Background

Metabolic syndrome (MetS) is generally defined as a complex disorder represented by a cluster of cardiovascular risk factors such as central obesity, dyslipidemia, hypertension, and impaired glucose metabolism, leading to an increased risk of coronary heart diseases, other types of atherosclerotic cardiovascular diseases, and type 2 diabetes (DT2) [1]. Recent evidence suggests that the prevalence of MetS is increasing in both developed and developing countries, such as Brazil [2, 3].

Diets rich in fruits and vegetables, especially those considered berries, increase the intake of polyphenols, which are known to confer benefits to the cardiovascular health [4, 5]. Cranberries (Vaccinium macrocarpon) are native fruits from North America that contain low carbohydrate concentrations in comparison to other fruits. Furthermore, they have high content of vitamins, minerals, and polyphenolic compounds [6], such as flavan-3-ols, anthocyanins, benzoic acid, and ursolic acid [7]. A-type proanthocyanidins are also present in high concentrations in cranberry, while other berries predominantly have B-type proanthocyanidins. B-type proanthocyanidins are believed to be less bioavailable than the A-type [8]. The most abundant flavonoids in cranberries consist mainly of quercetin and myricitrin [7].

Moreover, it has been demonstrated that cranberry juice may contain resveratrol in concentrations similar to grape juice [9]. Resveratrol has several biological effects related to cardiovascular health, including inhibition of platelet aggregation and reduction of inflammation [6]. The polyphenols present in cranberry have a wide variety of biological effects, including antibacterial, anticarcinogenic, antiangiogenic, anti-inflammatory, antioxidant, modulating enzyme activity, and gene expression regulation [7, 10,11,12,13,14,15,16].

Cranberry juice may contain 100% of the daily requirement of vitamin C, contributing to the beneficial effects of the fruit [10]. Cranberries can be consumed in various products such as industrialized juice, jam, frozen fruit pulp, sauce, cereal bars, and capsules and have become increasingly popular and consumed, after several researches have indicated health benefits including possibly preventing diseases such as urinary tract infection [17].

According to observational and interventional studies in humans, consumption of cranberry and cranberry products may be associated with beneficial effects on MetS, affecting one or more of its components [6, 18], a variety of inflammatory biomarkers and oxidative stress [19]. Thus, the present review gathers recent and relevant literature involving the consumption of cranberry products and the components of the MetS in humans, in addition to highlighting the most relevant mechanisms involved.

Main text

Cranberry and obesity

Obesity has become a major public health issue, and it is growing worldwide. In 2012, approximately 34.9% of American adults were classified as obese [20]. Obesity is usually defined when body mass index (BMI) is greater than or equal to 30 kg/m2. Abdominal obesity is defined as a waist circumference (WC) above 102 cm in men and 88 cm in women [21]. Additionally, other waist circumference values have been applied for the diagnosis of abdominal obesity in MetS to improve their applicability to different ethnic groups [21, 22]. Some recommended waist circumference thresholds are as follows: for Europeans and South Americans (≥94 cm in men and ≥80 cm in women), South Asians and Chinese (≥90 cm in men and ≥80 cm in women), Japanese (≥85 cm in men and ≥90 cm in women), and Americans and Canadians (≥102 cm in men and ≥88 cm in women) [21, 22].

An epidemiological study with data from the National Health and Nutrition Examination Survey (NHANES) including 10,891 American adults showed that cranberry juice consumers were more likely to have normal weight and lower waist circumference. The authors attributed the favorable effects on body composition to flavonoids, which are present in high levels in cranberries [23]. Other studies have demonstrated that bioactive compounds such as flavonoids have the potential to inhibit lipogenesis and adipogenesis, stimulate lipolysis, and induce apoptosis in adipocytes [24]. It has been previously demonstrated that cranberry reduces the proliferation and viability of 3T3-L1 pre-adipocytes in a dose-dependent manner. The nutritional intervention with this berry also reduced the number of adipocytes and reduced the accumulation of lipids in the 3T3-L1 pre-adipocytes, indicating an inhibitory effect on lipogenesis. Furthermore, it was demonstrated that cranberry induced lipolysis in adipocytes and reduced the expression of PPARγ, C/EBPb, and SREBP1, which are important transcription factors of the adipogenesis pathway [25].

