AIM: To investigate the pathophysiology of irritable bowel syndrome (IBS) by comparing the global mucosal metabolic profiles of IBS patients with those of healthy controls. METHODS: Fifteen IBS patients fulfilling the Rome Ⅱ criteria, and nine healthy volunteers were included in the study. A combined lipidomics (UPLC/MS) and metabolomics (GC × GC-TOF) approach was used to achieve global metabolic profiles of mucosal biopsies from the ascending colon. RESULTS: Overall, lipid levels were elevated in patients with IBS. The most significant upregulation was seen for pro-inflammatory lysophosphatidylcholines. Other lipid groups that were significantly upregulated in IBS patients were lipotoxic ceramides, glycosphingolipids, and di- and triacylglycerols. Among the metabolites, the cyclic ester 2(3H)-furanone was almost 14-fold upregulated in IBS patients compared to healthy subjects (P = 0.03).CONCLUSION: IBS mucosa is characterised by a distinct pro-inflammatory and lipotoxic metabolic profile.Especially, there was an increase in several lipid species such as lysophospholipids and ceramides.