Gastroenterology. 2022 Oct;163(4):922-936.e15.doi: 10.1053/j.gastro.2022.05.050. Epub 2022 Jun 7.

Mohammed Ghiboub ¹, Susanne Penny ², Charlotte M Verburgt ¹, Rotem Sigall Boneh ³, Eytan Wine ⁴, Alejandro Cohen ⁵, Katherine A Dunn ⁶, Devanand M Pinto ², Marc A Benninga ⁷, Wouter J de Jonge ⁸, Arie Levine ³, Johan E Van Limbergen ⁹

Author information

¹Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, the Netherlands.

²National Research Council Canada, Human Health Therapeutics, Halifax, Canada.

³Division of Pediatric Gastroenterology, Wolfson Medical Centre, Holon, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

⁴Division of Pediatric Gastroenterology, Department of Pediatrics, University of Alberta, Edmonton, Canada.

⁵Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada.

⁶Department of Biology, Dalhousie University, Halifax, Canada.

⁷Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, the Netherlands.

⁸Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Surgery, University Hospital of Bonn, Bonn, Germany.

⁹Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Emma Children's Hospital, Amsterdam, the Netherlands; Department of Pediatrics, Dalhousie University, Halifax, Canada. Electronic address: j.e.vanlimbergen@amsterdamumc.nl.

Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.