The human gut microbiome is tightly linked our health. Our analyses of diverse human populations from around the globe, ranging from hunter-gatherer to industrialized, show that the gut microbiome is profoundly influenced by lifestyle. With a large collaborative team, we conducted deep metagenomic sequencing of the gut microbiomes of Tsimane horticulturalists from Bolivia and compared them to those of Hadza hunter-gatherers from Tanzania. We are also investigating whether diet and microbial therapies can address deficiencies in the industrialized gut community. Molecular mechanisms of host-microbial interaction are pursued using an array of technologies and experimental approaches including gnotobiotic and conventional mouse models, quantitative imaging, and a metabolomics pipeline focused on investigating microbiota-dependent metabolites. (#40698)