Possible mechanisms of postprandial physiological alterations following flavan 3-ol ingestion

Possible mechanisms of postprandial physiological alterations following flavan 3-ol ingestion Abstract Foods rich in flavan 3-ols are known to prevent cardiovascular diseases by reducing metabolic syndrome risks, such as hypertension, hyperglycemia, and dyslipidemia. However, the mechanisms involved in this reduction are unclear, particularly because of the poor bioavailability of flavan 3-ols. Recent metabolome analyses of feces produced after repeated ingestion of foods rich in flavan 3-ols may provide insight into the chronic physiological changes associated with the intake of flavan 3-ols. Substantial postprandial changes have been reported after flavan 3-ol ingestion, including hemodynamic and metabolic changes as well as autonomic and central nervous alterations. Taken together, the evidence suggests that flavan 3-ols have both postprandial and chronic effects, which could involve different or common mechanisms. In general, the accumulation of acute functional changes induces chronic physiological alteration. Therefore, this review highlights the postprandial action of flavan 3-ols in order to address the yet unknown mechanism(s) for their physiological function. autonomic, central nervous system, flavan 3-ols, hemodynamics, metabolic, postprandial INTRODUCTION Flavan 3-ols are a subclass of plant flavonoids that possess a diphenylpropane structure and are categorized as monomeric [eg, (+)-catechin or (−)-epicatechin and its gallate type] or oligomeric catechins (eg, theaflavin and procyanidins). Extensive studies have been performed on the bioavailability and vascular functions of monomeric catechins in relation to their antiatherosclerotic effects.1–3 The present review focuses mainly on oligomeric procyanidins because the physiological function of oligomeric procyanidins has attracted considerable attention in recent years. Foods rich in flavan 3-ols, such as tea, cocoa, red wine, grapes, and apples, could have substantial potential for managing cardiovascular health.4–6 Recent meta-analyses have suggested that flavan 3-ol consumption reduces the risk of cardiovascular diseases, including coronary heart disease, myocardial infarction, and stroke.7–9 In addition, numerous randomized controlled trials confirmed that dark chocolate containing large amounts of flavan 3-ols improves several conditions that contribute to metabolic syndrome, including hypertension,10,11 dyslipidemia,12,13 and glucose intolerance,14,15 and subsequent meta-analyses confirmed that dark chocolate can reduce the risk of cardiovascular disease.16–20 In vitro evidence supports previous clinical data showing that flavan 3-ols affect nitric oxide (NO) production or breakdown,21–23 as well as lipid metabolism24,25 and platelet function.26,27 Ingestion of flavan 3-ols has also been suggested to be inversely associated with diabetes risk.28 The ingestion of flavan 3-ols has been reported to reduce peripheral insulin or glucose resistance in postmenopausal women,29 hypertensive patients with impaired glucose tolerance,15 and healthy volunteers.30,31 In addition, several animal studies have suggested that treatment with flavan 3-ols attenuates the risk factors for diabetes.32–34 Recent reports imply that flavan 3-ols attenuate mood disorders and cognitive impairment in elder healthy volunteers,35 although the mechanisms underlying the beneficial effect of flavan 3-ols is not well understood. A recent comprehensive review on polyphenol and human health