S-57-2: the gut microbiome and cardiovascular risk factors in humans

Animal studies to date have demonstrated the functional link between gut microbiota composition and cardiovascular outcomes, with specific microbial metabolites being involved. Examples of this include trimethylamine oxide (TMAO) involved atherosclerosis and more recently, studies proving that short chain fatty acids (SCFAs) acetate, butyrate and propionate are involved in blood pressure regulation and cardiovascular outcomes in animal models. At the same time, a number of epidemiological studies have highlighted the links in humans between gut microbiome composition and both hypertension and arterial stiffness. Additional factors involved in cardiovascular disease (CVD) risk that have come from human observational studies show that circulating levels of ceramides, GlycA (a marker of glycosylated acute phase proteins) and indole propionic acid (an antioxidant predictive of insulin resistance and arterial stiffness) are all modulated by the gut microbiome and alter cardiovascular risk in general. Dietary fiber supplementation results in reduced circulating levels of both GlycA and ceramides, both of which have been proven to be predictors of major acute cardiovascular events (MACE). Changes in gut microbiome composition induced by dietary interventions accompany decreases these markers of MACE. Formal mediation analyses of such data show that the effect of gut microbiome composition on the markers of MACE is mediated by increases in circulating levels of SCFAs. Butyrate, propionate and acetate activate the short fatty acid receptors FFAR2 and FFAR3 with different affinities, which might explain the different roles that these compounds play in blood pressure regulation and CVD outcomes. Furthermore, some SCFAs but not others are involved in modulation of the endocannabinoid system. Specifically, butyrate, but not propionate or acetate, affects endocannabinoid circulating levels and is involved in the gene expression levels of enzymes that modulate degradation of endocannbinoids. Importantly, butyrate levels can be modulated by diet but also by exercise. In addition, circulating levels of different SCFAs have different bacterial and host contributions, with serum levels of acetate being negligibly determined by gut microbiota composition (Figure 1). Joining together the evidence from human observational and interventional studies and the data from animal model data helps us delineate a complex series of interconnected pathways from bacterially produced SCFAs to blood pressure regulation and other cardiovascular outcomes, which are modifiable by both diet and exercise.