Various factors have been implicated in the pathogenesis of ulcerative colitis (UC), with immune system failure being the most important one. Calcitonin gene-related peptide (CGRP), a neuropeptide with two isoforms, CGRPalpha and CGRPbeta, has been reported to regulate the immune system. In this study, we investigated the role of CGRP isoforms in UC pathogenesis. We induced UC-like symptoms in CGRPalpha and CGRPbeta knockout (KO) mice using dextran sulphate sodium. Compared to wild-type and CGRPalpha KO mice, CGRPbeta-deficient mice exhibited severe symptoms with increased blood in the stool and diarrhoea. Proteome analysis revealed significant up-regulation of immune-related proteins and immunoproteasome components in CGRPbeta-deficient mice, suggesting that an enhanced immune response contributes to the severity of this disease. Treatment with ONX-0914, an immunoproteasome inhibitor, markedly improved these symptoms, highlighting the role of the immunoproteasome in exacerbating UC. This study provides the first evidence that CGRPbeta protects against UC by modulating immune responses, particularly those mediated by the immunoproteasome. Our findings suggest that functional differences in CGRP isoforms may influence the severity and management of UC. This insight into the neuro-immune mechanism of UC opens avenues for novel therapies that address both the neural and immune aspects of this disease.