The Many Healing Faces of Nisin - Nisin and its Probiotic Prevent Inflammatory Bone Loss while Promoting Reparative Proliferation and a Healthy Microbiome

Li Gao, Ryutaro Kuraji, Allan Radaic, Pachiyappan Kamarajan, Yvonne L. Kapila

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Periodontitis is a chronic inflammatory disease of the hard and soft tissues that support teeth, characterized by a dysbiotic oral microbiota. The administration of beneficial bacteria in the form of probiotics can be a valuable adjunct to scaling and root planing in the treatment of periodontitis. The probiotic Lactococcus lactis produces one of the most widely used bacteriocins, known as nisin. In our previous studies, we  demonstrated that nisin and the nisin-producing probiotic L. lactis prevents oral biofilm formation, decreases the levels of pathogens within these biofilms and returns microbial diversity back to control or ‘healthy’ levels in vitro, suggesting a promising role for nisin and the nisin-producing probiotic in mitigating disease and enhancing periodontal health. In this study, a polymicrobial mouse model of periodontal disease was induced by oral infection with four periodontal pathogens, and employed to examine the effects of nisin and the nisin-producing probiotic L. lactis in abrogating periodontal bone loss and modulating the composition of the oral microbiome and inflammatory landscape.

We found that nisin and a nisin-producing L. lactis significantly decrease the levels of several periodontal pathogens, alveolar bone loss, and the oral and systemic inflammatory host response. Nisin and probiotic treatment significantly shifted the oral microbiome towards the healthy control state; health was associated with Proteobacteria, whereas 3 retroviruses were associated with disease.

Furthermore, a surprising finding was that nisin and the nisin-producing L. lactis probiotic enhanced the number of gingival fibroblasts, periodontal ligament cells, and bone lining cells in response to the polymicrobial infection as evaluated by histopathological evaluation of the periodontal tissues, suggesting nisin’s potential in promoting cell proliferation and regeneration. Thus, to explore this further, in vitro proliferation experiments were performed, revealing that nisin mediated human periodontal ligament cell proliferation dose-dependently by increasing the proliferation marker, Ki-67. This is the first time that nisin, a bacteriocin, or a probiotic have been shown to promote cell proliferation and a regenerative potential especially in the context of a chronic inflammatory state.

    The multiple effects of nisin and nisin-producing probiotic in the treatment and abrogation of periodontitis suggest an application for nisin and a nisin-producing probiotic in other diseases, especially those mediated by microbial dysbiosis. Can nisin and its probiotic modulate intestinal flora especially when connected to oral dysbiosis? Can nisin ameliorate periodontitis-associated diseases, such as diabetes mellitus, cardiovascular diseases, and Alzheimer’s disease? More studies and reports from our group are on the way to help address these emerging questions.

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Nisin probiotic prevents inflammatory bone loss while promoting reparative proliferation and a healthy microbiome: Li Gao, Ryutaro Kuraji, Martin Jinye Zhang, April Martinez, Allan Radaic, Pachiyappan Kamarajan, Charles Le, Ling Zhan, Changchang Ye, Helene Range, M. Reza Sailani, Yvonne L. Kapila. NPJ Biofilms and microbiomes, 8(1), 45:  https://www.nature.com/articles/s41522-022-00307-x

Yvonne Kapila

Visiting Assistant Professor and Professor, UCSF

Oral Biology, Extracellular Matrix, Cell Signaling, Oral microbiome and metabolome, oral squamous cell carcinoma, translational research