This application for a NIH Director's New Innovator Award seeks to solve a major problem in the field of the microbiome: how does a host select for a beneficial microbiome? The microbiome is a critical determinant of human health and fitness, conferring both life-sustaining benefits and a wide array of disease and detriment to the host. The host is thus under strong evolutionary pressure to select for a beneficial microbiome. However the current paradigm of mammalian host control of the microbiome is based on negative selection: the killing or removing members of the ecosystem. Negative selection is capable of selecting against a microbiome, but not selecting for one. Here, I present a multidisciplinary approach to empirically test the hypothesis that the mammalian host solves this problem through positive selection; the selective retention of members of the microbiome. Positive selection has evolved in plants and invertebrates to shape a beneficial microbiome via convergent evolutionary mechanisms: the language of sugars. The information encoded by glycans and glycan binding proteins (lectins), allows these hosts to selective feed and tether specific, beneficial microbial partners. Plants and metazoans, from worms to humans, employ conserved ?anti-microbials? mechanisms of negative selection. Here we propose that host glycans and lectins represent a conserved mechanism of ?pro- microbials? mediating positive selection in mammals. Testing this hypothesis, which potentially holds the key to how hosts shape a beneficial microbiome, demands a rigorous set of experimentation requiring advancing functional glycoscience to unearth the biological properties of natural host glycans and lectins, in-depth empirical and phenotypic analysis of the broad membership of the microbiome, wide-scale genetic manipulation of these microbes, and tests of fitness at the ecological, genetic and molecular level. My unique expertise at the interface of immunology, the microbiome, molecular genetics and evolutionary ecology will allow me to comprehensively determine the existence and power of positive selection in microbial symbiosis in mammals. If successful, this work will develop a new paradigm of host-microbiome symbiosis: positive selection; which will transform our understanding of the human microbiome and provide evolution-tested approaches to target and shape beneficial microbiomes.
How the host maintains a healthy and beneficial microbiome is unknown. This work presents the paradigm shifting concept that rather than only eliminate detrimental members, the host keeps beneficial ones. This project seeks to test this hypothesis, determine the molecular mechanisms by which this occurs and apply this knowledge to shape healthier microbiome in disease.
