Metabolome remodeling with reverse-engineered exclusive enteral nutrition in children with active Crohn's disease

For children with Crohn's disease (CD), dietary therapy with exclusive enteral nutrition (EEN) is effective in achieving clinical and biochemical remission. We investigated changes in metabolites in multiple clinical sample types from children with CD following a whole foods-blended ("reverse-engineered") EEN formula and defined associations between these changes and remission.

Stool, urine, serum, and plasma from a prospective study of newly diagnosed pediatric patients with CD enrolled in a 4-week trial of reverse-engineered exclusive enteral nutrition (RE-EEN) were analyzed using mass spectrometry targeting aqueous metabolites, bile acids, and short-chain fatty acids. Principal component analysis, mixed-effects models, and exploratory multivariate approaches including random forest and partial least-squares discriminant analysis were used to identify patterns associated with diet and metabolite abundances.

Fecal, urine, serum, and plasma metabolomes changed significantly during RE-EEN treatment from baseline. These global changes were largely driven by increases in amino acids and related metabolites and decreases in different amino acids and metabolites reflecting carbohydrate and purine metabolism, in all sample types. While global bile acid profiles changed with the RE-EEN diet, no changes in specific bile acid levels reached significance, and no changes were found in short-chain fatty acid concentrations.

Metabolomic profiles for pediatric patients with CD changed broadly during RE-EEN, indicating that this therapy may modulate key systemic and gut-associated metabolic processes. The findings further suggest that the gut metabolic processes influenced by RE-EEN, and that contribute to clinical improvement, may differ from those impacted by commercial EEN diets. Further research is crucial to validate these findings, uncover causal relationships, and optimize dietary protocols to enhance therapeutic outcomes in CD.