Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract with unknown etiology. Although the incidence of IBD is increasing globally, there is no curative treatment for this complex disease. Therefore, revealing the etiology of IBD and identifying an optimal treatment is a major challenge. Mucosal changes in IBD are characterized by transmural inflammation and associated with an alteration in the prohormone chromogranin-A (CHGA) producing enterochromaffin (EC) cells. However, it is not clear whether the change plays any role in immune activation and in regulation of gut inflammation. The aim of this thesis was to identify the impact of catestatin (CTS), a bioactive peptide derived from the conserved C-terminal portion of CHGA on gut inflammation. In our first study, using an acute model of murine colitis and biopsy samples from ulcerative colitis (UC) patients, we demonstrated that CHGA and CTS were increased during inflammation. Moreover, we identified that administration of human (h) CTS significantly down- regulated gut inflammation. This down-regulation occurred via the modulation of pro-inflammatory cytokine secretion from the macrophage population. Although CTS is known as an antimicrobial peptide, there was no reported in vivo study demonstrating its antimicrobial impact in the gut. In our second study, we depicted that hCTS administration altered the gut microbiota composition, associated with a more prominent effect on the fecal microbiota than the mucosa-associated microbiota (MAM). In a separate study, we showed that the chemical agent (dextran sulfate sodium [DSS]), used in our colitis model, was also able to induce a microbial dysbiosis both in fecal and MAM samples. Finally, considering IBD as a relapsing disease of intestinal inflammation, we investigated the effect of hCTS in the context of intestinal inflammation reactivation using a chronic model of colitis mimicking the natural history of IBD. We observed that hCTS administration could down-regulate the reactivation of colitis through a down-regulation of the M1 but not the M2 macrophages and the gut microbiota. In conclusion, this Ph.D. thesis work revealed a novel anti-inflammatory effect of hCTS in gut inflammation which in the future might open novel therapeutic avenues for IBD.