Metabolic syndrome (MetS) is characterized by a cluster of metabolic abnormalities, such as impaired glucose metabolism, high blood pressure, low high-density lipoprotein cholesterol (HDL-c) levels, and dyslipidemia (1). Subjects with MetS mainly present with abdominal obesity, hyperglycemia, hypertension, and dyslipidemia (2). It was also closely associated with a higher cardiovascular disease (CVD) risk, type 2 diabetes (T2D) risk, and overall mortality (3, 4). MetS results from complicated risk factors interaction among genetic, metabolic, diet, lifestyle, and environmental factors (5). For instance, smoking, alcohol drinking, and an unbalanced diet contributed significantly to the development of MetS (5). Studies have demonstrated that some dietary life and nutrients played a protective role against MetS development (6, 7). For instance, Mediterranean diet (MedDiet) interventions could improve MetS (8, 9). MedDiet is characterized by a high concentration of polyphenols, which are prospective candidates for ameliorating the chronic low-grade inflammation and oxidative stress of MetS patients (10).

Previous research examined the relationship between dietary polyphenols and MetS, CVD, T2D, cancer, and all-cause mortality (11–17). For instance, high total polyphenols, flavonoids, and phenolic acid intake had 50, 51, and 45% lower odds of MetS, respectively, when compared to low total polyphenols, flavonoids, and phenolic acid intake. In contrast, larger intakes of total polyphenols, flavonoids, and phenolic acids were related to a reduced risk for elevated systolic blood pressure (SBP) and HDL-c, which were independent cardiovascular risk factors (16). However, no relationship was found between total polyphenols intake and other MetS components (18). A French prospective cohort study reported that individuals with polyphenols intake, including anthocyanins, dihydro flavonols, catechins, flavonols, hydroxybenzoic acids, lignans, and stilbenes, had a low risk of T2D, which is independent of major potential confounders (11). Furthermore, a decreased risk of gestational diabetes mellitus (GDM) is related to a large intake of fruit polyphenols. However, no clear association exists between total vegetable polyphenol intake and GDM risk (15). Moreover, a high intake of stilbenes, lignans, hydroxy benzaldehydes, hydroxy coumarins, and tyrosols was associated with a lower gastric cancer risk (12). Additionally, peonidin, naringenin, and catechin intakes were negatively correlated with cancer mortality (17). However, total polyphenols intake was not significantly associated with cancer mortality risk reported in Japanese adults (13). Importantly, individuals' biological aging or the discrepancy between the biological and chronological age of a subject (Δage) was inversely associated with the polyphenol antioxidant content (PAC) score (14). Therefore, a polyphenol-rich diet helps decelerate biological aging, which benefits the long-term risk of MetS, cardiovascular disease, and cancer.

Previous studies have highlighted dietary flavonoids intake as a potential protective factor against developing extra body fat (19). Studies have evidenced that flavonoids are strong antioxidants and metal chelators to decrease energy intake, increase energy expenditure and fat oxidation, influence macronutrient absorption and uptake, and inhibit adipogenesis (20–25). According to a previous study, long-term use of flavonoids may improve cardiovascular disease by restoring the body's natural antioxidant defenses and lowering the risk of low-density lipoprotein cholesterol (LDL) oxidation (26). In addition, flavonoid compounds extracted from apple peel can reduce blood pressure and control body fat (27, 28). Although a previous cross-sectional study including 9,108 Chinese individuals investigated the relationship between flavonoid and copper intake and MetS, there is no proof that any flavonoid compound can ameliorate MetS symptoms (5). A Tehran Lipid and Glucose Study based on Iran's population reported that only flavonols and flavones showed protective effects against MetS. Simultaneously, no significant association was found between the intake of other flavonoid subclasses and MetS risk (29). Due to the intricacy of MetS and the variety of flavonoids, additional research is required to assess the relationship between flavonoid consumption and MetS risk. Furthermore, because each flavonoid component has unique active activity, it was necessary to confirm whether consuming the various flavonoid subclasses was linked with lowering MetS (18).

Consequently, this study aimed to demonstrate the possible association of total flavonoids and subclasses of flavonoid intake with MetS in the USA using the NHANES data system from 2007 to 2010 and 2017 to 2018. We hypothesized that flavonoids intake would be positively associated with a reduced risk of MetS. Additionally, the impact of an individual's clinical characteristics and lifestyle on the MetS reduction brought on by using flavonoids was discussed. This study also explored the most effective dose of each flavonoid subtype for reducing the MetS rate.

