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. 2015 Mar;21(3):172-83.
doi: 10.1016/j.molmed.2014.11.004. Epub 2014 Nov 20.

Polymicrobial Synergy and Dysbiosis in Inflammatory Disease

Free PMC article

Polymicrobial Synergy and Dysbiosis in Inflammatory Disease

Richard J Lamont et al. Trends Mol Med. .
Free PMC article


Uncontrolled inflammation of the periodontal area may arise when complex microbial communities transition from a commensal to a pathogenic entity. Communication among constituent species leads to polymicrobial synergy between metabolically compatible organisms that acquire functional specialization within the developing community. Keystone pathogens, even at low abundance, elevate community virulence, and the resulting dysbiotic community targets specific aspects of host immunity to further disable immune surveillance while promoting an overall inflammatory response. Inflammophilic organisms benefit from proteinaceous substrates derived from inflammatory tissue breakdown. Inflammation and dysbiosis reinforce each other, and the escalating environmental changes further select for a pathobiotic community. We have synthesized the polymicrobial synergy and dysbiotic components of the process into a new model for inflammatory diseases.


Figure 1
Figure 1. The polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology
A. Model overview. Community formation driven by co-adhesion and physiological compatibility initially leads to a balanced interaction between host immunity and the metabolism of the inflammophilic microbiota. The identities of individual species are less important than the presence of the appropriate complement of genes. As established in mouse models, colonization by keystone pathogens such as P. gingivalis enhances community virulence through interactive communication with accessory pathogens such as S. gordonii and disruption of immune surveillance. The dysbiotic community increases in number, pathobionts (green) overgrow and become more active, and tissue destruction ensues. B. Summary of synergistic interbacterial interactions that have been documented among oral bacteria. Both direct contact, primarily through adhesin-receptor binding, and sensing of compounds in solution can effect signaling and modulate the phenotypic properties of partner organisms (e.g. induction of adhesin/invasin, protease or complement-resistance genes). Interspecies signaling can also increase levels of extracellular polymeric substances (EPS) which contribute to community cohesion and resistance to physical stresses.
Figure 2
Figure 2. The molecular basis of synergy between P. gingivalis and S. gordonii
A. The physical association between P. gingivalis and S. gordonii involves FimA–GAPDH and Mfa1–SspA/B adhesin–receptor pairs on the surfaces of the organisms. B. The upper panel shows the domain structure of the SspB protein and the amino acid residues involved in recognition of Mfa1. BAR spans aa residues 1167–1193, and the EAAP, KKVQDLLKK and NITVK sequences are involved in Mfa1 recognition. The lower panel shows the structure of the SspB C-terminal region with the protruding BAR domain stabilized by a calcium ion, and coordinated by three main chain and two side-chain oxygen atoms and a water molecule. Reproduced from [4] with permission. C. Signaling interactions between S. gordonii and P. gingivalis. S. gordonii induces autophosphorylation of the Ptk1 tyrosine kinase. Ptk1 activates a signaling cascade which converges on inactivation of the transcriptional repressor CdhR. As a result, expression of the minor fimbrial adhesin subunit Mfa1 is elevated and P. gingivalis is ‘primed’ for attachment to S. gordonii. Ptk1 is also a key component of the machinery for secretion of extracellular polysaccharide, and active Ptk1 increases the amount of polysaccharide material on the surface of P. gingivalis. Over time, however, direct contact mediated by Mfa1-SspA/B binding increases expression of the tyrosine phosphatase Ltp1, which dephosphorylates Ptk1, ultimately relieving repression of ChdR. Expression of the Mfa1 fimbrial adhesin is reduced and community development is constrained. Abbreviations: Ala, alanine-rich repeats; BAR, SspB Adherence Region, the Mfa1-interacting domain; CWA, cell wall anchor; LP, leader peptide; Pro, proline-rich repeats; V, variable region.
