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Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD.As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters.DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota.Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (

Background & Aims Increased intestinal permeability has been associated with Crohn’s disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. Methods We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6–35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. Results An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64–5.63; P = 3.97 × 10–4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051–2.50; P = .029). Conclusions Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.

BackgroundStatural growth impairment is more common in males with Crohn’s disease (CD). We assessed sex differences in height Z score differences and bone age (BA) Z scores and characterized age of menarche in a novel contemporary cohort of pediatric CD patients undergoing screening for enrollment in the multicenter longitudinal Growth Study.MethodsCrohn’s disease patients (females with chronological age [CA] 5 years and older and younger than 14 years; males with CA 6 years and older and younger than 16 years) participated in a screening visit for the Growth Study. Height BA-Z scores are height Z scores calculated based on BA. Height CA-Z scores are height Z scores calculated based on CA. The height Z score difference equals height CA-Z score minus height BA-Z score.ResultsOne hundred seventy-one patients (60% male) qualified for this analysis. Mean CA was 12.2 years. Mean height CA-Z score was −0.4, and mean height BA-Z score was 0.4 in females. Mean height CA-Z score was −0.1, and mean height BA-Z score was 0.2 in males. The absolute value of the mean height Z score difference was significantly greater in females (0.8) than males (0.3; P = 0.005). The mean BA-Z score in females (−1.0) was significantly lower than in males (−0.2; P = 0.002). The median CA at menarche was 13.6 (95% CI, 12.6–14.6) years.ConclusionsOur screening visit data suggest that standardized height gain is lower in males with skeletal maturation and delayed puberty is common in females in CD. We are investigating these findings in the ongoing Growth Study.

Background: Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). Methods: Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. Results: The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P < 0.01) within 90 days, but variation was not significant over a 3-year period (P = 0.13). Early anti-tumor necrosis factor (anti-TNF) exposure (within 90 days) varied from 2.1% to 65.7% (P < 0.01), but variation was not significant over a 3-year period (P > 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. Conclusions: Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care.

BACKGROUND: Vitamin D regulates intestinal epithelial and immune functions, and vitamin D receptor deficiency increases the severity of murine colitis. Bioavailable 25-hydroxyvitamin D (25(OH)D) is available to target tissues and may be a driver of immune function. The aim is to evaluate the relationship of bioavailable 25(OH)D to the clinical expression of treatment naive pediatric ulcerative colitis (UC). METHODS: The PROTECT (Predicting Response to Standardized Pediatric Colitis Therapy) study enrolled children ≤17 years newly diagnosed with UC. Free and total 25(OH)D were directly measured and 25(OH)D fractions were compared with disease activity measures. RESULTS: Data were available on 388 subjects, mean age 12.7 years, 49% female, 84% with extensive/pancolitis. The median (IQR) total 25(OH)D concentration was 28.5 (23.9, 34.8) ng/mL, and 57% of subjects demonstrated insufficient vitamin D status (25(OH)D < 30 ng/mL). We found no evidence of association between total 25(OH)D and disease activity. Regression models adjusted for age, sex, race, and ethnicity demonstrated that an increase from 25(th) to 75(th) percentile for bioavailable and free 25(OH)D were associated with a mean (95(th) CI) decrease in the Pediatric Ulcerative Colitis Activity Index (PUCAI) of -8.7 (-13.7, -3.6) and -3.1 (-5.0, -1.2), respectively. No associations were detected between 25(OH)D fractions and fecal calprotectin or Mayo endoscopy score. CONCLUSIONS: Vitamin D insufficiency is highly prevalent in children with newly diagnosed UC. We found associations of free and bioavailable, but not total 25(OH)D, with PUCAI. Bioavailable vitamin D may contribute to UC pathophysiology and clinical activity.

Background Long noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA. Methods Using RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RNA in situ hybridization was used to validate expression. Real-time polymerase chain reaction was used to test lncRNA regulation by IL-1β in Caco-2 enterocytes. Results We characterize widespread dysregulation of 459 lncRNAs in the ileum of CD patients. Using only the lncRNA in discovery and independent validation cohorts showed patient classification as accurate as the protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types 1showed that the upregulated LINC01272 is associated with a myeloid pro-inflammatory signature, whereas the downregulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We confirmed tissue-specific expression in biopsies using in situ hybridization, and validated regulation of prioritized lncRNA upon IL-1β exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury. Conclusions We systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.

