Dietary triggers of gut inflammation following exclusive enteral nutrition in children with Crohn's disease: a pilot study.

BACKGROUND: The anti-inflammatory effect of exclusive enteral nutrition on the gut of children with Crohn's disease is rapidly lost after food reintroduction. This study assessed disease dietary triggers following successful treatment with exclusive enteral nutrition. METHODS: Nutrient intake, dietary patterns and dietary biomarkers in faeces (gluten immunogenic peptides, undigestible starch, short chain fatty acids) were assessed in 14 children with Crohn's disease during early food reintroduction, following exclusive enteral nutrition. Groups above (Group A) and below (Group B) the median levels of faecal calprotectin after food reintroduction were assigned for comparative analysis. RESULTS: Intakes of fibre, gluten-containing cereals and red and processed meat were significantly higher in Group A than Group B; (median [Q1, Q3], g/day; Fibre: 12.1 [11.2, 19.9] vs. 9.9 [7.6, 12.1], p = 0.03; Red and processed meat: 151 [66.7, 190] vs. 63.3 [21.7, 67], p = 0.02; gluten-containing cereals: 289 [207, 402] vs. 203 [61, 232], p = 0.035). A diet consisting of cereals and meat products was predictive (92% accuracy) of higher faecal calprotectin levels after food reintroduction. In faeces, butyrate levels, expressed as absolute concentration and relative abundance, were higher in Group A than Group B by 28.4 µmol/g (p = 0.015) and 6.4% (p = 0.008), respectively. Levels of gluten immunogenic peptide and starch in faeces did not differ between the two groups. CONCLUSIONS: This pilot study identified potential dietary triggers of gut inflammation in children with Crohn's disease after food reintroduction following treatment with exclusive enteral nutrition. TRIAL REGISTRATION: Clinical trials.gov registration number: NCT02341248; Clinical trials.gov URL: https://clinicaltrials.gov/ct2/show/NCT02341248 (retrospectively registered).

Epstein-Barr Virus Status and Subsequent Thiopurine Exposure Within a Paediatric Inflammatory Bowel Disease Population.

ABSTRACT: The use of thiopurine therapy in Epstein-Barr virus (EBV)-naïve inflammatory bowel disease (IBD) patients remains controversial due to a risk of EBV-associated complications. We evaluated EBV status and outcomes within our paediatric IBD population over an 8-year period; finding that 217 of 409 (53%) screened patients were seropositive for EBV at IBD diagnosis; that thiopurines were used in 189 of 217 (87%) seropositive and 159 of 192 (83%) seronegative patients (P = 0.22); and that 7 of 192 (4%) previously seronegative patients subsequently tested positive for EBV with 6 of 7 (86%) patients having concurrently recorded thiopurine use. All six patients continued thiopurine with/without a period of cessation; no EBV-associated lymphoproliferative disorders/serious complications were recorded within our cohort. A significant proportion of our patients would not receive thiopurine therapy should their use be avoided in EBV-negative patients (47%) or seronegative males (30%). The small but significant risks of thiopurine treatment must be balanced against the potential benefits of successful IBD management; further research into this is required.

Prevalence of home parenteral nutrition in children.

BACKGROUND: Use of HPN in paediatrics in the UK has increased rapidly over the last 20 years but the prevalence of HPN has been challenging to define. Clinicians in the UK have noted an evolving complexity of cases and perceive improved outcomes and increased acceptability of long-term PN. These factors combined have the potential to increase the burden on existing paediatric gastroenterology services in the UK. METHODS: A national database was interrogated to define the prevalence of HPN in children in the UK and to explore outcomes for patients receiving HPN. RESULTS: Since 2015, 525 children were notified to the database; of these patients, mortality was <5% and intestinal transplant occurred in 1%. In 2019, 389 children received HPN in the UK; this is nearly double the number last reported in 2012 and is a prevalence of 30 per million children. Short bowel syndrome is the largest category of these patients. However, a poorly defined group including those with multisystem disease has increased 10 fold since 2012 and is now the second largest category. CONCLUSIONS: Long term HPN in childhood is safe and associated with good survival and low risk of the need for intestinal transplantation.

A Decade of Varicella Screening Within a Paediatric Inflammatory Bowel Disease Population.

