Urinary Metabolite ProfilingCombined with ComputationalAnalysis Predicts Interstitial Cystitis-Associated Candidate Biomarkers

摘要

Interstitial cystitis/painful bladder syndrome (IC) is a chronic syndrome of unknown etiology that presents with bladder pain, urinary frequency, and urgency. The lack of specific biomarkers and a poor understanding of underlying molecular mechanisms present challenges for disease diagnosis and therapy. The goals of this study were to identify noninvasive biomarker candidates for IC from urine specimens and to potentially gain new insight into disease mechanisms using a nuclear magnetic resonance (NMR)-based global metabolomics analysis of urine from female IC patients and controls. Principal component analysis (PCA) suggested that the urinary metabolome of IC and controls was clearly different, with 140 NMR peaks significantly altered in IC patients (FDR < 0.05) compared to that in controls. On the basis of strong correlation scores, fifteen metabolite peaks were nominated as the strongest signature of IC. Among those signals that were higher in the IC group, three peaks were annotated as tyramine, the pain-related neuromodulator. Two peaks were annotated as 2-oxoglutarate. Levelsof tyramine and 2-oxoglutarate were significantly elevated in urinespecimens of IC subjects. An independent analysis using mass spectrometryalso showed significantly increased levels of tyramine and 2-oxoglutaratein IC patients compared to controls. Functional studies showed that2-oxoglutarate, but not tyramine, retarded growth of normal bladderepithelial cells. These preliminary findings suggest that analysisof urine metabolites has promise in biomarker development in the contextof IC.