suggested that the mechanism for beneficial effect of flavan 3-ols has not been fully elucidated because of their poor bioavailability.36 (+)-Catechin and (−)-epicatechin are more readily absorbed than the other flavan 3-ols from the gastrointestinal tract, and almost all catechins are metabolized; therefore, unchanged forms are nearly absent in blood.37 In contrast, other flavan 3-ols, including gallate-type catechins and oligomeric catechins, are rarely absorbed from the gut into the blood.38–40 Consequently, flavan 3-ols pass from the upper digestive tract to the colon and are metabolized by gut microbiota to produce metabolites, primarily lactones and aromatic acids.41 Flavan 3-ol metabolites could be absorbed into the systemic circulation and are expected to play a role in the physiological changes that occur in response to frequent consumption of flavan 3-ols.42 In contrast, other studies have shown that flavan 3-ols exert postprandial actions on the hemodynamic,43 metabolic,44 and nervous systems,45 which seem to be unrelated to their metabolites when the passage time in the intestine is taken into account. As such, flavan 3-ols may have both postprandial and chronic activities, and different or common mechanisms may underlie these effects. In general, the accumulation of acute functional changes induces chronic physiological alterations. Moreover, these hemodynamic, metabolic, and nervous system changes following the ingestion of flavan 3-ols are likely to occur cooperatively, not independently. Therefore, this review highlights the postprandial action of flavan 3-ols in order to address yet unknown mechanisms for the beneficial effect in human health. FLAVAN 3-OLS AND BIOAVAILABILITY IN HUMANS Flavan 3-ols are a subclass of plant flavonoids possessing a diphenylpropane structure and are categorized as monomers [eg, (+)-catechin or (−)-epicatechin and its gallate type] or oligomers (eg, theaflavin and procyanidins) (Figure 1). They are included as antioxidants found in several plant-derived foods, such as tea, cocoa beans, grape (red wine), and apples.39,46–49 Figure 1 View largeDownload slide Flavan 3-ol subclasses, prominent chemicals, and typical food sources. Figure 1 View largeDownload slide Flavan 3-ol subclasses, prominent chemicals, and typical food sources. Nongallate type catechins such as (−)-epicatechin are absorbed via the gastrointestinal tract and exist in the blood primarily as metabolites, often as conjugates with glucuronide and/or sulfate50,51 (Figure 2). Approximately 20% of consumed (−)-epicatechin is absorbed, but unmetabolized (−)-epicatechin is nearly absent in the blood. The chemical structure of plasma (−)-epicatechin glucuronide differs between humans and murine animals52; (−)-epicatechin glucuronides isolated from human plasma have lower antioxidative activity than those isolated from rat plasma.52–54 Other flavan 3-ols (ie, gallate-type catechins and oligomeric catechins) are poorly absorbed in the gastrointestinal tract, because ATP-binding cassette (ABC) transporters, such as P-glycoprotein or a multidrug resistance protein (MRP), are involved in the elimination of flavan 3-ols from intestinal epithelial cells55 (Figure 2). In turn, gallate-type catechins and oligomeric catechins are present in the blood at very low concentrations.37–40,56–57 Figure 2 View largeDownload slide Absorption of flavan 3-ols from the digestive tract. Abbreviation: MRP, multidrug resistant protein. Figure 2 View largeDownload slide Absorption of flavan 3-ols from the digestive tract. Abbreviation: