Polyphenol-Derived Microbiota Metabolites and Cardiovascular Health: A Concise Review of Human Studies

Abstract

Polyphenols, plant-derived secondary metabolites, play crucial roles in plant stress responses, growth regulation, and environmental interactions. In humans, polyphenols are associated with various health benefits, particularly in cardiometabolic health. Despite growing evidence of polyphenols' health-promoting effects, their mechanisms remain poorly understood due to high interindividual variability in bioavailability and metabolism. Recent research highlights the bidirectional relationship between dietary polyphenols and the gut microbiota, which can influence polyphenol metabolism and, conversely, be modulated by polyphenol intake. In this concise review, we summarized recent advances in this area, with a special focus on isoflavones and ellagitannins and their corresponding metabotypes, and their effect on cardiovascular health. Human observational studies published in the past 10 years provide evidence for a consistent association of isoflavones and ellagitannins and their metabotypes with better cardiovascular risk factors. However, interventional studies with dietary polyphenols or isolated microbial metabolites indicate that the polyphenol-gut microbiota interrelationship is complex and not yet fully elucidated. Finally, we highlighted various pending research questions that will help identify effective targets for intervention with precision nutrition, thus maximizing individual responses to dietary and lifestyle interventions and improving human health.

Keywords: cardiovascular health; equols; gut microbiota; metabolites; polyphenols; urolithins.

Figure 1

Simplified route of digestion, absorption, metabolism, and excretion of dietary polyphenols. Intact polyphenols are poorly absorbed in the gastrointestinal tract. Small aglycones are absorbed in the small intestine and undergo phase I and II liver metabolism before reaching the bloodstream and target tissues. Complex polyphenols accumulate in the colon, where they undergo extensive catabolism by the gut microbiota. Microbial metabolites can then be absorbed and undergo further biotransformation before reaching circulation and target tissues. Created with BioRender.com.

Figure 2

Pomegranates, walnuts, and berries like strawberries and raspberries are dietary sources of parent polyphenolic compounds ellagitannins, such as (1) β-punicalagins, and (2) ellagic acid. Upon ingestion, these polyphenolic compounds are poorly bioavailable and accumulate in the lower gastrointestinal tract. Bacterial species in the colon are involved in the catabolism of ellagitannins and ellagic acids. Main catabolic reactions are ester hydrolysis to release ellagic acid from ellagitannins, cleavage of the carbon–oxygen bond to open a lactone ring, and sequential de-hydroxylation reactions to generate urolithins with different degrees of hydroxylation. Among urolithins, urolithins A and B are the most studied in the context of human health. Created with BioRender.com. Chemical structures created with Marvin JS (Chemaxon, Budapest, Hungary).

Figure 3

Legumes like soybeans, chickpeas, beans, and peanuts are dietary sources of parent polyphenolic compounds (1) daidzein and (2) genistein (isoflavones). Upon ingestion, these polyphenolic compounds are poorly bioavailable and accumulate in the lower gastrointestinal tract. Bacterial species in the colon are involved in the catabolism of isoflavones. Main catabolic reactions are de-glycosylation to release the polyphenolic aglycone and sequential hydrogenation and dehydroxylation reactions, generating equols. The alternative pathway involving ring cleavage and generation of O-desmethylangolensin is not shown in this figure. Created with BioRender.com. Chemical structures created with Marvin JS (Chemaxon, Budapest, Hungary).