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.

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.

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.

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.

YouTube as a Source of Information for Food, Diet-Related Items, and Advisory Comments for the Management of Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) often use the Internet to seek information beyond that received from healthcare professionals. This study assessed the perceptions of YouTube presenters on the role of diet in the management of IBD. METHODS: Videos discussing dietary aspects (food, diet-related items, and advisory comments [FODRIACs]) in the management of IBD were included. The perceptions of presenters toward each FODRIAC were labeled as positive, negative, or neutral/intermediate, and FODRIACs were classified according to their underlying role in the management of IBD (eg, symptom management, gut inflammation). Subgroup analysis was performed by type of video presenter (patients vs healthcare professionals), type of IBD (Crohn's disease vs ulcerative colitis), and reporting of scientific evidence supporting presenters' perceptions. RESULTS: We identified 122 FODRIACs within 160 videos. Patient videos received a higher number of likes (median 85 [interquartile range, 35-156]) than healthcare professional videos (median 44 [interquartile range, 16-1440]) (P = .01). Scientific evidence was cited in 2 (3%) of 76 patient videos compared with 25 (35%) of 71 healthcare professional videos (P < .001). Positive perceptions were expressed about avocadoes, salmon, bananas, white bread, and rice, whereas negative perceptions were reported for processed, high-fat and high-sugar foods and carbonated drinks. Fewer negative perceptions were expressed in videos supported by scientific evidence than in videos that lacked evidence (scientific: 4 positive, 0 negative vs nonscientific: 7 positive, 20 negative; P = .01). CONCLUSIONS: We have identified FODRIACs proposed as beneficial or detrimental in the management of IBD. The effect this information has on dietary practice as patients with IBD self-manage their condition needs further exploration.

Take-Home Messages from 20 Years of Progress in Dietary Therapy of Inflammatory Bowel Disease.

BACKGROUND: A significant body of literature has interrogated the critical role of diet in the development and management of inflammatory bowel disease (IBD). SUMMARY: This review provides a summary and critical appraisal of the literature in this area, focussing on four distinct themes: nutritional epidemiology, animal and in vitro experiments, enteral nutrition, and food-based dietary therapies. KEY MESSAGES: Nutritional epidemiology and data from experiments in animals indicate that a western-type diet pattern is associated with increased risk of IBD onset. However, these findings have not been consistently replicated in the dietary management of IBD. Exclusive enteral nutrition (EEN) is the only dietary therapy with reproducible evidence of efficacy in the management of active Crohn's disease (CD). Use of EEN may also be useful for improving perioperative outcomes in CD, and as an adjuvant therapy to biologic therapy. Several dietary therapies for CD and ulcerative colitis have been proposed in the literature, but replication in well-controlled studies is needed before their routine use enters the clinical setting. Precision nutritional therapy might be an attractive therapeutic paradigm in a heterogenous disease like IBD. However, no recommendations for personalised dietary therapy can currently be made, and it is imperative we unravel the complex interplay between diet and gut inflammation before we are able to do so. Undoubtedly, diet is of critical importance in the development and management of IBD. However, the exact mechanism by which diet causes gut inflammation is still elusive, and dietary guidance is difficult to formulate.

Development and Validation of the Glasgow Exclusive Enteral Nutrition Index of Compliance.

BACKGROUND AND AIMS: Treatment adherence is key to the efficacy of exclusive enteral nutrition [100% EN] in active Crohn's disease [CD], but there are no biomarkers to objectively estimate this. We explored faecal parameters as biomarkers of compliance with 100% EN, and subsequently developed and validated the Glasgow Exclusive Enteral Nutrition Index of Compliance [GENIE]. METHODS: Healthy adults replaced all [100% EN] or part [85% EN, 50% EN, 20% EN] of their diet with a formula for 7 days. Faecal pH, water content, short chain fatty acids, and branched chain fatty acids [BCFAs] were measured before [D0] and after [D7] each intervention. Optimal biomarkers and threshold values were derived using receiver operating characteristic curve analyses and machine learning to develop the GENIE. The GENIE was then validated in 30 CD children, during and after 100% EN. RESULTS: In all, 61 adults were recruited. D7 faecal pH and the ratios of BCFAs to either acetate or butyrate performed the best to differentiate between patients on 100% EN from <100% EN. Two models were generated; one included faecal metabolites (Laboratory GENIE, L-GENIE; sensitivity, specificity, and positive predictive value [PPV] of 88%, 94%, and 92%) and a second one [Clinical Genie, C-GENIE] which considers only faecal pH [sensitivity, specificity, and PPV of 84%, 86%, and 81%]. Validation of GENIE in CD children found that C-GENIE outperformed L-GENIE, producing a sensitivity, specificity, and PPV of 85%, 88%, and 88%, respectively. CONCLUSIONS: GENIE can help predict adherence to 100% EN and may complement current conventional dietary assessment.

The Impact of Compliance During Exclusive Enteral Nutrition on Faecal Calprotectin in Children With Crohn Disease.

