The Age of Next-Generation Therapeutic-Microbe Discovery: Exploiting Microbe-Microbe and Host-Microbe Interactions for Disease Prevention.

Humans are considered "superorganisms," harboring a diverse microbial collective that outnumbers human cells 10 to 1. Complex and gravely understudied host- and microbe-microbe interactions-the product of millions of years of host-microbe coevolution-govern the superorganism in almost every aspect of life functions and overall well-being. Abruptly disrupting these interactions via extrinsic factors has undesirable consequences for the host. On the other hand, supplementing commensal or beneficial microbes may mitigate perturbed interactions or enhance the interactive relationships that ultimately benefit all parties. Hence, immense efforts have focused on dissecting the innumerable host- and microbe-microbe relationships to characterize if a "positive" or "negative" interaction is at play and to exploit such behavior for broader implications. For example, microbiome research has worked to identify and isolate naturally antipathogenic microbes that may offer therapeutic potential either in a direct, one-on-one application or by leveraging its unique metabolic properties. However, the discovery and isolation of such desired therapeutic microbes from complex microbiota have proven challenging. Currently, there is no conventional technique to universally and functionally screen for these microbes. With this said, we first describe in this review the historical (probiotics) and current (fecal microbiota or defined consortia) perspectives on therapeutic microbes, present the discoveries of therapeutic microbes through exploiting microbe-microbe and host-microbe interactions, and detail our team's efforts in discovering therapeutic microbes via our novel microbiome screening platform. We conclude this minireview by briefly discussing challenges and possible solutions with therapeutic microbes' applications and paths ahead for discovery.