Diet is closely related to the development of obesity; therefore, a diet enriched with these compounds may serve as an additional strategy for the prevention and treatment of obesity. The main human-interventional studies with cranberry or cranberry products considering markers of obesity are listed in Table 1. In sum, although an epidemiological study [23] verified that consumers of cranberry drinks were more likely to have more favorable anthropometric measures, clinical trials on this subject are still scarce and the results are inconsistent. Therefore, more work is needed to obtain stronger evidence.

Table 1 Intervention studies with cranberry products evaluating markers of obesity
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Cranberry and glucose metabolism

Glucose homeostasis is disturbed when insulin and fasting glucose are greater than 20 mU/mL and 110 mg/dL, respectively, or when the patient has to use medication to control blood glucose [26]. Matthews et al. [27] described a mathematical relationship (HOMA-IR model) between fasting glycemia and insulin to predict insulin resistance [28]. Lower HOMA-IR values represent higher insulin sensitivity, and higher values correspond to decreased insulin sensitivity, also known as insulin resistance (IR). IR and hyperinsulinemia contribute to the pathogenesis of type 2 diabetes.

Wilson et al. [29] studied postprandial insulin and glucose response in patients with type 2 diabetes. The subjects were allocated into four groups that received: a single serving of white bread (57 g, 160 calories, 1 g of fiber); raw cranberries (55 g, 21 calories, 1 g of fiber); sweetened cranberries (40 g, 138 calories, 2.1 g of fiber); or cranberries with low sugar and high fiber content (40 g, 113 calories, 1.8 g of fiber, and 10 g polydextrose). The investigators found that the consumption of low-sugar, high-fiber cranberries resulted in more favorable glucose and insulin peaks. Thus, the selection of dry cranberries, a natural source of polyphenols and fibers, would enable a more favorable glycemic response in patients with T2D. The decrease in glucose peak may be due to the presence of the soluble fibers polydextrose and β-Glucan, which were present in the low-calorie serving, since these compounds have been related to the reduction in the rate of gastric glucose absorption [30, 31]. The presence of flavonoids in cranberry juice can also delay the intestinal absorption of glucose [32], contributing to the improvement in the glycemic response observed in previous studies carried out by the same research group [33].

In vitro studies have demonstrated that the extent of inhibition of α-glucosidase by berry extracts is related to its anthocyanin content [34]. Cyanidin-3-rutinoside [35] and cyanidin-3-galactoside [36] are considered α-glucosidase inhibitors. Proanthocyanidins are also considered potent α-glucosidase inhibitors [37]. Barrett et al. [38] conducted an in vitro study to investigate if the tannins (proanthocyanidins and elagitannins) present in pomegranate, cranberry, grape, and cocoa extracts could bind to the digestive enzymes α-amylase and glucoamylase, thus inhibiting starch hydrolysis. The authors concluded that not only were tannins capable of inhibiting these enzymes but also larger and more complex tannins such as cranberries would have the ability to inhibit enzymes more effectively than less polymerized tannins, such as those present in cocoa [38]. Another in vitro study has shown that cranberry procyanidins have the ability to inhibit the glycation of human hemoglobin and serum albumin by elimination of reactive carbonyl radicals [39].

Some phenolic acids, such as chlorogenic, ferulic, and caffeic acids, competitively inhibit glucose uptake mediated by sodium‐dependent glucose transporter 1 (SGLT1) [19]. This inhibition has also been observed by other glucosides and quercetin [32]. SGLT1 assists in the intestinal absorption of glucose through the aid of sodium-dependent transport and thereby facilitates the independent transport of sodium via GLUT [9]. The flavonoids mycetin and quercetin were responsible for the inhibition of GLUT2 glucose transport [37, 40]. These compounds that inhibit glucose uptake, such as phenolic acids and flavonoids, are components present in berries [41,42,43]. Furthermore, it has been demonstrated in porcine models that quercetin inhibits gastric uptake of glucose. Quercetin and myricetin have also been shown to inhibit GLUT4-mediated glucose uptake in rodent adipocytes, to inhibit aldose reductase, α-amylase and α-glucosidase in vitro [44].

Although polyphenolic compounds present in berries have been associated with the enhancement of glycemic regulation, other components may contribute to these effects. Törrönen et al. [45] investigated the effects of whole-berry purées on the postprandial glucose and insulin responses after consumption of white wheat bread or rye bread. The berry mixture (strawberries, bilberries, cranberries, and blackcurrants) significantly reduced the postprandial insulin response after the intake of white wheat bread or rye bread. The researchers observed that although the consumption of berries did not suppress postprandial peak glucose, less insulin was required for the maintenance of postprandial glucose metabolism [45]. According to the investigators, the more desirable postprandial insulin response did not appear to be related to the polyphenol composition of the berries, but rather the fiber content, especially soluble fiber [45].

