Tim Klomp, Andreas Braun, Georg Conrads
Background: Porphyromonas gingivalis is a Gram-negative, anaerobic keystone pathogen strongly implicated in the pathogenesis of periodontitis. Its pathogenicity is mediated through virulence factors, such as lipopolysaccharides (PG-LPS), which have been reported to display conflicting results regarding structural composition and immunogenicity. Objectives: This scoping review investigates how PG-LPS modulates host immunity and contributes to advanced periodontitis, with emphasis on its structural composition, divergent immunogenic properties, and the possible regulatory factors underlying these observations. Furthermore, PG-LPS interactions with periodontal tissues and associations with outer membrane vesicles (OMV) are examined. Materials and Methods: A structured literature search was conducted in PubMed following the PRISMA-ScR guidelines and PCC frameworks. Results: Structural heterogeneity, especially within the lipid A moiety of PG-LPS, accounts for previously inconsistent findings regarding its immunogenicity. Minor alterations in lipid A composition through enzymatic dephosphorylation or deacylation profoundly affect Toll-like receptor (TLR) engagement, antimicrobial resistance, and cytokine induction, and contribute to the biogenesis of OMVs. Environmental factors such as hemin availability and temperature influence enzymatic activity, resulting in lipid A isoforms that act as TLR4 agonists, antagonists, or remain immunologically inert. This structural plasticity mediates dynamic immune modulation that fosters polymicrobial dysbiosis and perpetuates non-resolving inflammation, leading to progressive tissue destruction, while concurrently contributing to the systemic inflammatory burden. Conclusions: Lipid A heterogeneity represents a central adaptive strategy potentially linking environmental cues and the bioenergetic status of P. gingivalis to immunomodulative properties. Verification of in vivo lipid A structural shifts in clinical isolates could inform novel therapeutic approaches targeting P. gingivalis-mediated inflammation.