This study first investigated the relationship between total flavonoids and their subclasses intake and the MetS risk in the USA population based on NHANES 2007–2010 and 2017–2018. The results demonstrated that higher total flavonoids intake was significantly related to a lower MetS risk, with 13 and 15% reductions in Q3 and Q2 vs. Q1, respectively. Moreover, this reverse effect of total flavonoids on MetS risk was considerably pronounced in men, younger, Mexican, obese, and CVD individuals. The flavanones, isoflavones, and anthocyanidins intake are also inversely related to MetS risk in any population. Furthermore, the dose–response effect demonstrated a U-shaped curve between the total flavonoids intake (change point at 237.67 mg/day), flavanones (change point at 34.37 mg/day), anthocyanidins (change point at 23.13 mg/day), and MetS risk.

Currently, MetS is an urgent public health problem. Previous epidemiological surveys predicted that the prevalence rate of MetS ranges from 20 to 45%. Additionally, over 85% of adults will be overweight or obese by 2030 (36). Therefore, it is critical to explore effective intervention manner for MetS. Flavonoid-enriched diet and moderate physical activity could be the most effective and less costly manner to improve MetS. A previous study investigated the relationship between flavonoids intake and MetS risk. For instance, higher dietary flavonoid intakes were negatively associated with MetS among Polish individuals (37), Iranian adults (29, 38), and Chinese urban adults (5). In this study, total flavonoids intake, flavanones, isoflavones, and anthocyanidins can also reduce the metabolic syndrome risk, even after adjusting for sex, age, and other factors, which was different from a previous study performed in the Iran population (29). Flavonoids have been associated with other health benefits, including reduced T2D and CVD risk, certain cancers, and neurodegenerative disorders. For example, the Health Professionals Follow-Up Study (1986–2006) reported that higher consumption of anthocyanins and anthocyanin-rich fruit was associated with a lower risk of T2D in the USA population (39). Total flavonoids, anthocyanidins, flavan-3-ols, and flavanones intake were also inversely associated with high CVD and atrial fibrillation (AF) risk (19, 40), whereas intakes of flavones and flavonols were not. Moreover, a high intake of flavones (OR 0.62), flavanones (0.64), and anthocyanins were associated with lower odds of subjective cognitive decline (SCD) (41).

Flavonoids are a large, diverse group of bioactive polyphenolic compounds mainly sourced from fruits, vegetables, cereals, and tea (19, 42). There are six subclasses of flavonoids: anthocyanidins (fruits, particularly berries), flavan-3-ols (tea), flavanones (citrus fruits and juices), flavones (tea, peppers, and celery), flavonols (tea, onions, and potatoes), and isoflavones (soy products) (43–45). An investigation of the main food sources of total polyphenol intake and subclasses between 2008–2009 and 2017–2018 in the Brazilian population showed that coffee was the most significant food source for hydroxycinnamic acids and phenolic acids, contributing with 59.4 and 54.1% to the daily total polyphenols intake (46). Tea, coffee, and fruits are the main sources of flavonoids. Among the population of the USA, flavan-3-ols, primarily derived from tea (94%), comprised 80% of flavonoids intake (47). It has been found that consumption of certain foods, such as blueberries, strawberries, apples, orange juice, grapefruit juice, bananas, onions, tea, and peaches, could independently predict the development of SCD in the future (41). However, future multiple-center longitudinal studies must confirm the causal relationship between each flavonoid intake and metabolic syndrome and other diseases.

