The inflammophilic character of the periodontitis-associated microbiota

Abstract

In periodontitis, dysbiotic microbial communities exhibit synergistic interactions for enhanced protection from host defenses, nutrient acquisition, and persistence in an inflammatory environment. This review discusses evidence that periodontitis-associated communities are 'inflammo-philic' (=loving or attracted to inflammation) in that they have evolved to not only endure inflammation but also to take advantage of it. In this regard, inflammation can drive the selection and enrichment of these pathogenic communities by providing a source of nutrients in the form of tissue breakdown products (e.g. degraded collagen peptides and heme-containing compounds). In contrast, those species that cannot benefit from the altered ecological conditions of the inflammatory environment, or for which host inflammation is detrimental, are likely to be outcompeted. Consistent with the concept that inflammation fosters the growth of dysbiotic microbial communities, the bacterial biomass of human periodontitis-associated biofilms was shown to increase with increasing periodontal inflammation. Conversely, anti-inflammatory treatments in animal models of periodontitis were shown to diminish the periodontal bacterial load, in addition to protecting from bone loss. The selective flourishing of inflammophilic bacteria can perpetuate inflammatory tissue destruction by setting off a 'vicious cycle' for disease progression, in which dysbiosis and inflammation reinforce each other. Therefore, the control of inflammation appears to be central to the treatment of periodontitis, as it is likely to control both dysbiosis and disease progression.

Keywords: P. gingivalis; Toll-like receptors; dysbiosis; inflammation; periodontitis.

Figure 1. Inflammation and dysbiosis in periodontitis

Various factors including defects in the immuno-inflammatory status of the host and/or the presence of keystone pathogens can tip the balance from a symbiotic periodontal microbiota to a dysbiotic state. The inflammation caused by the dysbiotic microbiota depends in great part on crosstalk signaling between complement and pattern-recognition receptors and exerts two major and interrelated effects: it causes inflammatory destruction of periodontal tissue (including bone loss, the hallmark of periodontitis) which in turn provides tissue breakdown-derived nutrients for the bacteria. The latter further promotes dysbiosis and escalates tissue destruction, thereby generating a self-perpetuating pathogenic cycle. Therefore, the periodontitis-associated dysbiotic communities are ‘inflammo-philic’ (= loving or attracted to inflammation) in that they appear to have evolved to not only endure inflammation but also to take advantage of it for enhancing their adaptive fitness.

Figure 2. Model of P. gingivalis subversion of neutrophils leading to dysbiotic inflammation

P. gingivalis co-activates TLR2 and C5aR in neutrophils and the resulting crosstalk leads to E3 ubiquitin ligase Smurf1-dependent ubiquitination and proteasomal degradation of MyD88, thereby inhibiting a host-protective antimicrobial response. Moreover, the C5aR-TLR2 crosstalk activates PI3K, which prevents phagocytosis through inhibition of RhoA activation and actin polymerization, while stimulating an inflammatory response. In contrast to MyD88, Mal is a component of the subversive pathway acting upstream of PI3K. The integrated mechanism provides ‘bystander’ protection to otherwise susceptible bacterial species and promotes polymicrobial dysbiotic inflammation in vivo. From Maekawa et al., 2014b with permission.