The main human-interventional studies with cranberry or cranberry products considering glycemic metabolism are listed in Table 2. In sum, although nutritional intervention studies with cranberries on glucose metabolism are still scarce, some of them have shown that cranberry products may promote glucose homeostasis by reducing fasting glycemia, improving HOMA-IR, increasing insulin sensitivity, and preventing compensatory insulin secretion [44, 46, 47], whereas others did not demonstrate any significant change on this feature [16, 48]. From these studies, it is still not possible to define if duration and consumed amount of cranberry are responsible for these controversial results. Certainly, more work is warranted on this issue.

Table 2 Intervention studies with cranberry products evaluating markers of glucose metabolism
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Cranberry and blood pressure

Polyphenols may significantly reduce cardiovascular disease (CVD) risk [49, 50]. In a study conducted during 18 years, it was demonstrated that the combined intake three times a week of berries was associated with a lower risk of myocardial infarction in middle-aged women [5]. Cranberries are rich sources of several polyphenols, such as quercetin which has been associated with significant blood pressure reduction in animal models [51,52,53,54] and human trials [51,52,53,54]. Mechanistic studies in mouse models have reported that cranberry juice induces vasodilation via endothelial nitric oxide synthase (eNOS) and significant reduction of blood pressure. These vasorelaxing properties would be comparable to those of red wine [55].

Thirty men participated in a 12-week intervention study and were asked to consume increasing daily doses of a cranberry juice cocktail (125, 250, and 500 mL/day) over three successive periods of 4 weeks. The investigators noted a slight but significant decrease in SBP (−3 mm Hg) over the course of the intervention [13]. This reduction was likely associated with the polyphenolic content of the beverage. Furthermore, nutritional studies have associated the intake of berries with cardioprotective effects [49, 56,57,58]. Intervention studies with flavonoids and anthocyanins have indicated that possible mechanisms for the reduction of blood pressure are inhibition of the activity of the angiotensin-converting enzyme [13], a significant increase in nitric oxide synthesis by endothelial cells [59, 60], reduction of vasoconstriction via nitric oxide-mediated pathway, or reduction of renal oxidative stress [61, 62]. Dietary intervention with polyphenol-rich foods and berry beverages has led to significant changes in MetS characteristics, including reduction of blood pressure, abdominal adiposity, dyslipidemia, inflammation, and oxidative stress [63].

The main human-interventional studies with cranberry or cranberry products considering blood pressure are listed in Table 3, and although this is a valuable area of interest, the scarce studies have found controversial results to date and for sure more studies are needed on this subject.

Table 3 Intervention studies with cranberry products evaluating blood pressure
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Cranberry and dyslipidemia

Cardiovascular diseases are among the leading causes of death in North America [64, 65]. Although LDL cholesterol is not included in the definition of metabolic syndrome, elevated concentration of low-density lipoprotein (LDL) is one of the most important cardiovascular risk factor [66]. LDL particles, such as oxidized LDL, could at least partially explain the atherogenicity of LDL [67, 68]. Oxidized LDL is not recognized by LDL receptors, but rather by cell-surface receptors on macrophages; oxidation of LDL promotes cholesterol absorption, leading to the formation of foam cells, which is the first step in the formation of the first atherosclerotic lesions [64]. A decrease in HDL concentration is also an independent risk factor for CVD [69]. Although the role of HDL in the cholesterol transport is known, HDL has several other cardioprotective effects such as antithrombogenic, antioxidant, fibrinolytic, antiadherence, and anti-inflammatory properties [70].

The lipid-lowering effects of cranberry can be attributed mainly to the phytochemical compounds contained in the fruit and to the fiber content, depending on the form of consumption. Cranberry is a relevant source of flavonoids, such as anthocyanidins, proanthocyanidins [71, 72], resveratrol [73], and phenolic acid [71]. Flavonoids, abundantly present in cranberry, would have the ability to inhibit the oxidation of LDL-cholesterol. Oxidized LDL plays a critical role in the initiation and progression of atherosclerosis; thus, supplementation with cranberry would have the potential to delay the process of atherosclerotic CVD [74]. In addition, flavonoids would have the ability to inhibit platelet adhesion and aggregation, inhibit enzymes involved in lipid and lipoprotein metabolism, and could increase reverse cholesterol transport, lowering total and LDL cholesterol [4]. Anthocyanin-rich products reduced triglycerides in animal models [75,74,77]. The total dietary fiber content of cranberry may reach 5 g/100 g in dried fruit and thus may contribute to its cholesterol lowering effects [4].