MRP, multidrug resistant protein. The bioavailability of flavan 3-ols may also be affected by the food matrix. Several previous studies reported that sugars enhance the absorption of flavan 3-ols in humans,58–60 with the different sugar types that coexist with flavan 3-ols affecting the absorption rate. Whether the interaction of flavan 3-ols and protein affects the bioavailability of flavan 3-ols is still controversial.61 Several in vitro studies have shown that several proteins, such as the major milk protein β-lactoglobulin62 and albumin,63 bind to flavan 3-ols tightly via covalent bonding. Serafini et al.64 reported that milk protein reduces the intestinal absorption of flavan 3-ols. However, other studies have shown that they do not inhibit flavan 3-ol absorption.59,65,66 Most of the remaining flavan 3-ols are metabolized by gut microbiota after passing from the upper digestive tract into the colon41 (Figure 2). A recent radiolabel study in rats reported that procyanidin B2 metabolite is absorbed into the systemic circulation, with peak levels 5–7 hours after oral administration.67 This finding is consistent with a study of the pig cecum system that demonstrated the degradation of procyanidins by microbiota 4–8 hours after consumption.68,69 Some of the main flavan 3-ol metabolites in humans are valerolactones, such as δ-(3, 4-dihydroxyphenyl)-γ-valerolactone, δ-(3-hydroxyphenyl)-γ-valerolactone,70 5-(3,4-dihydroxyphenyl)- γ-valerolactone, and 5-phenyl-γ-valerolactone.71 Phenolic acids, such as m-hydroxyphenylpropionic acid,70 3-hydroxyphenyl propionic acid, 3-phenylpropionic acid,72 hydroxyphenylpropionic acid, ferulic acid, 3,4-dihydroxyphenylacetic acid, m-hydroxyphenylacetic acid, vanillic acid, and m-hydroxybenzoic acid,73 are also flavan 3-ol metabolites detected in extracts derived from human samples. POSTPRANDIAL EFFECTS OF FLAVAN 3-OLS IN INTERVENTION TRIALS Circulatory system Several studies have described postprandial endothelial changes following the consumption of foods rich in flavan 3-ols. The elevation of flow-mediated dilatation (FMD), which occurs following the generation of endothelial-derived nitric oxide induced by shear stress, has been studied extensively.74 In various studies, FMD was measured after the consumption of flavan 3-ol–rich foods for a specified period in healthy volunteers,75–80 smokers,81,82 obese individuals,83,84 and patients with cardiovascular risk43,85–89 or end-stage renal disease90 (Table 143,75–90,91,92). In 19 trials and all but 2 reports,85,87 FMD substantially increased between 1 and 2 hours after the ingestion of flavan 3-ol–rich foods, including dark chocolate, red wine, and pure (−)-epicatechin. The flavan 3-ol dose in these studies varied widely, from 176 mg43 to 963 mg.88 The activity of pure (−)-epicatechin was described in the 2 papers with contrasting conclusions, and thus the activity of (−)-epicatechin remains poorly understood.93 In addition, portal or hepatic blood flow91 and cerebral blood flow92 have been reported to increase after the ingestion of flavan 3-ol–rich foods. A transient increase in blood pressure was demonstrated in the hepatic blood flow study.91 These results indicate that oral administration of flavan 3-ols increases NO production by vascular endothelial cells directly, or indirectly through blood flow that transmits shear stress to the endothelium. Table 1 Postprandial effects on circulation following ingestion of foods rich in flavan 3-ols in intervention trials Reference  Ingestion  Experimental period  Participants  Outcome  Heiss