A host-centric view of the microbiota metabolome

Host-associated microbes produce thousands of metabolites that influence diverse aspects of mammalian physiology, including the immune system. However, the organizing principles governing these interactions remain largely unclear. Here, we propose a host-centric teleological framework for classifying microbiota metabolites based on their impacts on host biology and co-evolutionary principles of host-microbiota symbiosis. We outline three broad functional categories of metabolite-mediated impacts on the host-niche expansion, perception, and (maladaptive) noise. We then discuss transitions between these categories over short and long-term timescales and define specific microbial features that may influence these transitions. Finally, because most microbial metabolites remain uncharacterized, we review approaches to discover novel bioactive microbial metabolites with a view toward comprehensive mapping of small molecule-mediated host-microbe interactions.