[38]
4. Flavonoids
While it is now widely acknowledged that supplementing diets with vitamins and minerals can be beneficial, the effects of flavonoid supplementation are less well-known. In fact, flavonoids rank just behind vitamins and minerals as one of the most promising and thoroughly researched plant nutrients that promote health and decrease the risk of disease. Flavonoids have historically had a considerable role in human diets. They can be traced back to the discovery of vitamins, when early studies on scurvy discovered a connection between vitamin C and another molecule (vitamin P), as well as potential interactions between the two
[39]. It was determined that the absence of vitamin C and other elements of lemon extract, which contains various flavonoid compounds, causes scurvy, or vitamin C deficiency
[3]. Since then, research has linked certain flavonoids to “vitamin P (P for permeability)” activity, which is crucial for maintaining human health
[3].
4.1. Human Research
A search on the PubMed database using the keywords “dietary flavonoids + human health” returned more than 570 results from randomized controlled trials (RCT), systematic reviews, and meta-analyses of RCT that are related to the consumption and use of dietary flavonoids and their diverse health benefits for humans. Table 1 summarizes the major clinical results from the most recent studies.
Numerous studies have demonstrated the benefits of flavonoids on cognitive health in humans
[40][41][42]. Notably, a recent observational study found a link between the long-term intake of dietary flavonoids and a lower risk of cognitive decline
[40]. A higher dietary intake of dietary antioxidants (e.g., anthocyanins) has been associated with a lower risk of Parkinson’s disease
[43], and a cohort study associated the long-term intake of dietary flavonoids with a lower risk of Alzheimer disease and related dementia
[44].
For cardiovascular health, systematic reviews and meta-analyses of randomized trials, as well as prospective cohort studies, have associated flavonoid consumption with a lower risk of cardiovascular disease mortality
[41][42][45]. Flavonoid-rich diets, such as the Mediterranean or Japanese diet, have been associated with a lower risk of cardiovascular disease and diabetes, as well as longevity
[46]. A Japanese study also found an inverse correlation between dietary flavonoid intake and total plasma cholesterol levels in Japanese women; the authors further associated these findings with a lower incidence of coronary heart disease in Japanese women
[47]. Singh et al. reported that the Indo-Mediterranean diet (flavonoid intake 1800 mg/day)—which is rich in fruits, vegetables, and whole grains, and has a low glycemic index—can significantly reduce the incidence of coronary artery disease in high-risk patients
[48]. Furthermore, study participants with type 2 diabetes mellitus showed reduced pro-inflammatory cytokine IL-6 concentrations and significantly increased plasma concentrations of naringin, hesperetin, and hesperidin when they followed a 12-week Mediterranean diet with a high intake of citrus bioflavonoids
[49].
As a point of reference, the average daily consumption of flavonoids from foods in various regions of the world is as follows: 132 mg in the United States, 250–900 mg in Europe, 200–650 mg in Asia, and 1650 mg in the Middle East
[46].
A recent systematic review concluded that flavonoid supplementation may help to improve the metabolic syndrome by enhancing the blood lipid profile, blood pressure, and blood glucose levels
[50]. Similarly, in randomized controlled trials, dietary flavonoids have demonstrated positive effects on type 2 diabetes by reducing insulin resistance
[51] and, consequently, may promote cardiovascular and metabolic health
[52][53]. As a result, flavonoids have been proposed as an effective adjunct therapy to other anti-diabetic medications
[52].
Additionally, several studies have highlighted wide-ranging bioactivities of flavonoid compounds which include antioxidant, anti-cancer, cardioprotective, anti-diabetic, anti-inflammatory, and anti-viral effects
[1][54][55][56][57]. Apigenin has been considered as a natural remedy against chronic inflammatory conditions that are commonly associated with cancer, cardiovascular disorders, or diabetes
[58][59]. Several flavonoids were found to interfere with the progression of cancer through diverse molecular mechanisms
[60]. In particular, flavanones, flavones, and isoflavones can affect hormone functions by inhibiting aromatase activity and binding to estrogen receptors, and, consequently, may play an important role in hormone related cancers
[61]. For instance, a recent systematic review and meta-analysis of observational studies found an association between a high intake of flavonols (e.g., kaempferol) and isoflavones (daidzein, genistein, glycitein, and formononetin) and a markedly reduced risk of ovarian cancer
[62]. Along the same line, Hui et al. reported an association between a reduced risk of breast cancer and a high intake of flavonols and flavones in women
[63].
The flavonol quercetin is a well-known antiplatelet compound which can inhibit platelet aggregation through various signaling pathways and, thus, may play a crucial role in the prevention of thrombosis and cardiovascular disease
[64][65]. Furthermore, the anticoagulant and anti-platelet effects of quercetin can be beneficial for treating viral diseases such as COVID-19, since the infection may initiate thrombotic events through changes in platelet aggregation
[66]. Thus, quercetin received attention during the COVID-19 pandemic because of its versatile anti-SARS-CoV-2 effects
[67][68][69]. Clinical studies have proposed quercetin as a promising natural molecule in the preventive treatment of coronavirus infections
[70], as well in the early stage of COVID-19 infections
[71][72].
