Host genetics and gut microbiome have an unquestionably powerful role in various chronic diseases. Currently, we are facing the critical challenge of translating this knowledge into an understanding of how we can harness the potency of gut microbiome to improve diverse aspects of human health. In this dissertation, I explore the potential of the complex interplay between host genetics, diet, metabolism, and gut microbial features as a tool to inform precision nutrition strategies to address the global burden of metabolic disorders. Chapter 1 is a comprehensive narrative review that synthesizes evidence on the role of AMY1 gene copy number variation (CNV) in human metabolic health, in relation to body adiposity and glucose homeostasis. Salivary amylase plays an important role in starch digestion. Consequently, its contribution to the regulation of human metabolism has gained substantial attention. We suggest that individuals’ usual starch intake and gut microbial features should be considered to understand the role of AMY1 CNV in health and disease. In the second chapter, I examined the link between AMY1 CNV, salivary amylase activity, and type 2 diabetes or prediabetes status. We found that having type 2 diabetes or prediabetes interacts with AMY1 copy number (CN) to impact the association between AMY1 and salivary amylase activity. This finding suggests that AMY1 CN expression may play a role in metabolic dysregulation or contribute to insulin resistance. Finally, in chapter three, I discuss a cross-over dietary intervention trial examining the interindividual variability in gut microbial response to resistant starch supplementation. Resistant starch is a type of dietary fiber with demonstrated metabolic health benefits. We supplemented the diet with two types of resistant starch, type 2 and type 4, and a control digestible starch. We found several factors that predict the change in gut microbiota composition or the change in fecal short-chain fatty acid concentrations in response to the consumption of resistant starch. Our findings show that a personalized nutrition approach by characterizing these features prior to a nutritional intervention with RS may increase the likelihood of favorable health outcomes. Overall, this dissertation sheds light on the interplay between salivary amylase, dietary carbohydrate intake, and the gut microbiome focusing on its implications for precision nutrition. Future work to elucidate the underlying biological mechanisms linking these factors to metabolic processes in the form of in vitro or in vivo studies is warranted to systematically analyze these predictors of response to dietary fiber intake.