The gut microbiota is an integrated part of human biology and has coevolved with us, passing from generation to generation for millions of years. Therefore, the species that are likely to have biology most compatible with the human genome are specific and not a random collection that we can assemble from the surrounding environment and let the prevailing selective forces shape. The plasticity of the gut microbiota offers tremendous potential for therapeutic manipulation, but this malleability can translate into species-loss during perturbations like those that have accompanied industrialization. The microbiota of people living a Western lifestyle differs substantially from that of traditional populations whose lifestyles are relatively free of the forces of modernization. These “traditional” microbiotas contain taxa that are common to traditional populations on different continents yet are absent or exceedingly rare among people in the industrialized world. This project aims to understand the species and genes that define and differentiate the microbiome of traditional populations. A primary goal of this research is to pursue a deep biological understanding of how compositional and functional differences between the traditional microbiota and Western microbiota affect human biology. Using existing de-identified archived stool samples from hunter-gatherers, a variety of tools will be applied including deep metagenomic sequencing, isolation and characterization of microbial species that are absent or rare in the Western gut, gnotobiotic mouse models, and molecular genetics. This study will result in an important, novel understanding of the human microbiome, one that addresses the fundamental question of what defines the microbiomes that our species evolved with. Investigating the microbiome from an evolutionary perspective will yield insight into how missing components of our biology may be complemented via gut microbiota colonization. This approach will significantly contribute to preventing and treating a spectrum of non-communicable chronic diseases.