The Other Side of the Coin: What Beneficial Microbes Can Teach Us about Pathogenic Potential.

Koch's postulates and molecular Koch's postulates have made an indelible mark on how we study and classify microbes, particularly pathogens. However, rigid adherence to these historic postulates constrains our view of not only microbial pathogenesis but also host-microbe relationships in general. Collectively, the postulates imply that a "microbial pathogen" is a clearly identifiable organism with the exclusive capacity to elicit disease through an arsenal of pathogen-specific "virulence factors." This narrow definition has been repeatedly contradicted. Advances in DNA sequencing technologies and new experimental systems have revealed that the outcomes of host-microbe interactions are highly contextual and dynamic, especially those involving resident microbiota and variable aspects of host biology. Clarifying what differentiates pathogenic from non-pathogenic microbes, including their paradoxical ability to masquerade as one another, is critical to developing targeted diagnostics and treatments for infectious disease. Such endeavors will also inform the design of therapeutic strategies based on microbiome engineering by providing insights into how manipulating entire host-microbe systems may directly or indirectly alter the pathogenic potential of microbial communities. With these goals in mind, we discuss the need to develop experimental models that better capture the contexts that determine the nature of host-microbe relationships. To demonstrate the potential of one such model-the zebrafish and its resident microbiota-we describe recent work that has revealed the thin line between pathogenic and mutualistic relationships, how the intestine physically shapes bacterial populations and inflammation, and the ability of microbial transmission to override the host's innate immune system.