UNVEIL THE CONNECTION BETWEEN METABOLIC AND INFLAMMATORY CARDIOVASCULAR RISK FOSTERED BY NUTRIENT INTAKES.

Background: Therapeutic strategies targeting the residual inflammatory risk (increased levels of inflammatory markers) effectively further reduced ACVD incidence. On the other hand, therapeutic strategies to contain the residual metabolic risk (increased TGRL) provided discordant results. Recent evidence support a casual association between metabolic and inflammatory risk, and also describe, at a molecular level, the immuno-metabolic effects of dietary intakes, and the potential implication of gut microbiome in these connections. In this context, we aimed to unveil the connection between the metabolic and inflammatory cardiovascular risk fostered by nutrient intakes. To achieve our aim the following tasks were settled: (i) deepen the relation between the metabolic and inflammatory risk, beyond LDL-C; (ii) identify the targetable dietary aspects to reduce both the metabolic and inflammatory risk; (iii) constraining the metabolic and its associated inflammatory risk by long-term targeting of those dietary aspects; (iv) identify the potential implications of gut microbiome composition in the association between dietary intakes, and the metabolic and inflammatory ACVD risk. Materials and methods: In two cohorts, one in primary and the other in secondary prevention for ACVD (PLIC-Progressione delle Lesioni Intimali Carotidee Study, SMART- Secondary Artery Manifestation Study), were compared the association of either the metabolic (as calculated TGRL-C levels) risk or LDL-C levels with the inflammatory risk, taking advantage of a wide set of proteins measured in plasma (Olink platformTM) and predicting their involvement in immune-inflammatory processes through Ingenuity Pathway Analysis. In the PLIC cohort, the same set of plasma proteins was employed to validate the predicted inflammatory potential of diet (estimated from the analysis of 7-day dietary record via the Dietary inflammatory Index, DII). Then, we explored the relation of the DII with circulating TGRL concentrations and triglycerides/cholesterol content of TGLR in serum samples analyzed by Nuclear Magnetic Resonance (Nightingale Health platform). Seven-teen subjects, from the PLIC cohort, were enrolled in a 4-week dietary interventional trial to test the effects of lowering the DII on the long-term metabolic and inflammatory risk but also on the acute metabolic and inflammatory risk fostered by the consumption of a pro-inflammatory/fat-enriched meal (OFL). Long-term and acute metabolic and inflammatory risk were measured as i) fasting, ii) postprandial, and iii) postprandial increase in TGRL triglycerides and cholesterol content and immune cells count and their markers expression levels. With an ex-vivo setting, we explored the acute and long-term effects of fasting and postprandial TGRL on inflammatory gene expression in immune cells before and after lowering the DII. We finally observationally correlated gut microbiome composition (assessed through Next-generation Sequencing analysis on DNA extracted from fecal samples) with the DII, and TGRL features from the Nightingale Health platform. Results: We found, both in primary and secondary prevention settings, a higher number of circulating plasma proteins associated with increased TGRL-C compared to increased LDL-C. On top of common ACVD risk factors (CVRFs) the performance of classifications of these proteins was impressively higher in identifying those subjects with increased TGRL-C compared to those with increased LDL-C. Furthermore, these proteins recapitulated the involvement of immune cell inflammatory processes. The inflammatory potential of diet (validated against circulating plasma proteins and inflammatory processes) marked increased levels of circulating TGRL and their triglycerides and cholesterol content. The dietary intervention resulted in a significant reduction in the inflammatory potential of diet and effectively improved both the long-term and acute metabolic and inflammatory risk. Some gut microbiome genera were mutually associated with the inflammatory potential of diet and TGRL concentrations and their triglycerides and cholesterol content. Conclusion: We provided novel human epidemiological and interventional evidence about the connection between the inflammatory potential of diet and individual metabolic and inflammatory risk. Integrating the inflammatory potential of diet as a target in actual therapeutic strategies, and individualizing these last according to gut microbiome composition, are two important points to account for containing the metabolic and inflammatory risk, thus optimizing ACVD risk prevention and treatment.