The Metabolome and Lipidome of Ulcerative Colitis

Abstract

The two major forms of Inflammatory bowel disease (IBD), Ulcerative Colitis (UC) and Crohn’s Disease (CD), are characterized by a dysregulated mucosal immune response triggered by several genetic and environmental factors in the context of host-microbe interaction. This overwhelming complexity makes IBD ideal for metabolomic studies to unravel the disease pathobiology and to improve the patient stratification strategies. Colon mucosa biopsies were collected from treatment-naive UC patients, UC patients in deep remission, and healthy subjects. Metabolomic analysis was performed by combining GC-TOF-MS and UPLC-QTOF-MS, while lipidomic analysis was performed by means of UPLC-QTOF-MS. In total, 177 metabolites from 50 metabolic pathways, and 220 lipids from 11 lipid classes were quantified. Additionally, we mapped the omega-3 and omega-6 polyunsaturated fatty acids related bioactive metabolites, which are known as oxylipins and endocannabinoids (eCBs). Accordingly, the levels of 35 oxylipins and 11 eCBs were quantified by means of UPLC-TQ-MS/MS. Multivariate analysis revealed a distinct lipidome and metabolome profile for each of the study groups. Altered phospholipids and sphingolipids metabolism is the hallmark of the active UC metabolome. Several mucosal metabolic signatures might reflect the mucosal inflammation and the state of dysbiosis in the gut, such as the disruption in acyl carnitine profile, amino acid metabolism, galactosylceramide profile, and short chain fatty acids metabolism. In addition, results showed increased levels of ω-6-related oxylipins and decreased levels of ω-3-related eCBs in UC patients. We report several metabolic fingerprints of potential clinical value as markers for UC activity and prognosis, such as PE38:3 and very log chain ceramids. Likewise, Trptophan metabolism seems to be a key aspect of the impaired metabolism in the onset of UC, and the levels of lipid mediators correlate with disease activity. This thesis demonstrates the importance of metabolomics in IBD to identify key drivers of pathogenesis which prerequisite personalized treatment.