Article first published online 27 March 2015., Background: Crohn's disease (CD) is associated with depression. It is unclear if psychosocial interventions offer benefit for depressive symptoms during active CD. In this secondary analysis of a larger study of treating depression in pediatric inflammatory bowel disease, we assessed whether cognitive behavioral therapy (CBT) would differentiate from supportive nondirective therapy in treating depression and disease activity in youth with CD. We also explored whether somatic depressive symptoms showed a different pattern of response in the overall sample and the subset with active inflammatory bowel disease. Methods: Youth with depression and CD (n = 161) were randomized to 3 months of CBT (teaching coping skills) or supportive nondirective therapy (supportive listening). Depressive severity was measured using the Children's Depression Rating Scale-Revised (CDRS-R) with the somatic depressive subtype consisting of those CDRS-R items, which significantly correlated with CD activity. Disease activity was measured by the Pediatric Crohn's disease Activity Index. Given the potential confound of higher dose steroids, subanalyses excluded subjects on >20 mg/d prednisone equivalent (n = 34). Results: Total CDRS-R scores in the overall sample significantly decreased over time after both treatments (P < 0.0001). Treatment with CBT was associated with a significantly greater improvement in the Pediatric Crohn's disease Activity Index (P = 0.05) and somatic depressive subtype (P = 0.03) in those with active inflammatory bowel disease (n = 95) compared with supportive nondirective therapy. After excluding those on steroids (n = 34), there was a significant improvement in total CDRS-R (P = 0.03) and in Pediatric Crohn's disease Activity Index (P = 0.03) after CBT. Conclusions: Psychotherapy may be a useful adjunct to treat depression in the context of CD-related inflammation in youth who are not concurrently on higher dose steroids.

Summary Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10–0·89; p=0·0296) but not stricturing complication (1·13, 0·51–2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12–2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. Funding Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.

Background: The Pediatric Crohn’s Disease Activity Index (PCDAI) has become the standard outcome measure in pediatric Crohn’s disease (CD) clinical research. Other versions have been proposed but without systematic evaluation. The aim was to assess validity and responsiveness of the abbreviated PCDAI (abbrPCDAI), short PCDAI (shPCDAI), and modified PCDAI (modPCDAI) as measures of disease activity and to compare these with a mathematically weighted version developed here (wPCDAI). Methods: The raw data from four prospectively collected datasets were used, totaling 437 children with CD (including two clinical trials). Discriminant validity utilized physician global assessment of disease activity (PGA), and construct validity the correlation with PGA and laboratory results. Feasibility and face validity were ascertained by a survey of 33 experts in pediatric CD. Results: The wPCDAI had better performance than the PCDAI in construct validity and responsiveness and it discriminated better between the disease activity categories (area under the receiver operator characteristic [ROC] 0.97; 95% confidence interval [CI]: 0.95–0.99). In comparison to the original PCDAI, the noninvasive versions (abbrPCDAI and shPCDAI) had lower face, construct, and discriminant validity but were judged to be significantly more feasible. The modPCDAI performed well in the construct validation but was consistently inferior in all other parameters. Cutoffs that correspond to remission, response, and gradations of disease activity were determined for each index. Conclusions: The newly weighted wPCDAI performed better than the original PCDAI and is more feasible. The noninvasive versions (shPCDAI and abbrPCDAI) are inferior to the full PCDAI, but when needed in retrospective studies either may be equally used.

Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), are chronic and debilitating conditions with unpredictable courses and complicated treatment. Pediatric IBD carries implications that extend beyond the health of the gastrointestinal tract. When these lifelong illnesses are diagnosed during adolescence, a critical developmental period, the transition to adulthood can be even more turbulent. Like other chronic diseases of childhood, patients with IBD are at risk for depression, anxiety, social isolation, and altered self-image, which can all negatively affect health-related quality of life (HRQOL). The review will draw from pertinent adult and pediatric literature about HRQOL over the past 10 years using a PubMed literature search to summarize instruments with which HRQOL is measured, and address factors that affect HRQOL in adolescents and young adults with IBD. Psychosocial interventions that have been utilized to improve quality of life in this population will also be covered. Identifying patients with impaired quality of life is of paramount importance, as is implementing strategies that may improve HRQOL, so that they may have an easier transition to adulthood while living with IBD.

Patients with Crohn’s disease are at risk for developing both internal and external fistulae. These can be asymptomatic incidental radiologic findings or causes of incontinence, chronic pain, abscesses, and sepsis. They can have a devastating impact on quality of life. Careful prospective studies of therapy are few in adult medicine and entirely lacking in the pediatric age group. Assessment and management require a coordinated effort between gastroenterologist, radiologist, and surgeon. Principles of management include surgical drainage of infection combined with medical therapy. Only infliximab has been studied in prospective, double-blinded fashion and clearly shown to be of use in the short term. There is good evidence that metronidazole may be useful acutely and that 6-mercaptopurine azathioprine may help to maintain closure. Diverting ostomies are of very limited value and corticosteroids seem to make matters worse. There are many other therapies that have been reported to be helpful in small, uncontrolled studies.