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The keystone-pathogen hypothesis
George Hajishengallis, Richard P.Darveau and Michael A.Curtis
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.
In architecture, the keystone is the central supporting stone at the apex of an arch. The term keystone has been introduced in the ecological literature to characterize species that have disproportionately large effects on their communities, given their abundance, and that are thought to form the keystone of the communitys structure13. Although this term was originally applied to a top predator (the starfish Pisaster ochraceus) in the rocky intertidal zone2,4, the keystone concept has been extended to species across different trophic levels and has been categorized to reflect specific functions. For instance, beavers exert keystone effects on their ecosystem by engineering the environment (making them keystone modifiers), whereas certain plants have an impact on the ecosystem by supporting pollinators and seed dispersers (making them keystone hosts)2. The influence of keystone species contrasts with that of dominant species, which are the major energy transformers in an ecosystem and thus influence it by virtue of their large biomass.
If keystone species can be identified in microbial ecology, this could yield enhanced insights into the structure of microbial communities and the interplay with their hosts or environment. In humans, given the central importance of the microbiome in health and disease, there is currently great interest in elucidating both the mechanisms that maintain hostmicroorganism homeostasis at mucosal surfaces and the mechanisms that disturb
this homeostatic balance, leading to dysbiosis (that is, a change in the relative abundance of individual microbiota components compared with their abundance in healthy individuals) and the initiation of inflammatory disease510.
A keystone microorganism that supports and stabilizes the dysbiotic microbiota associated with a disease state...