et al. (2003)43  Flavanol drink (10 or 176 mg )  2 h  Individuals with cardiovascular risk, n = 26  FMD↑ (vs baseline)  Vlachopoulos et al. (2005)75  1000 g of dark chocolate (>74% cocoa)  0.5, 1, 2,1.5, 3, 2.5, 3 h  Healthy individuals, n = 17  FMD↑ (vs baseline, 1 h)  Heiss et al. (2005)81  Flavanol drink (88–370 mg )  2 h  Smokers, n = 11  FMD↑ (176 or 370 mg vs baseline), RXNO↑ (176 or 370 mg vs baseline)  Farouque et al. (2006)85  Chocolate bar or placebo (444 or 19.6 mg)  90 min  Individuals with cardiovascular risk, n = 45  FMD ± (vs placebo, 90 min)  Schroeter et al. (2006)76  Flavanol drink (37 or 917 mg) 1 or 2 mg/kg of epicatechin  1, 2, 3, 4 h  Healthy individuals, n = 16 (flavanol drink study), n = 6 (epicatechin study)  FMD↑ (vs baseline, flavanol study, epicatechin study, 2, 4 h)  Hermann et al. (2006)82  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2, 4, 8, 24 h  Smokers, n = 25  FMD↑ (vs baseline, 2 h), platelet adhesion↓ (vs baseline, 2 h)  Balzer et al. (2008)88  Cocoa containing increasing concentrations of flavanols (75, 371, and 963 mg)  1, 2, 3, 4, 6 h  Individuals with cardiovascular risk, n = 10  FMD↑ (963 mg vs 75 mg flavanol)  Davison et al. (2008)83  Cocoa (36 and 902 mg)  2 h  Obese individuals, n = 49  FMD↑ (vs baseline)  Faridi et al. (2008)77  Cocoa powder or placebo  2 h  Healthy individuals, n = 45  FMD↑ (vs placebo)  Berry et al. (2010)84  Cocoa beverage powder (22 mg or 701 mg)  2 h  Obese individuals, n = 21  FMD↑ (701 mg vs 22 mg flavanol)  Westphal and Luley (2011)78  Flavanol drink (918 mg)  0, 2, 4, 6 h  Healthy individuals, n = 18  FMD↑ (vs control, 2, 4 h)  De Gottardi et al. (2012)91  Chocolate (>85%, 0.55 g/kg of body weight) or white chocolate  0, 0.5 h  Cirrhotic patients, n = 22  Hepatic venous pressure gradient↑ (vs white chocolate, 0.5 h), portal blood flow↑ (vs white chocolate, 0.5 h), blood pressure (vs white chocolate , 0.5 h)  Loffredo et al. (2014)86  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2 h  Individuals with cardiovascular risk, n = 20  FMD↑ (vs milk chocolate, 2 h), isoprostanes↓ (vs milk chocolate, 2 h), nitrite/nitrate (NOx)↑ (vs milk chocolate, 2 h), sNOX2‐dp↓ (vs milk chocolate, 2 h), maximal walking distance ↑ (vs milk chocolate, 2 h), and maximal walking time ↑ (vs milk chocolate, 2 h)  Hammer et al. (2015)87  50 g of dark chocolate or 50 g of white chocolate  2 h  Individuals with cardiovascular risk, n = 21  FMD ±  Lamport et al. (2015)92  Flavanol drink (494 mg or 23 mg)  2 h  Healthy individuals, n = 18  Cerebral blood flow↑  Rodriguez-Mateos et al. (2015)89  1.4, 2.7, 5.5, 10.9 mg/kg of cacao flavanol drink  1, 2, 3, 4 h  Healthy individuals, n = 15  ⊿FMD↑ (2.7, 5.5, 10.9 vs 1.4 mg/kg)  Dower et al. (2016)79  75 g of dark chocolate with placebo (150 mg of epicatechin) or 75 g of white chocolate with 100 mg of epicatechin or 75 g of white chocolate with placebo  2 h  Healthy individuals, n = 20  FMD↑ (dark chocolate vs white chocolate with placebo) FMD ± (white chocolate with epicatechin vs white chocolate with placebo)  Rassaf et al. (2016)90  Cocoa flavanol drink (900 mg) or placebo  1, 2, 3, 4, 5 h  Individuals with end-stage renal disease, n = 57  FMD↑ (vs placebo, 1, 2 h)  Sansone et al. (2017)80  0–880 mg of flavanol or 0–220 mg of methylxanthin  2 h  Healthy individuals, n = 47  FMD↑  Reference  Ingestion  Experimental period  Participants  Outcome  Heiss et al. (2003)43  Flavanol drink (10 or 176 mg )  2 h  Individuals with cardiovascular risk, n = 26  FMD↑ (vs baseline)  Vlachopoulos et al. (2005)75  1000 g of dark