RII Track-4:NSF: Determining the Functional Consequences of Co-adaptation Between Host and Gut Microbiota Across Closely Related Host Species

University Of Nebraska-Lincoln, Lincoln NE

Investigators

Abstract

This Research Infrastructure Improvement Track-4 EPSCoR Research Fellows (RII Track-4) project will provide a fellowship to an Assistant Research Professor at the University of Nebraska-Lincoln. This work will be conducted in collaboration with researchers at the University of Washington. The bacteria that reside in the guts of animals affect a wide range of host traits. These include their digestion, metabolism, immunity, disease, and even behavior. However, there is relatively little current understanding of what a healthy set of gut bacteria looks like. In addition, how these sets are built in each host as they grow is also not well known. Over time, bacteria have adapted to their host animal species. Lab mouse-adapted bacteria grow more easily in the gut of lab mice than bacteria that come from other mouse species. So, there is a home-site advantage for these bacteria. It is not known if the opposite is true in other mouse species. This project will generate new tools to look at host-bacteria relationships, including brand new germ-free mice that are closely related to widely-used lab mice. Competition between bacteria adapted to each mouse line will show how these animals adapt to their bacteria. Particular attention will be paid to how the host immune system responds to each set of bacteria and if non-adapted bacteria result in poorer health for the mice. Understanding how bacteria and hosts adapt to each other is vital to improving health via treatment of the gut. This project will advance the University of Nebraska’s Gnotobiotic Mouse program's capabilities and enhance research capacity in Nebraska and the Midwest region. The gut microbiota is known to exert a tremendous influence over host metabolism, immune development, behavior, and many other traits. Hosts and microbiota have adapted to each other over many years, and species have distinct bacterial population profiles. However, a lack of appropriate model organisms, including germ-free Mus species other than the laboratory strain Mus musculus domesticus, has limited the resolution at which research about adaptations and interactions between hosts and their resident microbiota can be addressed. The goal of this project is to determine host-microbiota co-adaptations that affect the assembly of microbial populations in the gut and alter host development. This Research Infrastructure Improvement Track-4 EPSCoR Research Fellows (RII Track-4) project will provide a fellowship to an Assistant Research Professor at the University of Nebraska-Lincoln. This work will be conducted in collaboration with researchers at the University of Washington. This fellowship will train the PI in germ-free mouse rederivation techniques and generate a first-of-their-kind resource, germ-free Mus spicilegus (shrew mouse) and Mus pahari (steppe mouse), two mouse species closely related to laboratory mice. It will also produce critical data on adaptations between hosts and microbes that define how microbes assemble within gut communities and how host immune responses are affected by those bacteria. The new germ-free mouse lines will be generated by sterile cesarean murine births. The new mouse models will be reconstituted with conspecific (from the same mouse species) and heterospecific (from alternate mouse species) microbiota to evaluate whether adapted bacteria outcompete non-adapted species. Host immune responses educated by those bacteria with be analyzed to determine changes in host inflammation driven by responses to those bacteria. Understanding these basic microbe-host interactions and the mechanisms underlying them provides a strong rationale for eventual therapeutic alterations of the gut microbiome. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.