An update on dietary therapies in paediatric Crohn's disease.

PURPOSE OF REVIEW: This article provides a literature update on original articles published in the past 18 months (May 2022-November 2023) in the dietary management of paediatric Crohn's disease. RECENT FINDINGS: There is more data to support the use of exclusive enteral nutrition in the management of active Crohn's disease in children. Several food-based dietary therapies have been proposed for the management of Crohn's disease. There is an interest in precision nutritional therapy in Crohn's disease, but current data are scarce. SUMMARY: Exclusive enteral nutrition is an effective treatment for paediatric Crohn's disease. Predictors of response to exclusive enteral nutrition include mild disease phenotype and ileal disease involvement, although data remain inconclusive. Adherence to exclusive enteral nutrition is cornerstone to its efficacy. Treatment with exclusive enteral nutrition modifies the gut microbiome, modulates bile acid metabolism and has significant effects on host immune responses. More studies are expected in which drugs need to be combined with dietary therapies and microbial therapeutics. The efficacy of Crohn's disease exclusion diet coupled with partial enteral nutrition is supported by independent studies, but tolerance remains an issue, particularly for long-term disease management. More research is anticipated in precision nutritional therapy in paediatric Crohn's disease, but currently no recommendations can be made.

Clinical performance of the infant nutrition early warning score in routine practice across four international clinical settings in Europe: A study by the ESPGHAN special interest group in clinical malnutrition.

There is a scarcity of nutritional screening tools for use in infants (<1 year). The infant Nutrition Early Warning Score (iNEWS) has been developed to identify infants who need further dietetic review. We introduced the iNEWS into clinical practice and evaluated its performance in Scotland, Belgium, Athens and Bulgaria. Of the 352 infants screened, 72 (20%) were placed in the high iNEWS category, and of these, 70 (97%) were reviewed by a hospital dietitian. iNEWS produced a true positive rate of 80% which increased to 96% after accounting for anticipated misclassified cases due to prematurity. In Belgium, false positive screens had a shorter length of stay (p = 0.014). Otherwise, misclassification was not related to a specific iNEWS component. This study corroborates previous research, underscoring the validity of iNEWS as a dietetic referral tool and demonstrating that it can be integrated into "real-world" clinical practice across international settings with diverse healthcare resources.

Exclusive enteral nutrition impacts peripheral blood mononuclear cell profile of children with Crohn's disease.

The immunological effects of exclusive enteral nutrition (EEN) in the treatment of active Crohn's disease (CD) are yet to be unveiled. The present study investigated changes in peripheral blood mononuclear cell profiles in children with active CD following 8-week treatment with EEN. In nine children, EEN significantly decreased the number and frequency of circulating effector memory CD8+ T cells re-expressing CD45RA, with corresponding increases observed in the frequency of circulating central and effector memory CD8+ T cells. These signals were conserved when looking at a subgroup of patients who achieved remission, and another who demonstrated the highest level of compliance to EEN. We speculate that the increases in circulating central and effector memory CD8+ T cells may be related to the extensive microbiome-modifying effects of EEN dampening immune response within the gastrointestinal tract.

Anthropometric assessment: ESPGHAN quality of care survey from paediatric hospitals in 28 European countries.

OBJECTIVES: Assessment of anthropometric data is essential for paediatric healthcare. We surveyed the implementation of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) evidence-based guidelines and practical recommendations on nutritional care, particularly regarding anthropometric measurements. METHODS: Paediatric hospitals from 28 European countries provided pseudonymized data through online questionnaires on hospital characteristics and their standards of nutritional care. Practical tasks assessed an unbiased collection and reporting of anthropometric measurements in random patients' files and discharge letters. RESULTS: Of 114 hospitals (67% academic), 9% have no nutritionist/dietitian available, 18% do not provide standard policy to assess weight and height and 15% lack training for nursing staff for accurate performance. A wall-mounted stadiometer to measure standing height and equipment for sitting weight is unavailable in 9% and 32%, respectively. Infant length is measured by one instead of two healthcare professionals and with a tape instead of a rigid length measuring board in 58% and 15% of hospitals, respectively. The practical tasks reviewed 1414 random patients, thereof 446 younger than 2 years of age. Missing documentation occurred significantly more often for height versus weight and their percentiles in infants ≤2 years versus older children, and in general paediatric versus gastrointestinal patients, with no difference between academic and nonacademic hospitals. Review of documented anthropometric data in discharge letters disclosed that consultants significantly underestimated the deficits in their units compared to documented data. CONCLUSIONS: The survey revealed significant gaps in performance and documentation of anthropometry in the participating hospitals. A resurvey will assess changes in quality of care over time.

Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals.

Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food-based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre- and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single-nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non-colonic CD, mild-to-moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required.

CViewer: a Java-based statistical framework for integration of shotgun metagenomics with other omics datasets.

BACKGROUND: Shotgun metagenomics for microbial community survey recovers enormous amount of information for microbial genomes that include their abundances, taxonomic, and phylogenetic information, as well as their genomic makeup, the latter of which then helps retrieve their function based on annotated gene products, mRNA, protein, and metabolites. Within the context of a specific hypothesis, additional modalities are often included, to give host-microbiome interaction. For example, in human-associated microbiome projects, it has become increasingly common to include host immunology through flow cytometry. Whilst there are plenty of software approaches available, some that utilize marker-based and assembly-based approaches, for downstream statistical analyses, there is still a dearth of statistical tools that help consolidate all such information in a single platform. By virtue of stringent computational requirements, the statistical workflow is often passive with limited visual exploration. RESULTS: In this study, we have developed a Java-based statistical framework ( https://github.com/KociOrges/cviewer ) to explore shotgun metagenomics data, which integrates seamlessly with conventional pipelines and offers exploratory as well as hypothesis-driven analyses. The end product is a highly interactive toolkit with a multiple document interface, which makes it easier for a person without specialized knowledge to perform analysis of multiomics datasets and unravel biologically relevant patterns. We have designed algorithms based on frequently used numerical ecology and machine learning principles, with value-driven from integrated omics tools which not only find correlations amongst different datasets but also provide discrimination based on case-control relationships. CONCLUSIONS: CViewer was used to analyse two distinct metagenomic datasets with varying complexities. These include a dietary intervention study to understand Crohn's disease changes during a dietary treatment to include remission, as well as a gut microbiome profile for an obesity dataset comparing subjects who suffer from obesity of different aetiologies and against controls who were lean. Complete analyses of both studies in CViewer then provide very powerful mechanistic insights that corroborate with the published literature and demonstrate its full potential. Video Abstract.

Perceptions Toward Established and Novel Dietary Therapies for Crohn's Disease Management Among Adult Patients: Results From a Questionnaire Survey.

Background: Exclusive enteral nutrition (EEN) and partial enteral nutrition (PEN) remain the only established dietary therapies in Crohn's disease (CD) management. We conducted a questionnaire survey to evaluate the perceptions of adults with CD toward established and emerging food-based dietary therapies. Methods: A 26-question anonymous survey was mailed to 300 adults receiving biologic treatment. Two researchers independently conducted a thematic analysis of open-ended responses. Machine learning with the Random Forest-Recursive Feature Elimination algorithm identified predictors of willingness to try dietary therapies. Results: One hundred and sixty patients (53% female) completed and returned the survey. Forty-two percent were following some form of exclusion diet, with low-spice and low-fiber diets being the most popular. Although only a quarter of patients believed that EEN/PEN could help with their CD, more than half believed that diet could help, with another 13% already using diet for CD management. While half of the patients were willing to try EEN, the majority were willing to try PEN instead (51% vs. 79%; P < .001). Forty-two percent of patients preferred food-based dietary plans prepared at home over EEN/PEN options. The most important predictors for willingness to try dietary therapies were age (25-65 years), recent symptoms, previous exposure to EEN/PEN, and current exclusion diet use. The top concerns about PEN were taste/palatability, satiety/hunger, and taste fatigue. Conclusions: Most adults preferred to follow a food-based dietary therapy over EEN/PEN. The majority would try PEN though which allows for more flexibility to incorporate in habitual diet and may be easier to comply with than the EEN.

Dose-dependent effects of enteral nutrition on the faecal microbiota and short chain fatty acids.