chocolate (>74% cocoa)  0.5, 1, 2,1.5, 3, 2.5, 3 h  Healthy individuals, n = 17  FMD↑ (vs baseline, 1 h)  Heiss et al. (2005)81  Flavanol drink (88–370 mg )  2 h  Smokers, n = 11  FMD↑ (176 or 370 mg vs baseline), RXNO↑ (176 or 370 mg vs baseline)  Farouque et al. (2006)85  Chocolate bar or placebo (444 or 19.6 mg)  90 min  Individuals with cardiovascular risk, n = 45  FMD ± (vs placebo, 90 min)  Schroeter et al. (2006)76  Flavanol drink (37 or 917 mg) 1 or 2 mg/kg of epicatechin  1, 2, 3, 4 h  Healthy individuals, n = 16 (flavanol drink study), n = 6 (epicatechin study)  FMD↑ (vs baseline, flavanol study, epicatechin study, 2, 4 h)  Hermann et al. (2006)82  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2, 4, 8, 24 h  Smokers, n = 25  FMD↑ (vs baseline, 2 h), platelet adhesion↓ (vs baseline, 2 h)  Balzer et al. (2008)88  Cocoa containing increasing concentrations of flavanols (75, 371, and 963 mg)  1, 2, 3, 4, 6 h  Individuals with cardiovascular risk, n = 10  FMD↑ (963 mg vs 75 mg flavanol)  Davison et al. (2008)83  Cocoa (36 and 902 mg)  2 h  Obese individuals, n = 49  FMD↑ (vs baseline)  Faridi et al. (2008)77  Cocoa powder or placebo  2 h  Healthy individuals, n = 45  FMD↑ (vs placebo)  Berry et al. (2010)84  Cocoa beverage powder (22 mg or 701 mg)  2 h  Obese individuals, n = 21  FMD↑ (701 mg vs 22 mg flavanol)  Westphal and Luley (2011)78  Flavanol drink (918 mg)  0, 2, 4, 6 h  Healthy individuals, n = 18  FMD↑ (vs control, 2, 4 h)  De Gottardi et al. (2012)91  Chocolate (>85%, 0.55 g/kg of body weight) or white chocolate  0, 0.5 h  Cirrhotic patients, n = 22  Hepatic venous pressure gradient↑ (vs white chocolate, 0.5 h), portal blood flow↑ (vs white chocolate, 0.5 h), blood pressure (vs white chocolate , 0.5 h)  Loffredo et al. (2014)86  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2 h  Individuals with cardiovascular risk, n = 20  FMD↑ (vs milk chocolate, 2 h), isoprostanes↓ (vs milk chocolate, 2 h), nitrite/nitrate (NOx)↑ (vs milk chocolate, 2 h), sNOX2‐dp↓ (vs milk chocolate, 2 h), maximal walking distance ↑ (vs milk chocolate, 2 h), and maximal walking time ↑ (vs milk chocolate, 2 h)  Hammer et al. (2015)87  50 g of dark chocolate or 50 g of white chocolate  2 h  Individuals with cardiovascular risk, n = 21  FMD ±  Lamport et al. (2015)92  Flavanol drink (494 mg or 23 mg)  2 h  Healthy individuals, n = 18  Cerebral blood flow↑  Rodriguez-Mateos et al. (2015)89  1.4, 2.7, 5.5, 10.9 mg/kg of cacao flavanol drink  1, 2, 3, 4 h  Healthy individuals, n = 15  ⊿FMD↑ (2.7, 5.5, 10.9 vs 1.4 mg/kg)  Dower et al. (2016)79  75 g of dark chocolate with placebo (150 mg of epicatechin) or 75 g of white chocolate with 100 mg of epicatechin or 75 g of white chocolate with placebo  2 h  Healthy individuals, n = 20  FMD↑ (dark chocolate vs white chocolate with placebo) FMD ± (white chocolate with epicatechin vs white chocolate with placebo)  Rassaf et al. (2016)90  Cocoa flavanol drink (900 mg) or placebo  1, 2, 3, 4, 5 h  Individuals with end-stage renal disease, n = 57  FMD↑ (vs placebo, 1, 2 h)  Sansone et al. (2017)80  0–880 mg of flavanol or 0–220 mg of methylxanthin  2 h  Healthy individuals, n = 47  FMD↑  Abbreviation: FMD, flow-mediated dilation. Two meta-analyses of randomized control intervention studies examining postprandial FMD alteration after ingestion of flavan 3-ols are available in the literature.19,94 These papers confirmed the postprandial increase in FMD following the ingestion of foods rich in flavan 3-ols. Interestingly, these papers also reported on medium- to long-term supplementation