The gut microbiome is comprised of trillions of microorganisms that collectively contain an estimated 100 times more genes than the human genome. Multiple lines of evidence implicate gut microbes and their metabolites as important modulators of health and disease. Cardiometabolic diseases, an umbrella term referring to disease states such as metabolic syndrome and type-2 diabetes which arise from metabolic dysregulation, have been linked to the gut microbiome because of its ability to influence inflammation, lipid metabolism, and glucose homeostasis. Gut microbes can also modify the effect of diet and pharmaceutical drugs on host physiology, thereby regulating responses to therapeutics. For example, dietary fiber is fermented by gut microbes which produce short-chain fatty acids (SCFAs) as a byproduct. SCFAs, particularly butyrate, have been found to be protective against cardiometabolic disease, but its production in the gut is dependent on the presence of specific bacterial taxa which often vary across individuals. Indeed, the gut microbiome exhibits a large degree of interpersonal variation and can therefore potentially modulate therapeutic effects in an individualized manner. Several gaps in our understanding of the relationship between the gut microbiome interpersonal variation, SCFAs, and cardiometabolic disease remain and this thesis attempts to fill some of these gaps. In Chapter 2, I examine the role of the gut microbiome in modifying the atheroprotective effect of dietary fiber through microbiome-dependent variations in butyrate production. In Chapter 3 I show that the gut microbiome alters the impact of a next-generation probiotic, Anaerobutyricum soehngenii, on glycemic control in gnotobiotic mice harboring distinct human communities and provide evidence that this effect is linked to differential responses to the SCFA propionate. Finally, Chapter 4 investigates the mechanism behind butyrate-induced atheroprotection by examining the roles of butyrate receptors Gpr41, Gpr43, and Gpr109a using knockout mice models in the context of hypercholesterolemia. Together, these studies demonstrate the ability of the gut-microbiome-SCFA axis to modulate responses to therapeutics and elucidate the effects of SCFA receptors on cardiometabolic disease and cholesterol metabolism.