Analysis of 61 Exclusive Enteral Nutrition Formulas Used in the Management of Active Crohn's Disease

New Insights Into Dietary Disease Triggers

Michael Logan; Konstantinos Gkikas; Vaios Svolos; Ben Nichols; Simon Milling; Daniel R. Gaya; John Paul Seenan; Jonathan Macdonald; Richard Hansen; Umer Z. Ijaz; Richard K. Russell; Konstantinos Gerasimidis


Aliment Pharmacol Ther. 2020;51(10):935-947. 

In This Article

Abstract and Introduction


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.


Inflammatory bowel disease (IBD) is more prevalent in Western countries and its incidence is increasing, particularly in low- and medium-income countries which are in financial transition, and in those who adopt a Western lifestyle.[1] This points to an environmental disease trigger, as the rapid increase in incidence outpaces changes in transcriptional human genetics.

Epidemiological evidence from observational studies has implicated certain dietary macronutrients, such as polyunsaturated fatty acids (PUFA) and fibre, in IBD onset,[2] but dietary intervention studies, based on this evidence, have been unable to reverse the disease course and induce or maintain disease remission in patients with IBD.[3,4] In preclinical studies in animal models, a diet high in total fat and sugars aggravated inflammatory response, induced intestinal dysbiosis, promoted overgrowth of pro-inflammatory Proteobacteria with a parallel decrease in protective members of the gut microbiome, reduced production of short chain fatty acids and suppressed the mucosal expression of their G-protein coupled receptor 43.[5]

Our habitual diet has evolved enormously in recent decades, not only in terms of nutrient composition but also, importantly, in terms of nonnutrient food ingredients used in food preservation and processing. Although food industrialisation has safeguarded humans from infectious diseases and increased food durability, availability and global accessibility, the effect this may have on host health and the onset of noncommunicable diseases is now becoming clearer. Recent studies in animal models have indicated that food additives might affect colonic and cardiovascular health, mediated by their effects on the gut microbiome, the mucus layer, the gut barrier function and the gut associated immune system.[6,7] Dietary emulsifiers, such as polysorbates and carboxymethyl cellulose have been shown to increase intestinal permeability, alter microbiome composition, promote Escherichia coli translocation across the intestinal epithelium and cause gut inflammation in M cells in vitro and in animal experiments.[6–10]

Such epidemiological and preclinical observations have quickly been translated to dietary recommendations and presumptive therapies for the management of IBD.[7] However, it is important to accept that there are currently no well-controlled intervention studies in humans to prove that exposure to food additives increases risk of IBD onset, or indeed aggravates gut inflammation in those with the illness. Likewise, there are no intervention studies to prove that exclusion of food additives, sugars or milk fat mitigates colonic inflammation in IBD patients or that their introduction to the diet of patients with disease in remission initiates disease flare. On the contrary, data from a dietary intervention showed that among patients with Crohn's disease in remission, the levels of red and processed meat consumption were not associated with time to symptomatic relapse.[11]

Exclusive enteral nutrition (EEN), a liquid-only diet using proprietary formula, is the only effective and established dietary treatment which induces remission in active Crohn's disease. It is the first-line treatment for children with active Crohn's disease throughout Europe, Oceania and parts of North America.[12] Treatment with EEN for 8 weeks induces clinical remission and disease improvement in approximately 80% of children with active Crohn's disease and suppresses colonic inflammation.[13–15] The EEN formulas used for the management of Crohn's disease are extensively industrialised products which vary considerably in terms of their composition of nutrients and nonnutrient food ingredients, including food additives. It is therefore possible to use the compositional profile of EEN formulas, shown to induce remission in Crohn's disease, to elicit clues about the role of various food components in the disease course. We hypothesise that nutrients and food ingredients which are included in one or more EEN formulas with clinical efficacy data in the management of active Crohn's disease are unlikely to play a major role in the disease course and are therefore unlikely to initiate or sustain a disease flare in Crohn's disease. Conversely, nutrients and food additives, or other nonnutrient food ingredients, which are both specifically absent from the composition of EEN formulas (eg lactose, gluten), and whose hypothetical inflammatory mechanism is supported by preclinical data, warrant further exploration of their role in Crohn's disease.

We performed an extensive nutrient, nonnutrient food ingredient and food additive compositional analysis of EEN formulas with published evidence of clinical efficacy in the management of active Crohn's disease. Subsequently, we compared the composition of EEN formulas with the UK dietary reference values (DRV), the dietary intake of children from the UK National Diet and Nutrition Survey (NDNS), the dietary intake of a group of children with Crohn's disease and against published preclinical evidence which implicates food additives and nonfood ingredients in Crohn's disease pathogenesis.