Metabolome Changes With Diet-Induced Remission in Pediatric Crohn’s Disease

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 163; no. 4; pp. 922 - 936.e15
• Main Authors: Ghiboub, Mohammed, Penny, Susanne, Verburgt, Charlotte M., Boneh, Rotem Sigall, Wine, Eytan, Cohen, Alejandro, Dunn, Katherine A., Pinto, Devanand M., Benninga, Marc A., de Jonge, Wouter J., Levine, Arie, Van Limbergen, Johan E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2022; Elsevier; American Gastroenterological Association
• Subjects: CDED+PEN; EEN; Metabolome; Metagenome; CD; RCT; KO; nr; Metabolome; LDA; CDED+PEN; AhR; IBD; PLS-DA; nsr; SCFA; EEN; AUC; PCA; LEfSe; FDR; W; PEN; rem; Metagenome; CDED; sr
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2022.05.050

The Crohn’s disease (CD) exclusion diet (CDED) plus partial enteral nutrition (PEN) and exclusive enteral nutrition (EEN) both induce remission in pediatric CD. CDED+PEN is better tolerated and able to sustain remission. We characterized the changes in fecal metabolites induced by CDED+PEN and EEN and their relationship with remission. A total of 216 fecal metabolites were measured in 80 fecal samples at week (W) 0, W6, and W12, of children with mild to moderate CD in a prospective randomized trial comparing CDED+PEN vs EEN. The metabolites were measured using liquid chromatography coupled to mass spectrometry. Metagenome Kyoto Encyclopedia of Genes and Genomes Orthology analysis was performed to investigate the differential functional gene abundance involved in specific metabolic pathways. Data were analyzed according to clinical outcome of remission (W6_rem), no remission (W6_nr), sustained remission (W12_sr), and nonsustained (W12_nsr) remission. A decrease in kynurenine and succinate synthesis and an increase in N-α-acetyl-arginine characterized CDED+PEN W6_rem, whereas changes in lipid metabolism characterized EEN W6_rem, especially reflected by lower levels in ceramides. In contrast, fecal metabolites in EEN W6_nr were comparable to baseline/W0 samples. CDED+PEN W6_rem children maintained metabolome changes through W12. In contrast, W12_nsr children in the EEN group, who resumed a free diet after week 6, did not. The metabolome of CDED+PEN differed from EEN in the purine, pyrimidine, and sphingolipid pathways. A significant differential abundance in several genes involved in these pathways was detected. CDED+PEN– and EEN-induced remission are associated with significant changes in inflammatory bowel disease–associated metabolites such as kynurenine, ceramides, amino acids, and others. Sustained remission with CDED+PEN, but not EEN, was associated with persistent changes in metabolites. Clinicaltrials.gov, Number NCT01728870. [Display omitted] Precis Crohn’s disease exclusion diet plus partial enteral nutrition– and exclusive enteral nutrition–induced remission in pediatric Crohn’s disease exhibited unique metabolome profiles. Dietary nonresponders showed metabolite profiles similar to baseline. Exposure to free diet led to return to baseline metabolomic profile.