism of intestinal contents by gut bacteria. Butyrate concentrations reflect, therefore, the bacterial microenvironment established within the intestine. We hypothesized that butyrate may alter the secretion of IL-8 by intestinal epithelial cells in response to stimulation by IL-1beta or lipopolysaccharide. Caco-2 cells were incubated in varying concentrations of sodium butyrate (0-20 mM) for 24 h before stimulation with lipopolysaccharide or IL-1beta. IL-8 secretion was measured over 24 h by ELISA. IL-8 mRNA accumulation was detected by Northern blots. Lipopolysaccharide induced the secretion of IL-8 only after Caco-2 cells cells had been cultured with sodium butyrate. Furthermore, butyrate significantly enhanced IL-8 secretion by cells stimulated with IL-1beta. Butyrate also increased IL-8 mRNA accumulation in stimulated Caco-2 cells. Intestinal epithelial cells can, therefore, be primed by butyrate to become activated by lipopolysaccharide and proinflammatory cytokines. This may represent a mechanism by which intestinal epithelial cells can regulate intestinal inflammation in response to changes in the intestinal milieu.

Gene expression is central to the pathogenesis of many disorders. An ability to alter the expression of genes would, if their relationship to disease processes were fully understood, constitute a new modality of treatment. This review examines the evidence that nutritional factors can regulate genes in the gastrointestinal epithelium and it discusses the physiological relevance of such alterations in gene expression. Dietary regulation of the genes expressed by the epithelium confers three fundamental advantages for mammals. It enables the epithelium to adapt to the luminal environment to digest and absorb food better; it provides the means whereby mother's milk can influence the development of the gastrointestinal tract; when the proteins expressed by the epithelium act on the immune system, it constitutes a signalling mechanism from the intestinal lumen to the body's defences. Each of these mechanisms is amenable to manipulation for therapeutic purposes.

Growth retardation, delayed puberty, decreased bone mass, altered bone architecture, hypovitaminosis D and skeletal muscle mass deficits are common in children with inflammatory bowel diseases. The Crohn's and Colitis Foundation of America sponsored a multidisciplinary workshop on the subject of Bone and Skeletal Growth in Pediatric IBD, held in New York City in November 2011. The topic of the workshop was a key recommendation of the Foundation's Pediatric Challenges meeting in 2005. The Litwin Foundation provided a generous grant to support this crucial research and workshop through the CCFA. The workshop featured 15 presentations by researchers from the United States, Canada, Switzerland, Germany, and the United Kingdom and a number of posters elucidating diverse aspects of the problem of growth retardation and compromised bone health in pediatric Crohn's disease and ulcerative colitis. The workshop comprised original, basic, and clinical research and relevant reviews of underlying genetics, molecular biology, endocrinology, immunology, and bone physiology research. Investigators funded by CCFA and the Litwin Family Foundation are marked by an asterisk after their name in the text. Workshop presentations fell under 3 broad categories: "Mechanisms of Suppression and Growth of Bone Cell Function by Inflammation," "Impact of IBD on Growth and Bone Health," and "Approaches to Address Growth Failure and Low Bone Mass in Children with IBD," summarized herein. We have cited the publications that resulted from this granting mechanism in the appropriate section and references for pertinent updates on each topic.