Inflammatory bowel disease (IBD) is a complex systemic condition originating within the intestinal mucosal immune system of a genetically susceptible host and may be modified or driven by microbial interactions with intestinal contents. Foods may contribute to this pathophysiologic state; however, whether particular dietary components are necessary or sufficient to cause IBD is unknown. This report sets out to promote harmonization of dietary studies by encouraging authors to provide clarity—in the underlying dietary principle studied and the dietary intervention being applied—and reproducibility. High-quality dietary interventions will be defined by their ability to be scrutinized by investigators to verify outcomes and their ability to be adopted by practitioners to deliver to their patients.
Recent experiments with animal models suggest a significant role of dietary components. Examples of potential mechanisms include disruption of the intestinal mucous layer by emulsifiers and activation of inflammatory cascades by specific sulfur-producing bacteria (1,2). Recent identification of molecular mechanisms associated with the alteration of nutrient composition has invigorated the pursuit of nutritional therapy in children with IBD (3–10). Exclusive enteral nutrition (EEN), a therapy in which a patient consumes a defined formula-only diet and by definition excludes regular food from the intestinal lumen, can effectively induce remission in pediatric patients with Crohn disease (CD). Rates of endoscopic remission are superior (3,4) or equivalent (6–9) to those of corticosteroids, and rates of clinical remission are comparable to those achieved by anti-tumor necrosis factor - alpha medications (10). With a favorable side effect profile, EEN is a first-line therapy for pediatric patients with CD under guidelines endorsed by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organization (11). EEN, furthermore, does not increase the risk of serious infection or malignancy and confers several additional benefits, most notably improved linear growth (12) and bone health (13).
With the promise of nonpharmacological and nonsurgical interventions to treat IBD, dietary approaches have proliferated including the specific carbohydrate diet (SCD) (14,15), CD exclusion diet (CDED) (16), and anti-inflammatory diet (17). Naturally, individuals prefer to eat real food over a formula-only diet, and substantial barriers exist to the adoption of a formula-only approach (18–20). Challenges to food-based dietary interventions include the intervention itself may lack precision, as variety and variability among the diets are common, imprecise or unclear prescribing make it difficult to determine adherence to the prescribed diet, and a lack of a sound rationale for the therapeutic regimen. The assessment of treatment success is fraught with ambiguity. Lack of wider acceptance may be attributable to a poorly defined or misunderstood intervention, an incomplete provision of the intervention, and/or inadequately defined outcomes. In addition, the perceived benefits of dietary therapy can be deceiving. Symptoms arising from food-microbe-intestine interactions may reflect physiologic pathways germane to mucosal inflammation but also may reflect physiologic pathways that play no role in mucosal damage (eg, lactose intolerance, irritable bowel syndrome [IBS]). Clinical improvement without mucosal healing may foster an environment of short-term gains with long-term complications, a treatment paradigm from which our field has fought vigorously to escape. Despite these challenges, nutritional therapy holds great promise in pediatric IBD; it is imperative to critically appraise forthcoming publications and hold our field accountable to rigorous and thoughtful research.
Dietary Components and Inflammatory Bowel Disease Pathophysiology
The evidence for the role of ingested material in IBD pathophysiology is broad, albeit loosely connected. Animal models have revealed signals that dietary factors play a role in inflammatory pathways in the intestine. Dietary emulsifiers cause intestinal inflammation in susceptible mice through disruption of the epithelial mucous layer (1). Short-chain fatty acid production by colonic bacteria, fueled by dietary fiber, promotes T-regulatory cell homeostasis and protects against colitis in mice (21). The rise in incidence of IBD tracks with human populations consuming an industrialized diet replete with food additives and deficient in dietary fiber (22). A variety of dietary components have been implicated in the development of IBD in epidemiologic studies: increased total fat, polyunsaturated fat, omega-6 fatty acids, and red meat (23). High proportions of fruit, vegetables, and fiber have been associated with lower risk of IBD (23). Collectively, there appears to be opportunity to alter IBD course through dietary modification.
Defining “Nutrition Therapy”: Basics of a “Diet”
Fundamentally, studies that employ “diet-as-therapy” require precise characterization of the trial diet and the comparator diet. Unfortunately, this is not a readily achievable goal and is one of the greatest challenges to studying the relationship between diet and IBD. Diets can be characterized by their exact components and by the relative amounts of those components. Well-defined dietary interventions often rely on isolation of a putative pathogenic component, focusing on elimination (eg, gluten in celiac, cow's milk, and soy protein in food protein–induced proctocolitis), or reduction, with variable threshold tolerance (eg, FODMAPs in IBS, lactose in lactase deficiency). Components of a diet include identifiable macronutrients, micronutrients, additives, contaminants, and byproducts of preparation. In addition, unidentified dietary components may contribute. Any of those factors may constitute a unique food, be separated into modular components (eg, protein powder), or be synthesized into a defined formula. The delineation of dietary constituents and relative amounts of these components provide a primary basis upon which to build a dietary intervention; however, the interaction of these components with each other, including any contributions by microbial elements, may obscure their role in pathophysiology. Furthermore, the relative timing of ingestion, absorption, and metabolism of these components in isolation and in reference to each other might also play a central role. These factors hinder the ability to establish a causal role of a single dietary component in disease pathogenesis.
