<b>Nisin, a probiotic bacteriocin, modulates inflammatory and microbiome changes in female reproductive organs mediated by polymicrobial periodontal infection</b>

Periodontitis-related oral microbial dysbiosis is thought to contribute to adverse pregnancy outcomes (APO), infertility, and female reproductive inflammation. Since probiotics can modulate periodontitis and oral microbiome dysbiosis, this study examined the effects of a probiotic bacteriocin, nisin, in modulating the reproductive microbiome and inflammation triggered by periodontitis. A polymicrobial (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum) mouse model of periodontal disease was used to evaluate the effects of this disease on the female reproductive system with a focus on the microbiome, local inflammation, and nisin’s therapeutic potential in this context. 16s RNA sequencing was used to evaluate changes in the microbiome and RT-PCR was used to evaluate changes in inflammatory cytokines. Periodontal pathogen DNA was detected in the reproductive organs, and heart and aorta at the end of the experimental period, and DNA was especially elevated in the oral cavity in the infection group. Although only P. gingivalis was significantly elevated in the oral cavity and uterus, and T. forsythia and F. nucleatum were significantly elevated in the oral cavity. Nisin treatment significantly decreased the levels of P. gingivalis, T. forsythia, and F. nucleatum in the oral cavity. Since periodontal pathogen DNA was also detected in the heart and aorta, this suggests potential circulatory system transmission. The polymicrobial infection generally decreased microbiome diversity in the uterus, which was abrogated by nisin treatment. The polymicrobial infection compared to the control generally decreased the Firmicutes and increased the Bacteroidota in all reproductive organs with similar trends revealed in the heart. However, nisin treatment alone or in the presence of infection compared to the control or infection groups generally increased the Proteobacteria and reduced the Firmicutes and Bacteroidota in reproductive organs and the heart. Nisin treatment also altered the microbiome community structure in the reproductive tract to a new state that did not mirror the controls. Periodontal disease triggered an increase in inflammatory cytokines (IL-6, TNF-) in the uterus, which was abrogated by nisin treatment. Polymicrobial periodontal disease alters the reproductive tract microbial profile, microbiome, and inflammatory status. Nisin modulates the microbial profile and microbiome of the reproductive tract and mitigates the uterine elevated inflammatory cytokines triggered by the periodontal disease.