Metabolomic dysregulation in the association between major depressive disorder and chronic pancreatitis: a large prospective cohort study.

BACKGROUND: Major depressive disorder (MDD) is increasingly recognized as a systemic condition accompanied by metabolic disturbances, particularly in lipid metabolism. However, whether MDD is associated with the development of chronic pancreatitis (CP), a chronic inflammatory disease with substantial metabolic and nutritional consequences, remains unclear. We aimed to investigate the prospective association between MDD and incident CP and to assess the potential mediating role of circulating nuclear magnetic resonance (NMR)-based metabolic biomarkers. METHODS: In this prospective study of 273,524 UK Biobank participants, MDD was identified using hospital records and self-reports. Incident CP was ascertained through linked health records. Cox proportional hazards models were used to estimate associations, and mediation analyses based on NMR metabolomics were performed. A metabolomic signature was further derived using least absolute shrinkage and selection operator (LASSO) regression. RESULTS: Over a median follow-up of 13.7 years, 411 incident CP cases were identified. MDD was independently associated with an increased risk of CP (HR 1.47, 95% CI 1.10-1.96). Exploratory mediation analyses suggested that lipid-related metabolites accounted for part of the observed association, including triglycerides in HDL particles (HDL-TG; 5.10%), triglycerides in LDL particles (LDL-TG; 4.19%), and fatty acid unsaturation (7.61%). A 51-metabolite signature explained 20.80% (95% CI 13.20-27.20%) of the association. The association was stronger in participants aged ≤60 years (P-interaction = 0.014). CONCLUSION: Major depressive disorder was associated with a higher risk of CP, and exploratory mediation analyses suggested that lipid related metabolomic alterations may account for part of this association. These findings highlight metabolic dysregulation as a potential biological correlate of the observed MDD-CP association.