BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.