Dietary intervention in IBD has taken 3 primary forms: exclusion, modification, and supplementation. Exclusion relies upon the hypothesis that a dietary component(s) potentiates intestinal inflammation—examples include the SCD, CDED, and low sulfur diet. Modification relies upon a dietary principle that extends beyond simple elimination, factoring in contributions like consistency of enteral nutrient delivery (as in EEN) (24). Supplementation is the most attainable and has modest, if any, specific therapeutic effects (eg, vitamin D (25), curcumin (26)).
Eating is a fundamental aspect of being human. Nutritional therapies require significant alteration of personal and family lifestyle. Adherence is essential to the efficacy of any given therapeutic plan; lack of adherence threatens to obscure the true benefits nutritional therapy. Accurate assessment of adherence both in clinical research and clinical care is challenging but critical. The therapeutic environment, especially as it relates to auxiliary providers, that is, nutritionists, IBD nurses, pediatric psychologists, and other support colleagues, must be well-characterized as it is a crucial factor in the acceptance of any trial regimen.
Adherence to Nutrition Prescriptions
Measurement of successful treatment delivery has transformed the field of IBD during the era of infusion-based therapies in which patients receive both directly observed treatments and benefit from therapeutic drug monitoring. Dose manipulation to achieve targeted therapeutic levels preceded the biologics during the era of thiopurines, and the expectation of pairing clinical outcomes with monitoring of therapeutic delivery has become standard. These comprehensive approaches have helped us achieve our current levels of disease control, and nutritional therapy deserves an equivalent paradigm.
Conventional tools for assessment of dietary intake include food frequency questionnaires and 24-hour dietary recalls (both self-administered and facilitated by a dietitian). Web-based applications with direct entry have been developed, and smartphone, camera-enabled applications hold promise for accurate capture of plated nutrient composition (27). If the prescribed nutritional regimen is provided (as an investigational drug product would be in a pharmaceutical trial), measurement of food not consumed may offer a reliable method to determine adherence. Biomarker development also holds promise to aid adherence measurement, with plasma and urinary metabolomics as key areas for future study. For example, serum cholesterol esters and phospholipids have previously been validated to reflect dairy consumption (28). Dietary intake paired with metabolomic profiles may transform nutritional therapy clinical trials, just as investigational drugs are increasingly being paired with targeted biomarker assays during drug development, advancing therapeutic precision (29).
Nutrition to Alter Inflammatory Bowel Disease Pathophysiology
The most widely adopted dietary intervention is EEN. The mechanism by which EEN is effective is unclear, but its primary role appears to be the exclusion of some entity in the food supply (10). Other hypothesized mechanisms include limitation of antigen exposure, stabilization of intestinal permeability, nutrient repletion, and carbohydrate monotony (24). Although the delineation of microbiome-metabolome pathways in IBD continues to be refined (30), reduced microbial diversity has been associated with intestinal inflammation. Paradoxically EEN reduces intestinal microbial diversity and leads to lower short-chain fatty acid production and yet has a therapeutic effect (31). The promise of seemingly divergent dietary approaches (EEN in contrast to dietary exclusion of processed food) suggests complex or distinct mechanisms. An ordinary food diet designed to resemble the composition of the predominant formula used for EEN in Europe (Modulen), known as CD-TREAT, showed similar alterations in microbial and metabolic composition of healthy adults compared with EEN (32). CD-TREAT mimics EEN to the extent that it excludes gluten, lactose, alcohols, and provides recommended levels of macronutrients, vitamins, minerals, and fiber; in addition, it is better tolerated compared with formula by adults and children (32).
Whole food-based diets-as-therapy rely on principles of excluding specific components, generally related to food processing, from the diet. The SCD eliminates all grains, milk products (except hard cheese and fermented yogurt), legumes (except lentils, split peas), sweeteners (except honey), and all canned or processed foods. Clinical and endoscopic improvement with microbial alterations has been shown in small uncontrolled studies of the SCD (14,15,33).
The CDED excludes gluten, milk products, gluten-free baked goods, animal fat, emulsifiers, and all canned or processed foods. A randomized trial comparing CDED plus partial enteral nutrition of 50% formula to EEN demonstrated similar rates of steroid-free remission and CDED was better tolerated (16). Other diets that have received attention but limited data include the IBD anti-inflammatory diet, derived from the SCD with restriction of complex carbohydrates, gluten-based grains and starches and supplemented with prebiotics and probiotics (17), and the low FODMAP diet, which entails reduction of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (34). Targeted restriction may have no impact; reduced intake of red and processed meat, a strategy with support from model organism and epidemiological data, failed to maintain remission in patients with CD (35).
