Porphyromonas gingivalis disturbs host-commensal homeostasis by changing complement function

Abstract

Porphyromonas gingivalis is a Gram-negative anaerobic rod that has been proposed as an orchestrator of complement-dependent dysbiotic inflammation. This notion was suggested from its capacities to manipulate the complement-Toll-like receptor crosstalk in ways that promote dysbiosis and periodontal disease in animal models. Specifically, while at low colonization levels, P. gingivalis interferes with innate immunity and leads to changes in the counts and composition of the oral commensal microbiota. The resulting dysbiotic microbial community causes disruption of host-microbial homeostasis, leading to inflammatory bone loss. These findings suggested that P. gingivalis can be considered as a keystone pathogen. The concept of keystone pathogens is one where their effects have community-wide significance and are disproportionate of their abundance. The present review summarizes the relevant literature and discusses whether the results from the animal models can be extrapolated to man.

Keywords: P. gingivalis; animal model; commensal microbiota; complement; keystone pathogen; periodontitis.

Figure 1.

Dysbiosis and periodontal disease. (A) Progression from a state of periodontal health and host–microbe homeostasis to gingivitis (periodontal inflammation without bone loss) and to periodontitis, associated with a dysbiotic biofilm, formation of periodontal pockets, and induction inflammatory bone loss. (B) Periodontitis is induced in susceptible hosts by a polymicrobial community, wherein different members fulfill distinct roles that converge synergistically to cause destructive inflammation. Keystone pathogens, the colonization of which is facilitated by accessory pathogens, initially subvert the host response, leading to a dysbiotic community where pathobionts over-activate the inflammatory response and induce periodontal tissue degradation, including resorption of the supporting alveolar bone. Inflammation and dysbiosis positively reinforce each other because inflammatory tissue breakdown products (e.g. collagen peptides, heme-containing compounds) carried in the pockets via the gingival crevicular fluid are used as nutrients by the dysbiotic microbiota. This process generates a self-perpetuating pathogenic cycle that may underlie the chronicity of periodontitis. (From Hajishengallis [23]. Used with permission.)

Figure 2.

Complement involvement in Porphyromonas gingivalis–induced dysbiosis and inflammation. At low colonization levels, P. gingivalis can act as a keystone pathogen that manipulates complement–Toll-like receptor crosstalk, leading to the dysbiotic transformation of the microbiota (increased counts and altered composition). In dysbiosis, pathobionts over-activate the inflammatory response in a complement C3-dependent manner, resulting in destructive periodontal inflammation and bone loss. Inflammation and dysbiosis create a feed forward loop, which is essentially a disease-provoking vicious cycle. Therapeutic intervention at the C3 level with a specific inhibitor (Cp40) appears to break the cycle and inhibits periodontitis in non-human primates. (From Mastellos et al. [92]. Used with permission.)