Indeed, earlier research specified that flavonoids improved metabolic syndrome through their antioxidant and anti-inflammatory properties to repair endothelial function and enhance nitric oxide (NO) bioavailability (48, 49). For example, naringenin, one flavanone compound, can downregulate the levels of triglyceride (TG) and phospholipid and increase the gene expression of PPAR-α, CPT-1, and uncoupling protein (UCP)-2 to reduce blood lipid (50, 51). It could also activate the peroxisome proliferator-activated receptor (PPAR) and adiponectin expression and decrease the liver X receptors (LXR)-α level (52, 53) to treat adiposity and atherosclerosis. Moreover, naringenin showed strong anti-inflammation activity by inhibiting NF-κB activation, the levels of myeloperoxidase (MPO), N-acetyl-β-D-glucosaminidase (NAG), TNF-α, interleukin (IL)-1β, IL-6, and IL-12 (54), and involved into the NO-cGMP-PKG-KATP signaling pathway (36). Therefore, naringenin can potentially improve MetS, which aligns with our findings that flavanones may lower the risk of MetS. Isoflavones, like genistein and puerarin, may influence insulin release and lipids metabolism by blocking adipocyte-specific proteins and controlling PPAR-γ levels (55–57). Additionally, consuming anthocyanins, such as pelargonidin, cyanidin, delphinidin, peonidin, and malvidin, can help treat the pathology of MetS and disorders linked to MetS by reducing body weight, insulin resistance, inflammation, and oxidative stress injury (36). Recent studies have found that dietary lifestyle can affect the structure of the gut microbiome and its metabolites, thereby influencing the development of MetS. By altering the host gut flora, resveratrol, for instance, could decrease body weight and body fat to improve glucose homeostasis and obesity (58). Future randomized clinical trials should be designed to confirm these potential mechanisms in multiple districts.

Although flavonoid intake effectively attenuated MetS, RCS curves showed complex non-linear relationships between flavonoids intake and MetS risk rather than monotonic increasing or decreasing relationships. Additionally, the RCS curves of flavonoids consumption showed slight differences for men and women, indicating that the prevalence of MetS and the amount of flavonoids intake varied by gender. Indeed, men had a significantly higher intake of flavanones (citrus) and flavonols (mixed dishes and beer) than women. Women had a significantly higher intake of anthocyanidins (berries) compared with men (47). Moreover, our previous study found that a diet of 7,8-dihydroxyflavone (7,8-DHF) could protect the function of the female hypothalamic–pituitary–ovarian (HPO) axis and activate tissue-specific ERα to maintain body metabolic homeostasis (59). Additionally, intake rates of flavonoids varied by geographic region, dietary preferences, sociodemographic characteristics, and lifestyle choices. Previous studies reported that the mean flavonoids intake was 34.68 mg/day in Chinese (5), whereas the mean flavonoids intake was 189.7 mg/day in 1999–2002 (60) in the U.S. population. Future large-scale and multi-center clinical trials should be conducted to establish safe doses and create an individual's healthcare program for the potential health implications of attuning the risk of MetS.

The strength of this study was that it was the first large sample, population-based, cross-sectional study that reported the effect of flavonoid intake and its subclasses on MetS based on NHANES from 2007–2010 to 2017–2018. The effects of total flavonoids, flavanones, isoflavones, and anthocyanidins consumption on MetS were evaluated, providing diet recommendations for people in the USA. However, this study has several limitations. First, this study is a cross-sectional investigation that could only present relationships between flavonoids and MetS. Second, flavonoid data was obtained by the 24-h recall, whereas MetS might have already occurred before the interview. Therefore, a bias in the effects of flavonoids intake on MetS is unavoidable. Third, the participants included in this study were all Americans. Consequently, the effects of flavonoids intake on MetS observed in this study may be unsuitable for Asians or other populations.

Higher flavonoid intakes could reduce MetS risk in the USA population. In addition, flavanones, isoflavones, and anthocyanidins are the most effective flavonoid subclasses in attenuating MetS, while other flavonoid subclasses showed a relatively small effect. Total flavonoids, flavanones, isoflavones, and anthocyanidins demonstrated non-linear relationships with MetS risk. The most effective doses of total flavonoids, flavanones, and anthocyanidins were 237.67, 34.37, and 23.13 mg/day, respectively. Further large-scale randomized controlled trials should be performed to establish causality between flavonoids intake and MetS risk and the safe doses of flavonoids in different populations. Regarding the perspective of public health, our findings may provide fresh insight into MetS risk based on flavonoids intake and build future tailored dietary recommendations as a preventative tool against metabolic syndrome based on the most effectively calculated amounts.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ZZ and WX: conceptualization and writing—review and editing. WG and XD: methodology. WG and CX: software. GM and CX: validation. ZZ: formal analysis. XX: data curation. GM and WX: writing—original draft preparation. All authors have read and agreed to the published version of the manuscript.