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Review
, 10 (10), 717-25

The Keystone-Pathogen Hypothesis

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Review

The Keystone-Pathogen Hypothesis

George Hajishengallis et al. Nat Rev Microbiol.

Abstract

Recent studies have highlighted the importance of the human microbiome in health and disease. However, for the most part the mechanisms by which the microbiome mediates disease, or protection from it, remain poorly understood. The keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one. In this Opinion article, we critically assess the available literature that supports this hypothesis, which may provide a novel conceptual basis for the development of targeted diagnostics and treatments for complex dysbiotic diseases.

Conflict of interest statement

Competing Interests Statement

The authors have no competing interests as defined by Nature Publishing Group, or other interests that might be perceived to influence the interpretation of the article.

Figures

Figure 1
Figure 1. Keystone vs. dominant pathogens
(a) Keystone pathogen-induced dysbiotic disease. Despite its low-level colonization of the periodontium, P. gingivalis causes inflammatory periodontitis through dysbiosis, i.e., an unbalancing of the relative abundance of individual components of the microbiota compared with their abundancies in health. This activity requires the bacterium’s gingipain, a C5 convertase-like enzyme which cleaves C5 generating high levels of C5a locally. C5a-induced activation of C5aR triggers inflammation but is also critically involved in a subversive crosstalk (with TLR2) that impairs leukocyte killing. The ability of P. gingivalis to orchestrate inflammatory disease via community-wide effects, while being a minor constituent of this community, qualifies it as a keystone pathogen. This process is reversible since C5aR blockade promotes the clearance of P. gingivalis and negates its dysbiotic effects. (b) Dominant pathogen-induced inflammation and effects on the microbiota. Salmonella enterica Serovar Typhimurium (S. Tm) induces and exploits inflammation to alter the composition of and outgrow the indigenous gut microbiota leading to colitis. Therefore, S. Tm incites inflammatory disease while becoming the dominant species, in stark contrast to P. gingivalis which acts as a “keystone” that supports the oral microbiota. Adapted from ref. .
Figure 2
Figure 2. P. gingivalis-induced dysbiosis and periodontal disease
P. gingivalis subverts complement and impairs host defense leading to overgrowth of oral commensal bacteria, which cause complement-dependent inflammation. Inflammatory tissue destruction is favorable to further bacterial growth as it provides a nutrient-rich gingival inflammatory exudate (degraded host proteins and hemin, a source of essential iron). These environmental changes are better exploited by and thus favor proteolytic and asaccharolytic bacteria, leading to compositional changes in the bacterial community. Inflammatory bone resorption, moreover, provides the dysbiotic microbiota with new niches for colonization. These alterations collectively lead to and sustain periodontal disease. The numbers indicate a possible sequence of events, which set off a self-feeding “vicious” cycle.
Figure 3
Figure 3. The “alpha-bug” hypothesis in colon cancer
Nonenterotoxigenic strains of B. fragilis (NTBF) are usually symbionts and those expressing polysaccharide A (PSA) have been shown to inhibit IL-17- and Th17-mediated immune responses. On the other hand, enterotoxigenic strains of B. fragilis (ETBF) activate Stat3 signalling in the colon leading to IL-17- and Th17-dependent inflammation, which is required for colonic hyperplasia and tumor formation in the multiple intestinal neoplasia (Min) mouse model. Although ETBF secretes a pro-oncogenic toxin (BFT), the participation of the colonic microbiota is necessary for colon carcinogenesis. According to the “alpha-bug” hypothesis, ETBF remodels the colonic microbiota and co-opts it in a collaborative manner to induce colon cancer in combination with disease modifiers and host genetics. It is currently unclear exactly how ETBF influences and interacts with the colonic microbiota to promote carcinogenesis. Moreover, it is uncertain whether the microbiota is modulated by Th17 inflammation or, conversely, contributes to its induction (hypothetical connections indicated by dashed arrows).

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