Urinary Level of D-2-Hydroxyglutarate During Inflammation Predicts Severity of Colitis-Associated Tumorigenesis in Mice

Although the association between inflammatory bowel diseases (IBD) and an increased risk of developing colorectal cancer is well‐established, the pathogenesis of colitis‐associated cancer is poorly understood. Quantitative metabolic profiling is a promising method to detect molecular pathways involved in disease progression from colitis to cancer. Wild‐type C57BL/6 male mice were i.p. injected with 7.6 mg/kg azoxymethane followed by 2 cycles of 3% dextran sodium sulfate (DSS; 1 week DSS and 3 weeks recovery). Urine was serially collected at baseline, the end of the first cycle of DSS (colitis stage), and the day before sacrifice (polyp stage). Urinary metabolites were analyzed using gas chromatography‐ mass spectrometry. Excised colons were observed for polyp number and embedded for dysplasia scoring or scraped for mucosal extracts. Findings in the mouse model were corroborated using human mucosal biopsies of IBD and matched IBD‐associated cancer. Six urinary metabolites were significantly altered during colitis and returned to baseline at the polyp stage. Of these, urinary D‐2‐hydroxyglutarate (D‐2‐HG) during colitis, an emerging oncometabolite, directly correlated with polyp number and dysplasia score. Colonic expression of D‐2‐hydroxyglutatric dehydrogenase, an enzyme that eliminates D‐2‐HG, was decreased during DSS colitis and human IBD but restored at the polyp stage and in IBD cancer. These results suggest that elevated D‐2‐HG during colitis may play a role in progression to cancer.