Dairy propionibacteria, mainly Propionibacterium freudenreichii, are consumed in high amounts within cheeses. They are also known as probiotics able to modulate the gut microbiota and the corresponding metabolic activities. Their immunomodulatory properties, analyzed here on human PBMCs, displayed a remarkable variability, depending on the P. freudenreichii strain. Moreover, such modulating properties varied depending on the culture medium considered, i.e. laboratory culture medium versus fermented dairy product. Selected anti-inflammatory strains were further tested in 2 distinct mice experimental colitis models, revealing significant protection and confirming for these cheese starter bacteria (i) probiotic potential and (ii) predictive value of immune-based selection criteria. The role of surface component, including surface exopolysaccharide (EPS) and surface exposed proteins (SEPs), in this modulation, was investigated. We showed that presence of EPS abrogates immunomodulation while presence of key SEPs determines nature and intensity of this modulation. These key SEPs are being identified, as well as the mechanisms leading to their variability. These results open new perspectives for propionibacteria selection aiming at probiotic applications and new mechanistic explanation of their effects on the digestive tract.