Polyphenol epidemiology: looking back and moving forward.

Polyphenols are bioactive compounds that are ubiquitous in plant-based foods and beverages, such as fruit, vegetables, nuts, legumes, whole-grain cereals, cocoa, tea, coffee, andwine (1). Dietary polyphenols comprise a large family of.500 different compounds with highly diverse chemical structures and are divided into 4 main classes: flavonoids, phenolic acids, stilbenes, and lignans. Flavonoids and phenolic acids are by far the most abundant (1). There is an enormous amount of scientific literature that supports the protective effects of polyphenols against disease. In cell, tissue, and animal models, polyphenols have been shown to induce antioxidant phase I and phase II enzymes, modulate cell signaling pathways, and mediate inflammatory response, among others (2); however, the epidemiologic evidence on the reduction in the chronic disease risk is still limited and usually inconsistent (1, 3). The first article on polyphenol epidemiology, to my knowledge, was published in 1993 by Hertog et al. (4) on the associations between flavonol and flavone intakes and coronary artery disease risk. At that point, an important limitation was the absence of a reference database for polyphenol or flavonoid composition. In 2003, the USDA developed the first comprehensive database on food flavonoid contents, and since then the field has grown rapidly (5). There are currently 2 main reference databases: the third edition of the USDA database (released in 2014) (5) and Phenol-Explorer (created in 2009 and updated in 2015) (6), which is the only database containing data on all classes of dietary polyphenols. The first studies were usually descriptive, presenting average dietary intakes, the main food sources, and the potential determinants of their intake (7). Afterward, association studies with clinical endpoints (e.g., overall mortality, cardiovascular diseases, type 2 diabetes, cancer) became more frequent, especially in European and US-based studies, moving from small retrospective case-control studies to large prospective cohorts (1, 3). In this issue of the Journal, we find 2 excellent examples of longitudinal studies: 1) Cassidy et al. (8) report a protective effect of anthocyanidin and flavanone intakes on cardiovascular disease risk in men in a large US cohort, confirming previous results observed in US women (9), and 2) Chang et al. (10) describe, for the first time to my knowledge, inverse associations between flavonol, flavone, and flavanone intakes and depression risk in women in 2 large US-based cohorts, showing potential beneficial effects of some polyphenols on neurocognitive function. Further studies will be needed to confirm the suggested protective effects of flavonoids against chronic diseases such as cardiovascular diseases, type 2 diabetes, obesity, and common types of cancer. Moreover, new studies are warranted to investigate their potential relations with the risk of rare cancers, cognitive and neurodegenerative diseases, and respiratory diseases. PhenolExplorer (6) allows us to evaluate the associations between intakes of other classes of polyphenols (phenolic acids, stilbenes, lignans, and other minor classes) and the risk of chronic diseases. Indeed, it is now possible to investigate the health effects of all known dietary individual polyphenols (n 1⁄4 w500). It is important to consider individual polyphenols, because structurally similar compounds may differ a lot in their bioactivity and bioavailability (11). To take into account the bioavailability of phenolic compounds, the use of blood and urinary biomarkers is useful as an alternative to traditional dietary surveys. To date, there is only 1 analytic methodology able to measure 38 polyphenol metabolites representative of the main classes and subclasses found in the diet (12); however, some important polyphenols, such as anthocyanidins and proanthocyanidins, are not covered by existing methods. Finally, more studies in different geographical areas (Asia, Africa, and Latin America) are required, because these countries have different dietary patterns, foods, and beverages from those of the United States and Europe. The amount and variety of polyphenols consumed may be totally different. For example, isoflavone intake in Asian countries (13) is generally 10-fold higher than in European countries (7). Furthermore, to confirm the findings in observational studies, more intervention trials are warranted. These trials, with the use of polyphenol-rich foods and pure compound doses, will help in the investigation of their underlying mechanisms of action, in isolating the effects of the bioactive compound of interest, and in evaluating their potential dose-response effects. The combination of the results derived from the observational and intervention studies will be essential to allow clinicians and policy makers to improve public health recommendations and dietary guidelines.