Cardiovascular disease is a major health concern in the United States. Dietary patterns like the Mediterranean diet have demonstrated beneficial effects on cardiovascular health. The health benefits of any dietary pattern likely stem from the combined effects of its individual dietary components that can exert their beneficial effects through affecting host biology directly, as well as through modulation of the gut microbiome composition and functionality. Two common dietary components, olive oil and walnuts, have been studied in relation to cardiometabolic and gut health in several randomized, controlled trials. The first chapter in this dissertation summarizes the current literature published on the role polyphenol and lipid-rich foods play in the gut-heart-brain axis. The review focuses on individual components in walnuts and olive oil that could potentially modulate gut microbiome composition and or functionality and consequently affect the gut, heart and brain health. With increased knowledge of how individual dietary components affect the host directly and indirectly through the gut microbiome changes, recommendations of foods to include in dietary patterns can be made with more confidence. Diet is one factor modulating gut microbiota composition and functionality. However, determining causal links between diet-gut microbiome interactions and human health is complicated by inconsistencies in the evidence, arising partially from differences in research methods and reporting. Widespread adoption of standardized best practices would help advance the field but requires those practices be identified, consolidated and discussed. The second chapter is an umbrella review that aims to identify recommended best practices, define existing gaps, and collate considerations for the design of studies investigating diet-gut microbiome interactions in relation to human health outcomes. Recommendations, considerations and gaps relating to best practices within the categories of study design, participant selection, dietary intervention/assessment, biological sample collection, and statistical analysis were extracted and consolidated to identify agreement and knowledge gaps. Eight narrative reviews were included. Several general points of agreement were identified but a recurring theme was that best practices will depend on the research aims, outcomes and feasibility. Multiple gaps were also identified. The third chapter investigates the effects of daily walnut consumption on established biomarkers of cardiovascular health, as well as gut inflammation and gut microbiome in adults between the age of 45 and 75 years with borderline elevated LDL-C levels. In this randomized crossover trial, thirty participants were randomized to consume 56 g of walnuts daily or follow a no-nut diet for 3 weeks. One-week run-in and a 3-week washout periods were also included in the study design. Blood, fecal, and urine samples were collected at the beginning and end of each intervention period. Blood lipids, circulating inflammatory markers, fecal gut inflammatory markers, walnut- and microbial-derived metabolites, as well as gut microbial relative abundancies were investigated. Walnuts decreased total cholesterol, LDL, lipocalin-2 and calprotectin. Fecal lithocholic bile acid and several short-chain fatty acids were also lower after walnut consumption compared to the no-nut diet. Percent relative abundance of Roseburia increased, while relative abundance of fecal Bifidobacteria and Alistipes decreased after walnuts. In addition, three urolithin metabotypes were identified and plasma/urine levels of various urolithin metabolites were correlated with blood lipids and fecal bile acid levels. The fourth chapter investigates the effects of consumption of two types of olive oil, low-polyphenol (LPOO) and high-polyphenol (HPOO), on biomarkers of cardiometabolic health in acute and short-term consumption settings. This chapter focuses on the effects of circulating blood cytokines and cytokines released from whole blood and peripheral blood mononuclear cells (PBMCs) either unstimulated or stimulated with bacterial lipopolysaccharide (LPS). Twenty-six generally healthy adults (BMI >18.5 kg/m2) participated in this randomized crossover trial. Participants were randomized to consume 40 ml of LPOO or HPOO. Following the assessment of acute consumption (2 hrs and 4 hrs postprandial), participants consumed their respective treatment daily for 2 weeks to determine effects of short-term consumption. There were no notable differences between treatments in levels of systemic cytokines and cytokines released from stimulated or unstimulated whole blood. We did not observe any significant between-group differences in systemic cytokines and cytokines secreted from unstimulated whole blood with two weeks of HPOO and LPOO consumption. However, in LPS stimulated PBMC samples, IL-1ß secretion was lower after short-term HPOO consumption compared to LPOO. After acute consumption, IL-6 and TNF-a spontaneously secreted from PBMCs were increased 4hrs after HPOO but not LPOO consumption. In contrast, TNF-a secreted from LPS stimulated PBMCs was lower 4hrs after HPOO intake compared to LPOO. The fifth chapter is the conclusion. This chapter briefly summarizes the major findings of the literature review, umbrella review and the walnut and olive oil studies. Furthermore, it provides overall interpretation of these findings, as well as several future directions.