Effects of Akkermansia muciniphila on Porphyromonas gingivalis-induced periodontal disease : immune modulation and microbiome regulation

Abstract

Periodontal disease, a prevalent inflammatory condition affecting the supporting structures of teeth, is primarily driven by microbial dysbiosis, particularly involving the keystone pathogen Porphyromonas gingivalis. This thesis explored the therapeutic potential of the next-generation probiotic Akkermansia muciniphila in mitigating P. gingivalis-induced periodontal disease. The study began with a comprehensive literature review detailing the impact of oral microbiome dysbiosis on systemic and periodontal health, and the role of P. gingivalis in periodontal disease. It highlighted the pathogenic mechanisms of P. gingivalis, including its ability to evade host immune responses and promote microbial dysbiosis, leading to chronic inflammation and tissue destruction. The literature review continued with a discussion on A. muciniphila, highlighting its potential as a next-generation probiotic for therapeutic approaches to periodontal disease. It covered the current understanding of probiotics, their health benefits, and the limitations of existing probiotic research. Finally, the chapter explored various model systems used to study host-microbial interactions, emphasizing the applications and limitations of current in vivo and in vitro models, and introduced innovative microfluidic organ-on-chip technology. The experimental section investigated the effects of A. muciniphila on host immune responses and microbial interactions using both in vitro and in vivo models. In vitro studies with human gingival epithelial cells and human gingival fibroblasts demonstrated that A. muciniphila could restore immune responses suppressed by P. gingivalis, enhance the expression of pro-inflammatory cytokines, and promote the recruitment of immune cells. Additionally, A. muciniphila significantly reduced the adhesion and invasion of P. gingivalis, enhancing the resistance of host cells to infection. In vivo studies using a murine model of periodontitis revealed that A. muciniphila administration mitigated alveolar bone resorption and reduced bacterial load in the periodontal compartment. The study showed that A. muciniphila enhanced the phagocytic activity of THP-1 differentiated macrophages via the MyD88 pathway, disrupting the TLR2/C5aR interaction exploited by P. gingivalis and promoting bacterial clearance. A novel gum-on-a-chip model was developed to simulate the periodontal environment and study host-microbe interactions in a controlled setting. This microfluidic device, incorporating human-derived cells and a mixed matrix gel, successfully replicated the structural and functional characteristics of periodontal tissues. The model demonstrated robust barrier and immune functions, providing a valuable platform for evaluating the effects of probiotics like A. muciniphila on periodontal health. The gum-on-a-chip model revealed that P. gingivalis suppressed immune cell recruitment and migration, leading to significant inflammation and tissue damage. Conversely, A. mucniphila enhanced the host’s immune response, counteracting the detrimental effects of P. gingivalis. This finding underscores the potential of A. muciniphila as a therapeutic agent in periodontal disease, supporting its role in modulating immune responses. In conclusion, this thesis provides insights into the interactions between the oral microbiome and host immune system, highlighting the potential of A. muciniphila as a therapeutic agent for periodontal disease. The development of the gum-on-a-chip model offers a tool for studying these interactions and evaluating therapeutic agents. Future research should focus on elucidating the mechanisms of action, conducting long-term studies, and exploring personalized probiotic treatments to improve periodontal health and overall well-being.