Postbiotics Derived from Lactococcus lactis and Streptococcus thermophilus Attenuate Experimental Periodontitis by Modulating Macrophage Polarization and Osteoclastogenesis

<b>Background/Objectives</b>: The potential of probiotics and postbiotics as adjunctive or alternative therapies for periodontal disease, which is characterized by chronic inflammation and alveolar bone loss, is gaining increasing attention. In this study, we aimed to elucidate the impact of postbiotic <i>Lactococcus lactis</i> HY449 and <i>Streptococcus thermophilus</i> HY9012 on key cellular processes implicated in the pathogenesis of periodontitis. <b>Methods</b>: THP-1 cells were polarized into M1 macrophages by exposure to <i>Porphyromonas gingivalis</i> lipopolysaccharide in the presence of postbiotics, i.e., heat-killed forms of HY449 or HY9012. The effect of postbiotics on the differentiation of bone marrow-derived macrophages into osteoclasts was analyzed using tartrate-resistant acid phosphatase staining. An in vivo mouse model of ligature-induced periodontitis was used to assess changes in periodontal tissues. <b>Results</b>: The combination of postbiotic <i>L. lactis</i> HY449 and <i>S. thermophilus</i> HY9012 synergistically modulated macrophage polarization by significantly suppressing pro-inflammatory M1 markers and enhancing anti-inflammatory M2 markers. Additionally, postbiotic HY449 and HY9012 inhibited osteoclast differentiation, downregulating the expression of key osteoclastogenic genes and master transcription factors of osteoclast differentiation. In a mouse model of ligature-induced periodontitis, co-treatment with postbiotic HY449 and HY9012 demonstrated synergistic effects in reducing alveolar bone loss. <b>Conclusions</b>: The present findings support the use of postbiotic HY449 or HY9012 as adjunct treatments for the management of periodontitis.