Nutritional Adequacy in Diet-as-therapy
Patients recognize that certain dietary components affect their disease and often avoid or limit what they perceive to be obvious triggers. This observation leads families to seek guidance in diet modification, and may provide a sense of control over their disease. Often, however, families receive the message that medical therapy is the only path and receive dietary guidance from outside the core medical team.
Without proper dietitian support, children are at risk of nutritional deficiency because exclusion of food groups, such as grains, milk and vegetables may lead to inadequate nutrient intake and micronutrient deficiencies (36). Growth failure, albeit of multifactorial etiology, is partly the result of nutritional inadequacy.
The nutritional inadequacy that results from restrictive eating habits before diagnosis can become compounded when dietary restriction is pursued as treatment. Elimination diets, while aiming to achieve clinical improvement, may foster orthorexia, with its attendant obsession with “healthy” dieting.
Deficiencies in iron, vitamin D, calcium, zinc, vitamin B12, folate, and protein occur in children with IBD and may worsen without proper oversight of nutritional therapy (37). Expert and intensive dietary counseling and follow-through may mitigate this risk. Direct provision of all meals, ensuring a nutritionally complete diet, may also abrogate this concern. The SCD in children has been shown to provide adequate intake of a majority of macro- and micronutrients compared with the intake of healthy volunteers (38). In any dietary approach, it is imperative that prescribed nutritional treatment plans ensure adequate intake of macro- and micronutrients and are paired with sufficient dietitian support.
Nutrition as Intervention
The utility of nutritional therapy will be widely acceptable only when the therapeutic diet is regarded as equivalent to medical therapy and studied with appropriate rigor. To this end, a nutritional therapy should be precisely defined and placed as an intervention in comparator arms against current standard of care therapies, such as anti-TNF medications. EEN has shown benefit above and beyond corticosteroids in pediatric CD, but comparative effectiveness study in the context of anti-TNF medication reveals a more moderate impact (10). We should additionally consider formal investigation of diet as adjunctive therapy in clinical trials.
The prospect of the inferiority of precisely defined nutritional therapy (to anti-TNF medication, for example) should neither temper the pursuit of rigorous study nor necessarily detract from their use. Rates of remission in IBD are not ideal, and for any 1 individual; nutritional therapy may offer a preferable therapeutic approach. Since we are not always able to allay parental concerns about the safety and overall efficacy of the regimens we do recommend, nutritional therapy may provide approaches that satisfy goals of harm reduction.
Nutritional therapy may yet address a wide swath of IBD subtypes through personalized approaches. As multiomics discovery reveals key aspects of IBD pathophysiology, the predictive potential of transcriptome, microbiome, and metabolome signatures to treatment efficacy must be incorporated into the study of nutritional therapies. Several emerging therapeutic approaches to immune targets are being paired with predictive assays (29). Alterations of microbial composition and function through dietary manipulation signal an opportunity to develop predictive markers in concert with dietary intervention trials.
The complexity of the issue demands that investigators be specific with regard to their intended dietary intervention. This includes at the minimum:
- 1. A rationale for why the offending agent(s) are being excluded, added, or otherwise manipulated.
- 2. A well-characterized dietary plan that is replicable (the trial diet).
- 3. An a priori prospective description of expected outcomes and methods for assessment.
- 4. Description of the nutritional adequacy of the trial diet.
- 5. Clear delineation of the prescribed dietary intake, how intake will be monitored and a method to determine adherence.
- 6. Clear primary endpoints, which must harmonize with those for current drug development trials in pediatric IBD (eg, mucosal healing, patient-reported outcomes instruments).
- 7. A clear comparison with a control or comparator diet.
SUMMARY AND FUTURE DIRECTIONS
Nutritional therapy for pediatric IBD holds great promise and deserves critical investigation. To the extent possible, our need for precise answers must be appropriately satisfied in a setting where ambiguity currently reigns. Clear definition of the trial diet, comparator diet, trial design, adherence measure, and harmonized endpoints will ensure these therapeutic approaches are used effectively if they are, indeed, proven to be effective. Furthermore, nutritional therapies must be placed within the context of available pharmacologic therapies and directly compared. Without this scientific rigor, we risk exposing children with IBD to suboptimal treatment and resultant poor outcomes. We also risk underutilizing nutrition therapy as an approach and increased reliance on pharmacologic approaches when less harmful, equally effective nonpharmacologic approaches may be available. The overall wellbeing of the child and family is paramount. If we are able to establish solid, foundational evidence we will employ nutritional therapies confidently.
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