Aims: To investigate whether there is a relationship between interaction sites in the gut, hydrophobicity, mucosal immunomodulating capacities and cell wall protein profiles in lactobacilli, bifidobacteria and enterococci. Methods and Results: Hydrophobicity, cell wall protein profiles and sites of interaction in the gut (by using fluorescein isothiocyanate-labelled bacteria) were determined for Lactobacillus casei, L. acidophilus, L. fermentum, Bifidobacterium bifidum, B. animalis and Enterococcus faecalis. We also determined the number of immunoglobulin (Ig)A(+), tumour necrosis factor (TNF)alpha(+), interleukin (IL)-6(+) and IL-10(+) cells after oral administration of the above bacteria to BALB/c mice. All strains assessed were found to interact with the sites of induction of the immune response in the gut. No correlation with hydrophobicity was observed. When some strains at certain doses were administered to mice, bacterial translocation to liver was observed. The oral administration of indigenous (10(4) cells day(-1)) and exogenous (10(7) cells day(-1)) bifidobacteria and lactobacilli for 5 consecutive days activated the systemic and intestinal mucosal immune response in a strain-specific way, independently whether the strain was indigenous or exogenous in relation to the host. The differences in the immunopotentiating capacity of the various strains might be related to the differences in their cell wall protein profiles. Conclusions: Indigenous bacteria activated the mucosal immune response at a dose significantly smaller than the one required for probiotic exogenous bacteria. However, probiotic exogenous bacteria can be used at high concentrations in fermented dairy products with a great impact on the immune system, favouring its immunomodulation. Significance and Impact of the Study: The immunomodulation capacity of probiotic bacteria is strain specific and independent of the specificity of the host. The ability of certain strains to down-regulate the production and release of IL-6 by IL-10 may have potential implications in their use in cases in which cytokine deregulation or excessive production at the mucosal level can be the cause of tissue damage.