Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites such as prostaglandin E2 (PGE2) are elevated in IBS and implicated in visceral hypersensitivity. The aim of this study was to quantify PUFA metabolites in IBS patients and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increase in 5-oxo-eicosatetraenoic acid (5-oxoETE) only in biopsies taken from IBS with predominant constipation (IBS-C) patients. Local 5-oxoETE administration induced somatic and visceral hypersensitivity with no tissue inflammation. 5-oxoETE directly acts on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca2+-imaging of dorsal root ganglia (DRG) neurons. 5-oxoETE selectively stimulated isolectin B4 (IB4)-positive DRG neurons through a PLC and pertussis toxin-dependent mechanism, suggesting a G-protein coupled receptor-mediated effect. The MAS-related G protein coupled receptor D (Mrgprd) was found in mouse colonic DRG afferents and was identified as the target receptor for 5-oxoETE. In conclusion, 5-oxoETE, a potential biomarker of IBS-C, activates Mrgprd in nociceptors and induces somatic and visceral hyperalgesia without inflammation. Thus, 5-oxoETE may play a pivotal role in abdominal pain associated with IBS-C.
