**7. Conclusions**

GI tract is the organ that is exposed frequently to proteases both during physiological and pathophysiological conditions. Besides degradative enzymatic roles, the proteases also act as signaling molecules in various gut diseases. Understanding the exact mechanism of VH is pivotal to identifying the novel efficacious therapy for IBDs. PAR-2 activation by tryptase, trypsin, and cathepsin-S causes the release of CGRP and SP in extrinsic primary afferent fibers and intrinsic enteric neurons [45, 77]. Both CGRP and SP facilitate the excitation of extrinsic afferents as well as participate in the central transmission of nociceptive traffic between afferent neurons and higher-order neurons in the spinal cord and brainstem. The blockade and/or antagonism of PAR-2

and CGRP release can effectively relieve VH in IBDs, IBS, or other functional bowel disorders. Further research is required to deepen our understanding of the blockade or antagonism of PAR-2 or CGRP before these potential therapies can be clinically translated for the management of VH in humans.