The flavonoid quercetin has been shown to inhibit de novo TAG synthesis [78]. Casaschi et al. [78] analyzed the activity of diacylglycerol acyltransferase (DGAT), an enzyme in the final reaction of the glycerol phosphate pathway for TAG synthesis, and found reduced DGAT activity after treatment with quercetin. The investigators also found that quercetin inhibits microsomal TAG transfer protein (MTP) activity, an enzyme that catalyzes the transfer of lipids, such as TAG and cholesterol esters, which would inhibit intestinal apolipoprotein B secretion and total cholesterol, TG and LDL levels [78].

Ruel et al. [12] proposed that the HDL increase could be related to an increased production of apolipoprotein A-I or a decreased clearance of HDL particles following intervention with cranberry juice. The authors also hypothesized that a reduction in apolipoprotein A-I oxidation (related to a decrease in oxidative stress) and an increased expression of paraoxonase-1 (related to the high content of quercetin in the beverage) could be at least partially responsible for the increase in HDL. Another proposed mechanism to explain HDL increase after intervention with cranberry products and reduction in serum triglyceride (TG) levels is the inverse relationship between TG and HDL [12, 79]. In hypertriacylglycerolemic states, HDL particles exchange cholesterol for TG with LDL and very low-density lipoproteins (VLDL) and become TG-rich. The TG-rich HDL particles are more rapidly catabolized in the liver than normal HDL particles. Thus, after a decrease in serum levels of TG, an increase in serum HDL levels may occur [12, 79, 80].

The main human-interventional studies with cranberry or cranberry products considering lipid profile are listed in Table 4. Collectively, these nutritional findings suggest that although cranberry products have shown promising beneficial effects on lipid profile, this is observed only in interventions lasting at least 12 weeks. Thus, further clinical trials are needed to confirm these findings and establish the duration and dose of the intervention.

Table 4 Intervention studies with cranberry products evaluating lipid profile
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Cranberry and markers of inflammation and oxidative stress

Central obesity and insulin resistance are the main features involved in MetS, but low-grade chronic inflammation is considered a major link between the MetS and CVD [81]. In MetS, central obesity is considered an important source of low-grade chronic inflammation [82].

Free radicals and reactive metabolites, also known as reactive oxygen species (ROS), are normal products of cellular metabolism and are generated primarily by the mitochondrial respiratory chain. When there is an imbalance between the production of these reactive species and their elimination by antioxidant mechanisms, an accumulation of ROS occurs, leading to oxidative stress. Several diseases such as cancer, chronic inflammatory diseases, and aging are all conditions associated with increased oxidative stress [83,84,85,86]. Furthermore, continuous oxidative stress may lead to chronic inflammation [87].

A methanol extract prepared from dehydrated cranberries inhibited the activity of cyclooxygenase-2 and also inhibited the NF-κβ transcriptional activation in human T lymphocytes. Furthermore, the extract inhibited the release of interleukins (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α from lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells in vitro. The authors attributed the anti-inflammatory effects to ursolic acid and ursolic acid derivatives present in the cranberry extract [88].

Vinson et al. [89] investigated the quantity of both free and total phenolic antioxidants in cranberry products and plasma antioxidant capacity after the consumption of a single 24-mL serving of cranberry juice. The authors found cranberries and cranberry products to be a significant source of antioxidants both in vitro and in vivo.

Anthocyanin-rich products reduced inflammatory factors in humans [90, 91]. Furthermore, several studies have shown that antioxidant compounds, especially polyphenols, can inhibit the oxidation of LDL, which in turn, would reduce the expression of adhesion molecules in the endothelium [92, 93]. In addition, cranberry has salicylic acid [94], which has anti-inflammatory activity and has been shown to decrease the expression of vascular cell-1 adhesion molecule in vitro [95].