INTRODUCTION: Increased risk of opportunistic infection-e.g., varicella zoster infection-secondary to therapies is a cause of morbidity in inflammatory bowel disease [IBD] patients. The UK vaccination schedule does not include varicella immunisation. We aimed to evaluate the varicella screening and immunisation programme in a paediatric IBD population. METHODS: Data regarding IBD diagnosis, varicella status, and consequent immunisations/treatment interventions were collected retrospectively from the records of patients diagnosed with IBD over a 10-year period [2009-2018]. RESULTS: In all, 520 IBD patients were diagnosed; 505/520 [97%] had varicella testing; 46/505 [9%] were naïve. Of 501 patients, 391[78%] were tested before or within 7 days of diagnosis; this increased in the second 5-year period compared with the first (229/268 [85%] versus 162/233 [70%]; p <0.00001). Median diagnosis age of naïve patients was lower [8.3 years versus 12.8 years; p <0.00001]. Where vaccination was feasible, 21/31 [68%] had two and 7/31 [23%] one immunisation. Prednisolone induction led to lower rates of vaccination (5/13 [39%] versus 23/33 [70%] for other induction therapies; p =0.02). Of 28 vaccinated patients, 5 [18%] had suspected breakthrough varicella; and 6/18 [33%] unimmunised patients required post-exposure prophylaxis or treatment for varicella. Immunisation was associated with a decrease in patients requiring post-exposure prophylaxis (0/28 [0%] versus 5/18 [28%]; p =0.0006) and varicella-related hospital admission (1/28 [4%] versus 4/18 [22%]; p =0.01). CONCLUSIONS: High rates of varicella screening and immunisation within a PIBD population are possible, resulting in a reduction in hospital admissions for varicella treatment. Varicella immunisation may be of increasing importance within the PIBD population with the emergence of novel therapeutic strategies.

Using a Steroid-sparing Tool in Paediatric Inflammatory Bowel Disease to Evaluate Steroid Use and Dependency.

OBJECTIVES: The aim of the study was to evaluate the use of steroids within the paediatric inflammatory bowel disease (PIBD) population at a tertiary paediatric centre over a year; to identify cases of steroid dependency; and assess factors associated with steroid excess. METHODS: The prevalent PIBD population (May 1, 2017-April 30, 2018) were reviewed. Data were collected retrospectively from patient records and entered into an online steroid assessment tool (modified for paediatrics). RESULTS: A total of 229 patients (181 Crohn disease, 31 ulcerative colitis [UC], and 17 inflammatory bowel disease-unclassified) were included. Of the 229 patients 38 (16.6%) received oral steroids; 12 of 38 (31.6%) receiving >3-month course. Eleven of 38 (28.9%) received >1 steroid course (maximum 2). Of the 229 patients 37 (16.2%) had exclusive enteral nutrition, with 26 of 37 (11.4% total cohort) avoiding steroid use during the study period.Quiescent disease activity had a negative correlation with steroid use (11/127 [8.7%] vs 27/102 [26.5%] P < 0.01), and steroid dependency (3/127 [2.4%] vs 12/102 [11.8%] P < 0.01). Patients with UC were more likely to be steroid dependent (5/31 [16.1%] UC vs 10/198 [5.1%]; P = 0.02); as were network-managed patients (8/11 [72.7%] vs 7/27 [25.9%]; P = 0.01). Fourteen of 15 (93.3%) of steroid-dependent patients had active steroid sparing strategies in place (eg, commencement, switching, or optimization of therapies). CONCLUSIONS: We have described rates of steroid use and dependency within our PIBD population. Exclusive enteral nutrition served as a steroid sparing tool in 11.4% of the total cohort. Replication of this study in other paediatric centres would allow comparative analysis.

The reduction of faecal calprotectin during exclusive enteral nutrition is lost rapidly after food re-introduction.

BACKGROUND: Faecal calprotectin decreases during exclusive enteral nutrition in children with active Crohn's disease. It is unknown how faecal calprotectin changes during food re-introduction and the influence of maintenance enteral nutrition. AIMS: To study changes to faecal calprotectin during exclusive enteral nutrition and at food reintroduction, and explore associations with maintenance enteral nutrition. METHODS: Children with Crohn's disease were followed during exclusive enteral nutrition and during food-reintroduction. Faecal calprotectin was measured before, at 33 and 54 days of exclusive enteral nutrition, and at 17, 52 and 72 days after food-reintroduction. Maintenance enteral nutrition use was recorded with estimated weight food diaries. Data are presented with medians and Q1:Q3. RESULTS: Sixty-six patients started exclusive enteral nutrition and 41 (62%) achieved clinical remission (weighted paediatric Crohn's disease activity index <12.5). Baseline faecal calprotectin (mg/kg) decreased after 4 and 8 weeks of exclusive enteral nutrition (Start: 1433 [Q1: 946, Q3: 1820] vs 33 days: 844 [314, 1438] vs 54 days: 453 [165, 1100]; P < .001). Within 17 days of food reintroduction, faecal calprotectin increased to 953 [Q1: 519, Q3: 1611] and by 52 days to 1094 [660, 1625] (both P < .02). Fifteen of 41 (37%) children in remission used maintenance enteral nutrition (333 kcal or 18% of energy intake). At 17 days of food reintroduction, faecal calprotectin was lower in maintenance enteral nutrition users than non-users (651 [Q1: 271, Q3: 1781] vs 1238 [749, 2102], P = .049) and correlated inversely with maintenance enteral nutrition volume (rho: -0.573, P = .041), kcals (rho: -0.584, P = .036) and % energy intake (rho: -0.649, P = .016). Maintenance enteral nutrition use was not associated with longer periods of remission (P = .7). Faecal calprotectin at the end of exclusive enteral nutrition did not predict length of remission. CONCLUSIONS: The effect of exclusive enteral nutrition on faecal calprotectin is diminished early during food reintroduction. Maintenance enteral nutrition at ~18% of energy intake is associated with a lower faecal calprotectin at the early phase of food reintroduction but is ineffective in maintaining longer term remission.

