Elevated proteolytic activity mediates visceral hypersensitivity, especially in IBS and IBD patients.13,92–95 This effect could be ascribed to the crucial role played by proteases in the epithelial-neuronal communication through activation of PARs, particularly PAR2, highly expressed in epithelial cells and sensory neurons.92,95,96 Our data showed an imbalance in the expression of some calpains and cathepsins, with Ctsl, Ctse, Ctsh, Capn5, and Capn2 upregulated in FSDSS and only Capn8 downregulated. Here, CTSS is linked to inflammatory bowel disease.