Fecal and Serum Metabolome in Crohn's Disease is Linked With Future Flare

Metabolites are key mediators of various physiological functions. However, there is a lack of data linking their levels to future Crohn's Disease (CD) flares.

We aimed to identify systemic and gut metabolic changes that precede flare and generate metabolite-based indexes that predict flare using a test cohort, with validation using an independent cohort.

We analyzed serum and fecal metabolomes in a prospective cohort of patients with quiescent Crohn's Disease monitored until a clinical flare or the end of the study follow-up.

We identified specific metabolic changes in pre-flare samples of Crohn's Disease patients and developed prediction models for a subsequent flare using serum and fecal metabolic signatures. Among the fecal metabolites linked to future flares, metabolite classification indicated significantly fewer fatty acids and more carbohydrates in pre-flare samples of patients that eventually flared. Serum metabolites linked with future flares included reduced levels of two Krebs cycle ketogenic derivatives (3-hydroxybutyrate and acetoacetate) and higher urate in pre-flare samples. The predictions based on fecal metabolomics were validated in an independent Crohn's Disease cohort with a similar design. Higher urate levels in the serum metabolomics of the test cohort led us to develop a clinical blood-based index composed of normalized urate-to-creatinine ratio together with CRP [urate/creatinine ratio+log2 (CRP)], which was predictive of flare in the validation cohort 2.

Metabolites linked to future flares can provide insight into mechanisms prompting the transition from quiescent to inflammatory Crohn's Disease states and may help identify those at risk for a clinical flare.