Propionibacterium freudenreichii is a beneficial bacterium consumed as a cheese starter and as a probiotic. It displays promising immunomodulatory properties and selected strains exert an anti-inflammatory effect via key surface proteins. Cheese constitutes an important source of bacteria, which can have beneficial effects, depending on the species or strain. We developed here a single-strain experimental pressed cheese, exclusively fermented by P. freudenreichii, in order to investigate its health effects, which is not possible in a complex cheese ecosystem. Key immunomodulatory surface proteins were expressed within the cheese matrix. Consumption of this axenic cheese protected mice from acute colitis induced by TNBS (trinitrobenzenesulphonic acid). Induction of local and systemic inflammatory markers, as well as colon epithelial oxidative stress markers, was prevented. This work confirms the probiotic potential of P. freudenreichii and provides a new functional fermented product for preclinical and clinical studies aimed at prevention or treatment of IBD.