Over the past 2 decades, multiple studies have reported low-grade inflammation in the mucosal biopsies of irritable bowel syndrome (IBS) and postinfectious (PI)-IBS patients. The increases in the inflammatory mediators were modest, variable and often inconsistent between studies,1,2 whereas other studies found no change or even a decrease in some inflammatory mediators.3–5 This key question arose: Do any of these inflammatory mediators underlie the generation of IBS symptoms? The publication by Cenac et al6 in this issue of Gastroenterology uses an interesting and potentially powerful interspecies experimental approach to answer this question.