Abstract: The gut microbiota is increasingly recognized as an important contributor to a range of human physiological processes and is attracting increasing attention as a dynamic area for the development of therapeutics. To realize the potential of the gut microbiome in a therapeutic context, animal models are necessary to generate causal, mechanistic data describing host-microbe interactions. While mice and fish have been critical in generating foundational microbiome data toward this goal, they have key genetic, physiological, and behavioral differences from humans that can interfere with the translation of findings. Non-human primates share many genetic, physiological, and behavioral traits with humans, increasing their translational potential. Although non-human primates are used for research across the NIH, they are currently underutilized in microbiome research and have not been systematically validated as models in this context. Given the significant investment required for non-human primate studies, it is especially important to characterize which models are best suited for particular questions as we seek to examine how microbiomes impact human health and disease. Here we propose to develop non-human primates as valuable model organisms for functional studies of the human microbiota. Specifically, we aim to identify the best uses for different non-human primate species in microbiome research. We will generate baseline microbiome (shotgun metagenomics, analysis of SCFA concentrations, untargeted metabolomics) and physiological data (metabolic panels, immune cell populations, serum metabolomics) from humans and five non-human primate species commonly used as biomedical models (marmosets, owl monkeys, squirrel monkeys, baboons, and macaques). These data will allow us to determine which non-human primate species model different taxonomic and functional features of the human gut microbiome and to measure the consistency of host-microbiome interactions across human and non-human primate species. Our efforts hold potential to unlock critical insight about the utility of longstanding non-human primate biomedical models for different aspects of microbiome research and will ultimately help researchers accelerate the translation of microbiome discoveries into clinical settings. By identifying how well different non-human primate species model humans in a subclinical context, the proposed project will lay the groundwork for future R01 proposals that use non-human primate models to interrogate host-microbe interactions in a disease context. Overall, this line of inquiry will facilitate future studies targeting key questions about host-microbe interactions with a high potential for translational science and medical benefit.

Narrative: This project aims to provide a foundation for accelerating the development of microbiome therapeutics by systematically validating non-human primate animal models that can provide causal, mechanistic data regarding microbial impacts on host physiology. Specifically, it will improve the utility of longstanding non-human primate biomedical models for microbiome research by determining which non- human primate species model different taxonomic and functional features of the human gut microbiome and measuring the consistency of host-microbiome interactions across human and non-human primate species. Overall, the results will facilitate future studies targeting key questions about host-microbe interactions and disease in non-human primate models that, due to their genetic, physiological, and microbiomic similarities with humans, have a higher translational potential than mouse models.