INTRODUCTION: Enteral nutrition (EN) involves replacing all or part of a person's habitual diet with a nutritional formula. The impact of varying doses of EN on the gut microbiome remains understudied. METHODS: Healthy adults replaced all (100% EN) or part (85% EN, 50% EN and 20% EN) of their energy requirements with EN for 7 days. Faecal samples were collected before and on day 7 of interventions. Faecal pH, short chain fatty acids (SCFAs), branched-chain fatty acids (BCFAs) and 16S rRNA sequencing were performed. Dietary assessment was performed with 7-day food diaries. RESULTS: Sixty-one participants (31 females; median (IQR) age: 24.7 (23.0-27.8) years) were recruited. A dose-dependent impact of EN on faecal microbiota, SCFAs, BCFAs) and pH was observed, with changes detectable at EN intakes of at least 50% of energy requirements. 100% and 85% EN reduced the abundance of fibre-fermenting taxa such as Agathobacter, Faecalibaterium, Succinivibrio and Acidaminococcus. In parallel, potentially harmful organisms like Eubacterium, Actinomyces, and Klebsiella increased. In the 50% EN group, adherence to a diet high in fish, vegetables, potatoes, non-alcoholic beverages, and fat spreads, and low in cereal products, milk, and meat negatively correlated with changes in microbiota structure (r = -0.75, P = 0.025). This signal was not observed when using compositional tools for microbiota analysis. CONCLUSIONS: EN detrimentally influences the faecal microbiota and diet-related bacterial metabolites in a dose-dependent manner, particularly at doses of at least 50%. The findings of this study have implications for the dietary management and counselling of patients receiving high volume EN.

Inflammation-related Proteins Support Diagnosis of Inflammatory Bowel Disease and Are Modified by Exclusive Enteral Nutrition in Children With Crohn's Disease, Especially of Ileal Phenotype.

BACKGROUND: The immunological effects of treatment with exclusive enteral nutrition (EEN) in Crohn's disease (CD) remain unknown. We characterized the plasma levels of inflammation-related proteins (IRPs) in children with CD and ulcerative colitis (UC) compared with noninflammatory controls (non-IBD) and explored the effect of EEN in CD. METHODS: Ninety-two IRPs were quantified using Olink proteomics in children with CD (n = 53), UC (n = 11), and non-IBD (n = 19). For 18 children with active CD, IRPs were measured before and after 8 weeks of EEN. Relationships with disease phenotype and response to EEN were studied. RESULTS: Compared with non-IBD, patients with active UC and CD had different levels of 27 (24 raised, 3 decreased) and 29 (26 raised, 3 decreased) IRPs, respectively. Exclusive enteral nutrition modified the levels of 19 IRPs (13 increased, 6 decreased including CCL23, interleukin-24, interleukin-6, and MMP-1). More pronounced changes in IRP profile were observed in patients with ileal involvement and a ≥50% decrease in fecal calprotectin during EEN compared with those with colonic involvement and a <50% decrease in fecal calprotectin, respectively. A machine-learning model utilizing baseline IRP profile predicted response to EEN with a sensitivity of 89%, specificity of 57%, and accuracy of 73%. Thymic stromal lymphopoietin was the most important IRP in the model, this being higher in responders. CONCLUSIONS: Inflammation-related proteins may be useful in the differential diagnosis of IBD. Exclusive enteral nutrition extensively modulated IRPs levels in children with active CD with more pronounced effects observed in patients who showed a reduction in FC and had ileal disease involvement.

Plasma inflammation-related proteins are altered in children with inflammatory bowel disease. In active Crohn's disease, exclusive enteral nutrition modified several of these proteins, particularly in disease involving the ileum and in patients whose fecal calprotectin levels significantly decreased.

Treatment of Active Crohn's Disease With Exclusive Enteral Nutrition Diminishes the Immunostimulatory Potential of Fecal Microbial Products.

BACKGROUND: Exclusive enteral nutrition (EEN) is an effective treatment for active Crohn's disease (CD). This study explored the immunostimulatory potential of a cell-free fecal filtrate and related this with changes in the fecal microbiota and metabolites in children with active CD undertaking treatment with EEN. METHODS: Production of tumor necrosis factor α (TNFα) from peripheral blood mononuclear cells was measured following their stimulation with cell-free fecal slurries from children with CD, before, during, and at completion of EEN. The metabolomic profile of the feces used was quantified using proton nuclear magnetic resonance and their microbiota composition with 16S ribosomal RNA sequencing. RESULTS: Following treatment with EEN, 8 (72%) of 11 patients demonstrated a reduction in fecal calprotectin (FC) >50% and were subsequently labeled FC responders. In this subgroup, TNFα production from peripheral blood mononuclear cells was reduced during EEN (P = .008) and reached levels like healthy control subjects. In parallel to these changes, the fecal concentrations of acetate, butyrate, propionate, choline, and uracil significantly decreased in FC responders, and p-cresol significantly increased. At EEN completion, TNFα production from peripheral blood mononuclear cells was positively correlated with butyrate (rho = 0.70; P = .016). Microbiota structure (ß diversity) was influenced by EEN treatment, and a total of 28 microbial taxa changed significantly in fecal calprotectin responders. At EEN completion, TNFα production positively correlated with the abundance of fiber fermenters from Lachnospiraceae_UCG-004 and Faecalibacterium prausnitzii and negatively with Hungatella and Eisenbergiella tayi. CONCLUSIONS: This study offers proof-of concept data to suggest that the efficacy of EEN may result from modulation of diet-dependent microbes and their products that cause inflammation in patients with CD.

