Homeostasis of the intestinal mucosa relies on different factors including growth factors, antimicrobial peptides, oxygen radicals and proteases. Among them, we observed that the equilibrium of proteolytic activity plays a central role at mucosal surfaces. This equilibrium can be modified both by the host and by the microbiota, which both can release proteases and protease inhibitors. This lecture will review the effects of proteolytic activity at the intestinal mucosa surface in physiology and pathophysiology. Next, the identification of mucosal proteolytic actors will be discussed. Finally, new therapeutic approaches manipulating the microbiome and its properties to release protective molecules in the context of inflamed intestinal mucosa will be reviewed. Manipulation of proteolytic activity but also of mucosal cytokines, growth factors and oxygen radicals will be evoked.