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Recent discoveries of the purpose and potential of microbial interactions with humans have broad implications for our understanding of metabolism, immunity, the host−microbe genetic interactions. Bioavailability and bioaccessibility of phytonutrients in foods not only enrich microbial diversity in the lower human gastrointestinal tract (GIT) but also direct the functioning of the metagenome of the microbiota. Thus, healthy choices must include foods that contain nutrients that satisfy both the needs of humans and their microbes. Physical activity interventions at a moderate level of intensity have shown positive effects on metabolism and the microbiome, while intense training (>70% VO2max) reduces diversity in the short term. The microbiome of elite endurance athletes is a robust producer of short-chain fatty acids. A lifestyle lacking activity is associated with the development of chronic disease, and experimental conditions simulating weightlessness in humans demonstrate loss of muscle mass occurring in conjunction with a decline in gut short-chain fatty acid (SCFA) production and the microbes that produce them. This review summarizes evidence addressing the relationship between the intestinal microbiome, diet, and physical activity. Data from the studies reviewed suggest that food choices and physical fitness in developed countries promote a resource “curse” dilemma for the microbiome and our health.