Treatment of active Crohn's disease with exclusive enteral nutrition diminishes the proinflammatory potential of fecal microbial components, hence suggesting a mechanism of action involving modulation of diet-dependent microbes and their products that cause gut inflammation.

Serum Metabolites Relate to Mucosal and Transmural Inflammation in Pediatric Crohn Disease.

BACKGROUND AND AIMS: We aimed to identify serum metabolites associated with mucosal and transmural inflammation in pediatric Crohn disease (pCD). METHODS: Fifty-six pCD patients were included through a pre-planned sub-study of the multicenter, prospective, ImageKids cohort, designed to develop the Pediatric Inflammatory Crohn's MRE Index (PICMI). Children were included throughout their disease course when undergoing ileocolonoscopy and magnetic resonance enterography (MRE) and followed for 18 months when MRE was repeated. Serum metabolites were identified using liquid chromatography/mass spectroscopy. Outcomes included: PICMI, the simple endoscopic score (SES), faecal calprotectin (FCP), and C-reactive protein (CRP), to assess transmural, mucosal, and systemic inflammation, respectively. Random forest models were built by outcome. Maximum relevance minimum redundancy (mRMR) feature selection with a j-fold cross validation scheme identified the best subset of features and hyperparameter settings. RESULTS: Tryptophan and glutarylcarnitine were the top common mRMR metabolites linked to pCD inflammation. Random forest models established that amino acids and amines were among the most influential metabolites for predicting transmural and mucosal inflammation. Predictive models performed well, each with an area under the curve (AUC) > 70%. In addition, serum metabolites linked with pCD inflammation mainly related to perturbations in citrate cycle (TCA cycle), aminoacyl-tRNA biosynthesis, tryptophan metabolism, butanoate metabolism, and tyrosine metabolism. CONCLUSIONS: We extend on recent studies, observing differences in serum metabolite between healthy controls and Crohn disease patients, and suggest various associations of serum metabolites with transmural and mucosal inflammation. These metabolites could improve the understanding of pCD pathogenesis and assess disease severity.

Gut metabolome and microbiota signatures predict response to treatment with exclusive enteral nutrition in a prospective study in children with active Crohn's disease.

BACKGROUND: Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization. OBJECTIVES: This study aimed to explore the ability of pretreatment parameters to predict fecal calprotectin (FCal) levels at EEN completion in a prospective study in children with CD. METHODS: In children with active CD, clinical parameters, dietary intake, cytokines, inflammation-related blood proteomics, and diet-related metabolites, metabolomics and microbiota in feces, were measured before initiation of 8 wk of EEN. Prediction of FCal levels at EEN completion was performed using machine learning. Data are presented with medians (IQR). RESULTS: Of 37 patients recruited, 15 responded (FCal < 250 µg/g) to EEN (responders) and 22 did not (nonresponders). Clinical and immunological parameters were not associated with response to EEN. Responders had lesser (µmol/g) butyrate [responders: 13.2 (8.63-18.4) compared with nonresponders: 22.3 (12.0-32.0); P = 0.03], acetate [responders: 49.9 (46.4-68.4) compared with nonresponders: 70.4 (57.0-95.5); P = 0.027], phenylacetate [responders: 0.175 (0.013-0.611) compared with nonresponders: 0.943 (0.438-1.35); P = 0.021], and a higher microbiota richness [315 (269-347) compared with nonresponders: 243 (205-297); P = 0.015] in feces than nonresponders. Responders consumed (portions/1000 kcal/d) more confectionery products [responders: 0.55 (0.38-0.72) compared with nonresponders: 0.19 (0.01-0.38); P = 0.045]. A multicomponent model using fecal parameters, dietary data, and clinical and immunological parameters predicted response to EEN with 78% accuracy (sensitivity: 80%; specificity: 77%; positive predictive value: 71%; negative predictive value: 85%). Higher taxon abundance from Ruminococcaceae, Lachnospiraceae, and Bacteroides and phenylacetate, butyrate, and acetate were the most influential variables in predicting lack of response to EEN. CONCLUSIONS: We identify microbial signals and diet-related metabolites in feces, which could comprise targets for pretreatment optimization and personalized nutritional therapy in pediatric CD.