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The design of multiscale strategies integrating in vitro and in vivo models is necessary for the selection of new probiotics. In this regard, we developed a screening assay based on the investigation of the potential of yeasts from cheese as probiotics against the pathogen <i>Salmonella</i> Typhimurium UPsm1 (ST). Two yeasts isolated from raw-milk cheese (<i>Saccharomyces cerevisiae</i> 16, Sc16; <i>Debaryomyces hansenii</i> 25, Dh25), as well as <i>S. cerevisiae</i> subspecies <i>boulardii</i> (CNCM I-1079, Sb1079), were tested against ST by applying in vitro and in vivo tests. Adherence measurements to Caco-2 and HT29-MTX intestinal cells indicated that the two tested cheese yeasts presented a better adhesion than the probiotic Sb1079 as the control strain. Further, the Dh25 was the cheese yeast most likely to survive in the gastrointestinal tract. What is more, the modulation of the TransEpithelial Electrical Resistance (TEER) of differentiated Caco-2 cell monolayers showed the ability of Dh25 to delay the deleterious effects of ST. The influence of microorganisms on the in vivo model <i>Caenorhabditis elegans</i> was evaluated by measuring the longevity of the worm. This in vivo approach revealed that this yeast increased the worm’s lifespan and protected it against ST infection, confirming that this in vivo model can be useful for screening probiotic cheese yeasts.