Table 1.
Dietary flavonoids and their clinical benefits for human health.
4.2. Flavonoid Bioavailability
Low oral bioavailability is yet another problem that flavonoids have in common with other bioactive plant compounds. A compound must be absorbed (i.e., “biologically accessible”) in order to exert any beneficial health effects in the body. The poor bioavailability of flavonoids makes it more difficult to determine whether a person’s dietary intake is sufficient. Furthermore, after the oral ingestion of foods or dietary supplements, flavonoids undergo extensive Phase I and Phase II metabolism in the liver. The metabolic process starts as early as when the compounds are absorbed in both the small and large intestines
[73], and several conjugated forms are produced (e.g., glucurono-, sulpho-, and methyl-derivatives). These conjugated forms are the ones that pass into the blood stream. Eventually, they are deconjugated in the cells by enzymes such as β-glucuronidase and then excreted by the kidneys
[42].
Numerous factors can influence bioavailability and limit clinical efficacy. For instance, differences in age, sex, genetic polymorphisms, lifestyle, dietary history, overall health state (e.g., presence of disease), and the microbiome may affect metabolic processes
[73]. Hence, the bioavailability of dietary flavonoids can be highly variable between individuals—likely generating different biological responses. Furthermore, there is mounting evidence suggesting that the gut microbiota may play a key role in catabolizing flavonoids into smaller molecules (e.g., phenolic and aromatic acids), which makes them more bioavailable
[73][74][75]. As a result, bioavailability is likely to be affected by the food matrix/composition, the food compound interactions, the food processing (e.g., high-temperature treatments
[76]), and the plant source
[42].
4.3. Ways to Improve Flavonoid Absorption and Clinical Benefit
Enhancing the clinical effectiveness and therapeutic potential of flavonoids requires increasing their bioavailability. The oral absorption of dietary flavonoids has been improved through several methods. Making the parent molecule more soluble and stable typically improves bioavailability by increasing the cellular absorption with amplified pharmacological effects. In a few human studies, using novel food-grade delivery systems that microencapsulate the compound in a lipomicel or liposome matrix resulted in significantly higher plasma concentrations of quercetin
[77][78]. However, because flavonoids have diverse chemical structures, each flavonoid would need to undergo its own optimization for greater bioavailability.
4.4. Interactions
Egert and Rimbach (2011) reviewed the interaction mechanisms of flavonoids with trace elements and vitamins, as well as chemical drugs
[79]. Several studies have already demonstrated that flavonoid compounds such as quercetin, as well as flavonoid-rich foods (e.g., black and green tea, coffee, red wine, and legumes), may interfere with iron absorption in the body
[80]. However, iron absorption is a complex process that is affected by numerous dietary factors. This is especially true for the absorption of non-heme iron (i.e., from plant-based foods) because the process is more affected by food compounds than the absorption of heme iron from animal tissues
[81][82][83]. Therefore, individuals who are already at risk of iron deficiency may need to carefully consider the high intake of dietary flavonoid-containing supplements. On the other hand, recent studies have reported that flavonoids may be beneficial as a complementary therapy to reduce iron overload due to their iron chelating and antioxidant activities
[84]. Since both iron deficiency and iron overload can cause severe health issues such as hematological, metabolic, and neurodegenerative disorders, as well as carcinogenesis
[85][86], flavonoids could play an essential part in regulating iron homeostasis
[86].
Additionally, a few studies have discussed the interaction of flavonoid compounds with thyroid functions in terms of the synthesis and metabolism of thyroid hormones
[87]. While some studies have demonstrated the antithyroid and goitrogenic effects of flavonoids, other studies found that flavonoids can stimulate the uptake of iodide
[88], which is a key parameter in thyroid cancer, thus highlighting the therapeutic potential of flavonoids in radioiodine therapy
[87].
Numerous in vitro drug interaction studies have investigated the inhibitory activity of flavonoids on various cytochrome P450 monooxygenase (CYP) enzymes (summarized by
[79]). For example, Li et al. reported a structure-dependent inhibition of CYP3A4 by some flavonoids
[89]. Šarić Mustapić et al. reported similar study results in which 7 out of 30 screened flavonoids showed significant inhibition of CYP3A4
[90]. Despite all the in vitro evidence, more definitive results from clinical research are needed to confirm these observations and determine the clinical significance of drug–flavonoid interactions.
Flavonoids can also affect drug transporters (so called “efflux pumps”) involved in the cell uptake and the extrusion of drugs and, therefore, can alter the metabolism and the absorption of drugs. In in vitro studies, flavonoids exhibited inhibitory effects on proteins which confer resistance to various conventional drugs. These include, for example, ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein, breast cancer resistance protein (BCRP), and multidrug resistance-related protein 1 (MRP1)
[91][92]. On the one hand, the efflux pump inhibitory activity of flavonoids can be highly beneficial for improving the clinical efficacy of otherwise poorly absorbed drugs (e.g., chemotherapeutics); on the other hand, it can alter the toxicity profile of drugs, which may be problematic for drugs with a narrow therapeutic index.