The research described here was aimed at the selection of oral bacteria that displayed properties compatible with their potential use as probiotics for the pharyngeal mucosa. We included in the study 56 bacteria newly isolated from the pharynges of healthy donors, which were identified at the intraspecies level and characterized in vitro for their probiotic potential. The experiments led us to select two potential probiotic bacterial strains (Streptococcus salivarius RS1 and ST3) and to compare them with the prototype oral probiotic S. salivarius strain K12. All three strains efficiently bound to FaDu human epithelial pharyngeal cells and thereby antagonized Streptococcus pyogenes adhesion and growth. All were sensitive to a variety of antibiotics routinely used for the control of upper respiratory tract infections. Immunological in vitro testing on a FaDu layer revealed different responses to RS1, ST3, and K12. RS1 and ST3 modulated NF-B activation and biased proinflammatory cytokines at baseline and after interleukin-1 (IL-1) induction. In conclusion, we suggest that the selected commensal streptococci represent potential pharyngeal probiotic candidates. They could display a good degree of adaptation to the host and possess potential immunomodulatory and anti-inflammatory properties.Metagenomics and functional molecular immunology substantiate the interpretation of humans as holobionts, in the sense of functional superorganisms, combining the self and microbes acting in concert to produce phenomena governed by the collective (25,42). The association between host and symbionts affects the fitness of the holobiont within its environment, and it often governs the physiological homeostasis of the narrow balance between host well being and dysfunction (13,35).The mechanisms underlying the cross talk between a human host and microbes are only marginally understood. Their elucidation at a molecular level could supply the theoretical bases to develop strategies for preventing or treating several human dysfunctions, such as autoimmune diseases, through the reconstitution of a proper human-microbe mutualism.The probiotic approach, in its widest sense, falls into this context, since it consists of the modification of a human microbiota by exogenous administration of microbial cells (or cell components), aimed at benefiting the host's health. A most commonly accepted definition comes from FAO/WHO, which states that probiotics are "live microorganisms which when administered in adequate amounts confer a health benefit on the host" (17).So far, probiotics have been most predominantly investigated for and applied to the intestinal tract. Nevertheless, a few applications beyond the gut have proposed the potential beneficial role of probiotics for the stomach (23), vaginal mucosa (36), urinary tract (6), skin (27), and oral cavity (39). With respect to oral probiotics, particularly noticeable are the studies done by J. R. Tagg and coworkers of Streptococcus salivarius strain K12. Tagg and others, in fact, showed that, follow...