In a comparative study, cranberry juice had the same amount of resveratrol as grape juice [73]. The health benefits associated to resveratrol are many, especially in promoting cardiovascular health, elimination of reactive oxygen species, inhibition of platelet aggregation, and decrease of inflammation [9].

Although cranberries are rich in known antioxidant substances, the number of human-interventional studies with this berry considering oxidative stress is unexpectedly small. The main intervention studies considering oxidative stress and markers of inflammation are shown in Table 5. Altogether, these nutritional intervention studies seem to confirm the expected antioxidant action effect of cranberry products. However, the effects on inflammatory markers are still inconsistent. Certainly, more studies are required to confirm these results and define the optimal dose and duration of treatment.

Table 5 Intervention studies with cranberry products evaluating markers of inflammation and oxidative stress
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Cranberry and other markers of cardiovascular risk

The intake of fruits and vegetables is beneficial for reducing the risks of some human diseases, such as CVD and cancer. In addition to being rich in soluble and insoluble fibers, the positive health effects are attributed to elements with antioxidant properties such as vitamins E, C, and carotenoids, which have the capacity to inactivate ROS involved in the process or progression of chronic diseases [96]. The presence of anthocyanins in berries is responsible for its coloration and comprises the largest group of natural species with water soluble vegetable pigments [97,98,99,100]. Normally, the intensity of the color is directly proportional to its anthocyanin content and can range from 2–4 g/kg, increasing as berries ripen. The average anthocyanin consumption in the USA is 12.5–215 mg per day [101]. Studies have shown that anthocyanins have low bioavailability, are widely conjugated in the liver and the intestine, and are excreted by the kidney within 2–8 h of ingestion [102, 103]. The content of polyphenols (including anthocyanins) and some vitamins in berries may be affected by post-harvest processing techniques, such as pressing and pasteurization, and thus reduce their effects on CVD risk [104,105,106].

In an in vitro study, anthocyanins were shown to be effective biomarkers of heart diseases and cancer, inhibiting the release of ROS from active human granulocytes [107] and suppressing free radical-mediated lipid peroxidation and apoptosis in cultured aortic endothelial cells [108, 109]. In addition, anthocyanins, aglycones, and glycosides are effective inhibitors of oxidative-induced DNA damage in human colon cells [110] and are potent inhibitors of tumor cell growth in vitro [111, 112].

The main intervention studies considering other markers of cardiovascular risks are shown in Table 6. The findings suggest that cranberry products may significantly improve several markers of cardiovascular risk, such as adhesion molecules, homocysteine, and arterial stiffness. Nevertheless, it still remains to be determined if this changes translate into prevention of cardiovascular events.

Table 6 Studies considering other cardiovascular risk markers and consumption of cranberry
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Gut microbiota and metabolism

A large body of evidence has elegantly demonstrated that the gut microbiome regulates fat storage, lipid metabolism, insulin resistance, and overall metabolism [113,114,115]. A disturbance in gut microbiota, marked by an imbalance between intestinal bacteria (e.g., increase in Firmicutes and reduction in the abundance of Bacteroidetes), known as dysbiosis, has been associated with several components of MetS, such as obesity and IR, via modulation of inflammatory pathways. Thus, microbiota modulation through various nutritional interventions has been researched [80]. Recently, it has been demonstrated that polyphenolic compounds from various berries may possess prebiotic activity [116]. Additionally, Anhê et al. [117] recently demonstrated that oral administration of a cranberry extract prevented several detrimental features of the MetS in a mouse model. The authors associated these metabolic improvements with a remarkable increase in the abundance of the mucin-degrading bacterium Akkermansia in the gut microbiota of mice [117]. Thus, although we are not aware to date of any human intervention study with cranberries investigating gut microbiota, this prebiotic effect may also be at least partially responsible for the beneficial health effects demonstrated.

Conclusions

Although several studies have shown beneficial effects, there are still few clinical and epidemiological studies evaluating the relationship between cranberry intake and the various components directly or indirectly associated with the MetS. In addition, most clinical studies are of relatively short duration (8 to 12 weeks), which often prevents the verification of additional beneficial effects. Another factor to consider is the amount of product to be ingested. The antioxidant action of cranberry is already well known and some authors have suggested the conduction of clinical trials to verify anti-inflammatory activity. The mechanisms of action associated to cranberry also require further studies. Although results especially related to lipid profile and blood pressure are promising, further research is needed to support the recommendation of cranberry intake as a nutritional intervention for the treatment of metabolic syndrome.