Metabolic network analysis of Crohn's disease reveals sex- and age-specific cellular phenotypes.

Crohn's disease (CD) is an inflammatory gastrointestinal disease affecting approximately 1 in 1,000 people in North America. Incidence of pediatric CD has been rising in recent decades, and this group is especially at risk of more severe disease development because of the association of CD with developmental deficits. Genome-scale metabolic models (GEMs) present an opportunity to investigate systems-level changes in metabolism in specific contexts, such as pediatric CD. In this work, we utilized pediatric and adult omics data to create an ileum-specific GEM, Ileum1. We also developed reaction inclusion analysis (RIA) to quantify broad metabolic differences of several clinical cohorts and used this method to compare hundreds of subject-specific GEMs. RIA predicted altered cholesterol metabolism in males with CD, and in vitro testing found that cholesterol synthesis inhibition prevented an increase of inflammatory cytokines. We used transcriptomics from adult subjects and found that metabolism is uniquely altered in adult CD. A record of this paper's transparent peer review process is included in the supplemental information.