Our findings shed new light on the double-faced role of 5-HT in intestinal delayed inflammation: the prevailing deleterious contribution mediated by 5-HT2A and 5-HT4 receptors activation co-exists and is partially counteracted by 5-HT1A stimulation, suggesting that agents targeting serotoninergic system could be beneficial as an additional therapeutic strategy in IBD only by carefully dissecting the monoamine antithetical effects. Here, HTR2A is linked to inflammatory bowel disease.