ABSTRACT: It remains unclear whether suboptimal response to exclusive enteral nutrition (EEN) in some children with Crohn disease (CD) is explained by poor compliance. The present study measured faecal gluten immunogenic peptides (GIP), a biomarker of gluten intake, in 45 children (3- 17 years) with CD, and explored associations with faecal calprotectin (FC) levels at 33 and 54 days of EEN. FC decreased in patients with undetectable GIP at both 33 and 54 days of EEN (mean decrease, 33 days: -743 mg/kg, 54 days: -1043 mg/kg, P  < 0.001) but not in patients who had detectable levels. At EEN completion, patients with undetectable GIP had a lower FC by 717 mg/kg compared with patients with a positive GIP result (P = 0.042) and demonstrated a greater decline from baseline FC (-69% vs +5%, P = 0.011). Poorer response to EEN is explained in part by diminished compliance. Faecal GIP might be useful as proxy biomarker of EEN compliance.

Microbiome and paediatric gut diseases.

In the human gut resides a vast community of microorganisms which perform critical functions for the maintenance of whole body homeostasis. Changes in the composition and function of this community, termed microbiome, are believed to provoke disease onset, including non-communicable diseases. In this review, we debate the current evidence on the role of the gut microbiome in the pathogenesis, outcomes and management of paediatric gut disease. We conclude that even though the gut microbiome is altered in paediatric inflammatory bowel disease, coeliac disease, intestinal failure, necrotising enterocolitis and irritable bowel syndrome, there are currently very few implications for unravelling disease pathogenesis or guiding clinical practice. In the future, the gut microbiome may aid in disease differential diagnosis and prediction of clinical outcomes, and comprise a target for therapeutic interventions.

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).

Diet and gut microbiota manipulation for the management of Crohn's disease and ulcerative colitis.

The aetiology of inflammatory bowel disease (IBD) is multifactorial, with diet and gut microbiota playing an important role. Nonetheless, there are very few studies, particularly clinical research, which have explored the interaction between diet and gut microbiota. In the current review, we summarise the evidence from clinical trials exploring the interactions between the gut microbiota and diet in the management of IBD. Data from the effect of exclusive enteral nutrition (EEN) on the gut microbiota of children with active Crohn's disease (CD), receiving induction treatment, offer opportunities to understand the role of gut microbiota in underlying disease pathogenesis and develop novel dietary and pharmacological microbial therapeutics. In contrast, the evidence which links the effectiveness of food-based dietary therapies for IBD with mechanisms involving the gut microbiota is far less convincing. The microbial signals arising from these dietary therapies are inconsistent and vary compared to the effects of effective treatment with EEN in CD.

Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells.

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE2-EP4 signaling modulates mucosal Treg responses and exacerbates intestinal inflammation. Mechanistically, PGE2-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE2-dependent Treg inhibition. Together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation.

Dietary Strategies for Maintenance of Clinical Remission in Inflammatory Bowel Diseases: Are We There Yet?

The etiopathogenesis of Inflammatory bowel disease (IBD) is a result of a complex interaction between host immune response, the gut microbiome and environmental factors, such as diet. Although scientific advances, with the use of biological medications, have revolutionized IBD treatment, the challenge for maintaining clinical remission and delaying clinical relapse is still present. As exclusive enteral nutrition has become a well-established treatment for the induction of remission in pediatric Crohn's disease, the scientific interest regarding diet in IBD is now focused on the development of follow-on dietary strategies, which aim to suppress colonic inflammation and delay a disease flare. The objective of this review is to present an extensive overview of the dietary strategies, which have been used in the literature to maintain clinical remission in both Crohn's disease and Ulcerative colitis, and the evidence surrounding the association of dietary components with clinical relapse. We also aim to provide study-related recommendations to be encompassed in future research studies aiming to investigate the role of diet during remission periods in IBD.

Analysis of 61 exclusive enteral nutrition formulas used in the management of active Crohn's disease-new insights into dietary disease triggers.

BACKGROUND: Exclusive enteral nutrition (EEN) is an effective treatment for Crohn's disease. AIMS: To investigate the hypothesis that ingredients of EEN formulas are unlikely to initiate a disease flare and that their dietary elimination is not essential for disease amelioration. METHODS: We performed compositional analysis of EEN formulas with evidence of efficacy in management of active Crohn's disease. Macronutrient content was compared against the dietary reference values (DRV), the UK National Diet and Nutrition Survey (NDNS) and intake of Crohn's disease children. Food additives were cross-referenced against the FAO/WHO database. RESULTS: Sixty-one formulas were identified with variable composition (carbohydrates [22.8%-89.3%], protein [7.8%-30.1%], fat [0%-52.5%]). Maltodextrin, milk protein and vegetable/plant oils were the commonest macronutrient sources. Their n-6:n-3 fatty acid ratio varied from 0.25 to 46.5. 56 food additives were identified (median per formula: 11). All formulas were lactose-free, gluten-free, and 82% lacked fibre. The commonest food additives were emulsifiers, stabilisers, antioxidants, acidity regulators and thickeners. Food additives, implicated in Crohn's disease aetiology, were present in formulas (modified starches [100%], carrageenan [22%], carboxymethyl cellulose [13%] and polysorbate 80 [5%]). Remission rates did not differ between EEN formulas with and without those food additives. Analysis including only formulas from randomised controlled trials (RCTs) retained in the latest Cochrane meta-analysis produced similar findings. EEN formulas contained less energy from saturated fat than NDNS intake. CONCLUSION: We have identified food ingredients which are present in EEN formulas that are effective in Crohn's disease and challenge perceptions that these ingredients might be harmful.