Figure 3
Figure 3. Mechanisms of localized chemokine paralysis
Many oral bacteria such as F. nucleatum engage TLRs on epithelial cell surfaces and activate pro-inflammatory signaling pathways. However, production of the neutrophil chemokine IL-8 (CXCL8) and the T-cell chemokine IP-10 (CXCL10) from epithelial cells is suppressed by P. gingivalis. Invasive P. gingivalis inactivates Stat1 which in turn reduces expression of IP10 promoted by the IRF1 transcription factor. Intracellular P. gingivalis also secretes the serine phosphatase SerB which specifically dephosphorylates the serine 536 residue of the p65 NF-κB subunit, and prevents the formation of p65 homdimers. Translocation of NF-κB into the nucleus is impeded, and transcription of the IL8 gene is reduced.
Figure 4
Figure 4. Synergistic inhibition of complement-dependent antimicrobial activities
P. gingivalis, P. intermedia, and T. forsythia can inhibit the classical, lectin, and alternative pathways of complement activation by degrading C3, C4, mannose-binding lectin (MBL), or ficolins (FCN) through the action of proteases, as indicated. These activities are synergistic and prevent the deposition of C3b opsonin or the membrane attack complex (MAC) on the surface of these pathogens as well as bystander bacterial species. Moreover, P. gingivalis and P. intermedia protect themselves against complement also by using surface molecules (HRgpA gingipain for P. gingivalis, undefined molecule for P. intermedia) to capture the circulating C4b-binding protein (C4BP), a physiological negative regulator of the classical and lectin pathways. Furthermore, P. gingivalis (via its Arg-specific gingipains HRgpA and RgpB) and T. forsythia (via its karilysin) can release biologically active C5a from C5, thereby stimulating inflammation through the activation of the C5a receptor (C5aR). Abbreviations: InpA, interpain A; Kgp, Lys-specific gingipain.
Figure 5
Figure 5. Subversion of neutrophil function and dysbiosis
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, another TLR2 adaptor, Mal, is involved in the subversive pathway and acts upstream of PI3K. The integrated mechanism provides ‘bystander’ protection to otherwise susceptible bacterial species and promotes polymicrobial dysbiotic inflammation in vivo. Reproduced from [61] with permission.
Figure 6
Figure 6. Mechanisms of inhibition of macrophage intracellular killing
P. gingivalis interacts with the TLR2/1 receptor complex, whereas it evades or antagonizes TLR4 by expressing atypical lipopolysaccharide structures (with non-phosphorylated tetra-acylated lipid A or mono-phosphorylated tetra-acylated lipid A, respectively). The TLR2 response is proactively modified through crosstalk with other receptors that are under P. gingivalis control, C5aR and CXCR4. P. gingivalis induces C5aR activation by virtue of its Arg-specific gingipains (HRgpA and RgpB) which attack C5 and release biologically active C5a. C5a stimulates Gαi-dependent intracellular Ca2+ signaling which synergistically enhances the otherwise weak cAMP responses induced by TLR2 activation alone. Maximal cAMP induction is achieved through the participation of CXCR4, which is activated directly by the pathogen’s FimA fimbriae and coassociates with both TLR2 and C5aR in lipid rafts. The ensuing activation of the cAMP-dependent protein kinase A (PKA) pathway inactivates glycogen synthase kinase-3β (GSK3β) and impairs the inducible nitrogen synthase (iNOS)-dependent killing of the pathogen in macrophages. The expression of evasive or antagonistic lipid A moreover allows internalized P. gingivalis (possibly entering via complement receptor 3 [CR3] which promotes its intracellular survival) to prevent caspase 11–dependent non-canonical activation of the inflammasome. This mechanism is normally triggered by LPS of intracellular gram-negative bacteria and leads to pyroptosis, a proinflammatory mode of lytic cell death that protects the host against bacterial infection. P. gingivalis also inhibits F. nucleatum-induced NLRP3 inflammasome activation and cytokine secretion by inhibiting its endocytosis, although it is uncertain whether this is mediated by extracellular or intracellular P. gingivalis.

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