The continued rise of paediatric home parenteral nutrition use: Implications for service and the improvement of longitudinal data collection.

BACKGROUND & AIMS: Robust data from the United Kingdom (UK) regarding the current epidemiology of patients with types II and III intestinal failure (IF; ≥28 day parenteral nutrition; home parenteral nutrition) are limited. We aimed to analyse trends in type II and III IF in children in the UK using historical and novel data. METHODS: A point survey of the 32 nutrition support teams that register patients with the British Intestinal Failure Survey was carried out in November 2012. Basic demographics for patients on home parenteral nutrition and receiving parenteral nutrition for ≥28 days were collected. Data were anonymised, collated by the registry coordinator and compared to previous surveys by the British Paediatric Surveillance Unit in 1993 and data from 2010. RESULTS: All 32 participating centres responded giving complete UK ascertainment. There were 195 type III patients, representing a four-fold increase since 1993. The proportion of patients with short bowel syndrome had almost doubled from 1993 (27% vs. 50% p = 0.001). The ratio of type II to type III IF patients varied considerably between centres. CONCLUSION: These data suggest that type III IF point prevalence has risen in the short term, coincident with individual centres' reporting improved survival in IF. Refinement in the methodology for prospective data collection is needed to gather more accurate incidence, period prevalence and outcome data for UK type II and type III IF.

Scottish outcomes for extra hepatic biliary atresia post-rationalisation of services.

AIMS: To evaluate the outcome of Scottish children with extra hepatic biliary atresia (EHBA) since rationalisation of Kasai services to three English centres in 2002 (The 'Group A' centres). METHODS: All Scottish children with EHBA diagnosed between 2002 and 2009 were identified via the Scottish Society of Paediatric Gastroenterology, Hepatology and Nutrition (SSPGHAN) clinicians. A case-note review was conducted with demographics, presentation and outcome data recorded. These data were compared with historical Scottish data and data published previously by the supraregional liver units. RESULTS: 25 patients were identified, of whom 22 were referred for Kasai in the group A centres, and of whom 19 had a Kasai. 2 year transplant-free survival (TFS) was significantly lower in the SSPGHAN 2002-2009 group than the group A centres in (1) (6/18 (33%) vs 36/57 (63%), p=0.023). CONCLUSIONS: These postrationalisation data are disappointing. The emphasis for care will now focus on improved communication between, primary care, general paediatricians and surgical centres through regional and national managed clinical networks, aiming to improve future outcomes for Scottish children with BA.

Use of stable isotopes to measure the metabolic activity of the human intestinal microbiota.

The human intestinal microbiota is a complex biological system comprising a vast repertoire of microbes with considerable metabolic activity relevant to both bacterial growth and host health. Greater strides have been made in the analysis of microbial diversity than in the measurement of functional activity, particularly in vivo. Stable isotope probing offers a new approach by coupling measurements of metabolic activity with microbial identification. Using a low-enrichment labeling strategy in vitro, this study has identified metabolically active bacterial groups via magnetic-bead capture methodology and stable isotope ratio analysis. Using five probes (EUB338, Bac303, Bif164, EREC482, and Clep866), changes in the activities of key intestinal microbial groups were successfully measured by exploiting tracers of de novo RNA synthesis. Perturbation of the nutrient source with oligofructose generated changes in the activity of bifidobacteria as expected, but also in the Bacteroides-Prevotella group, the Eubacterium rectale-Clostridium coccoides group, and the Clostridium leptum subgroup. Changes in activity were also observed in response to the medium type. This study suggests that changes in the functional activity of the gut microbiota can be assessed using tracers of de novo nucleic acid synthesis combined with measurement of low isotopic enrichment in 16S rRNA. Such tracers potentially limit substrate bias because they are universally available to bacteria. This low-enrichment labeling approach does not depend on the commercial availability of specific labeled substrates and can be easily translated to in vivo probing experiments of the functional activity of the microbiota in the human gut.

Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease.

OBJECTIVES: To assess the current evidence for the role of breastfeeding in the development of early onset inflammatory bowel disease (IBD) with a systematic review. STUDY DESIGN: An electronic database search was performed (January 1966-January 2008) with keywords related to IBD and breastfeeding, looking specifically for studies that reported outcome in early-onset disease (<16 years of age) and "any exposure" to breast milk as the variables. Meta-analysis of studies included for review was then performed by using a random effects model, and results were expressed as odds ratios (OR) with 95% CIs. RESULTS: A total of 79 articles were identified, 20 of which were found describing breastfeeding in relation to the development of IBD; 8 of these articles included separate early-onset groups. One study did not describe "any exposure" to breast milk for the early onset group, so 7 studies were included in the meta-analysis. Breast milk exposure had a significant protective effect (OR, 0.69; 95% CI, 0.51-0.94; P = .02) in developing early-onset IBD. A non-significant difference was demonstrated for ulcerative colitis and Crohn's disease individually (OR, 0.72; 95% CI, 0.51-1.02; P = .06; OR, 0.64; 95% CI, 0.38-1.07; P = .09, respectively). CONCLUSIONS: The current evidence demonstrates a possible protective effect for breast milk in the development of early onset IBD. However, the quality of existing data is generally poor. These findings need to be investigated in well-designed prospective studies.

What is the role of the metabolic activity of the gut microbiota in inflammatory bowel disease? Probing for answers with stable isotopes.

The pathogenesis of inflammatory bowel disease remains obscure. However, there has been increasing interest in the role of the gut microbiota, focusing in particular on the "unculturable majority" of luminal and mucosal bacteria, which until recently have been difficult to study owing to the technical challenges of identification and elucidating function. Bacterial components and metabolites have been implicated in signalling to host immune systems and regulating inflammatory responses. Although the rapid expansion in techniques of molecular microbiology has increased our understanding of bacterial diversity, the tools to assess bacterial metabolic activity, and to link the 2, lag behind. Stable isotope probing is a powerful technique to link the metabolic activity and diversity of "unculturable" bacteria through isotopic labelling of biomarkers such as DNA and RNA. Progression of current stable isotope probing methodology with high-resolution oligonucleotide 16s rRNA probe technology and high precision liquid chromatographic isotope ratio mass spectrometry may facilitate application in human microbial ecology. Progress towards stable isotope probing use in vivo, in concert with other advances in bacterial metabolome analysis, will lead to the development of a dynamic picture of the metabolic activity and diversity of intestinal bacteria in inflammatory bowel disease. Such insights will, over time, lead to fuller understanding of inflammatory bowel disease pathogenesis and the development of targeted therapies to reverse the "dysbiosis" that precedes disease relapse.

Probiotics for necrotizing enterocolitis: a systematic review.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most commonly acquired neonatal intraabdominal emergency and causes significant morbidity and mortality. A proposed strategy for the prevention of NEC is the administration of oral probiotics. Probiotics have been shown to reduce NEC in experimental rat models and have been used in clinical trials. The authors aimed to review the existing data on the use of oral probiotics for the prevention of NEC in preterm infants (age <33 weeks) and those with very low birth weight (VLBW). MATERIALS AND METHODS: Systematic review of randomized controlled trials (RCTs) and quasi-RCTs was performed to find outcome measures of incidence, severity, need for surgery, and mortality in NEC. Electronic searches were performed on Medline and CINAHL databases using key word and subject headings with combinations of the terms "infant, preterm"; "infant, VLBW"; "enterocolitis, necrotizing"; and "probiotics." In addition, citation searches were performed for all potential studies. RESULTS: Six potential RCTs were identified for inclusion, but there were no systematic or Cochrane database reviews identified. One study was discounted because of the use of historical controls, so 5 studies were selected for analysis. Cumulatively, 640 infants were treated with probiotics and 627 were used as control subjects. All of the studies showed a trend toward less NEC in the treatment group. The heterogeneity of probiotic formulations and the timing and methods of interventions in the identified studies made synthesis and comparison of data inappropriate. CONCLUSIONS: The data appear to lend support to the use of oral probiotics for the prevention of NEC in preterm infants and those with VLBW. However, the data are insufficient to comment on their short- and long-term safety. Type of probiotics used, as well as the timing and dosage, are still to be optimized. Further understanding of the pathogenesis of NEC and the mechanisms by which probiotics prevent it may lead to evidence-based treatment strategies.