Nowadays, Western diets and lifestyle lead to an increasing occurrence of chronic gut inflammation, that represents an emerging health concern with still a lack of successful therapies. Fermented foods, and their associated Lactic Acid Bacteria, have recently regained popularity for their probiotic potential including the maintenance of gut homeostasis by modulating the immune and inflammatory response. Our study aims to investigate the cross-talk between the food-borne strain Lactiplantibacillus plantarum C9O4 and intestinal epithelial cells in an in vitro inflammation model. Cytokines profile shows the ability of C9O4 to significantly reduce levels of IL-2, IL-5, IL-6, and IFN-γ. Proteomic functional analysis reveals an active host-microbe interaction that highlights an immunoregulatory role of C9O4, able to revert both the detrimental effects of IFN-γ through the JAK/STAT pathway and the apoptosis process in inflamed cells. These results suggest a promising therapeutic role of fermented food-associated microbes for the management of gastrointestinal inflammatory diseases.