trials that suggested that changes in FMD were greater following a single oral administration than repeated ingestion of flavan 3-ol–rich foods. In contrast, recent meta-analyses have indicated that flavan 3-ol–rich food consumption for 2–18 weeks substantially reduces blood pressure in healthy volunteers or patients with moderate hypertension.95 This hypotensive activity of flavan 3-ols seems to be reflected in the initial hemodynamic changes, but further studies are needed to explain the relevance of the acute and chronic effects of flavan 3-ols on the systemic circulation or microcirculation. Metabolic system In oral glucose or meal tolerance tests44,93,96,97 in healthy individuals, postmenopausal woman, and diabetic patients, flavan 3-ols were reported to induce postprandial metabolic changes such as improvement of glucose or insulin tolerance (Table 244,93,96–98). In addition, energy expenditure as measured by respiratory analysis was substantially increased after obese individuals ingested 1 mg/kg body weight (−)-epicatechin.98 These rapid metabolic changes were also observed 2–4 hours after ingestion of food rich in flavan 3-ol, and several in vitro studies found that high concentrations of flavan 3-ols pulled down in micelles99,100 consisted of dietary fat and bile acid or inhibited glycolytic digestive enzymes.101,102 These actions observed in in vitro studies may reduce the increase in blood glucose or insulin. Table 2 Postprandial effects on metabolic system following ingestion of foods rich in flavan 3-ols in intervention trials Reference  Ingestion  Experimental period  Participants  Outcome  Naissides et al. (2004)44  400 mL of red wine (2.2 g/L of total polyphenols)  0, 1, 2, 3, 4, 5, 6 h  Postmenoposal women, n = 17  Plasma insulin in oral glucose tolerance test, AUC↑ (vs placebo), plasma triglyceride in oral lipid tolerance test, AUC↑ (vs placebo)  Gutierrez-Salmean et al. (2014)98  Epicatechin 1mg/kg  0, 2, 4 h  Obese individuals, n = 24  Respiratory quotient↑ (vs, baseline, 2 h), plasma glucose↓(vs, control, 4 h)  Schulze et al. (2014)96  2.8 g of apple extract  0, 15, 30, 45, 60, 90, 120, 180 min  Healthy individuals, n = 10  Plasma glucose in oral glucose tolerance test, AUC↓, plasma glucose in oral glucose tolerance test, AUC↓, urine glucose excretion ↑ (0–3 h, vs placebo)  Basu et al. (2015)93  Cocoa beverage or placebo (480 mg or less than 0.1 mg flavanols)  0, 0.5, 1, 2, 4, 6 h  Diabetic individuals, n = 24  HDL↑ (vs baseline, 1, 4 h), plasma insulin↑ (vs baseline, 0.5, 1, 2, 4, 6 h), insulin resistance ↑ (vs baseline, 4 h), artery elasticity ↑ (vs placebo, 2 h)  Bernardo et al. (2015)97  Cinnamon tea (557 mg of polyphenol)  0, 0.5, 1, 1.5, 2 h  Healthy individuals, n = 15  Plasma glucose in oral glucose tolerance test, Cmax↓, ⊿Cmax ↓ (vs placebo)  Reference  Ingestion  Experimental period  Participants  Outcome  Naissides et al. (2004)44  400 mL of red wine (2.2 g/L of total polyphenols)  0, 1, 2, 3, 4, 5, 6 h  Postmenoposal women, n = 17  Plasma insulin in oral glucose tolerance test, AUC↑ (vs placebo), plasma triglyceride in oral lipid tolerance test, AUC↑ (vs placebo)  Gutierrez-Salmean et al. (2014)98  Epicatechin 1mg/kg  0, 2, 4 h  Obese individuals, n = 24  Respiratory quotient↑ (vs, baseline, 2 h), plasma glucose↓(vs, control, 4 h)  Schulze et al. (2014)96  2.8 g of apple extract  0, 15, 30, 45, 60, 90, 120, 180 min  Healthy individuals, n = 10  Plasma glucose in oral glucose tolerance test, AUC↓, plasma glucose in oral glucose tolerance test, AUC↓, urine glucose excretion ↑ (0–3 h, vs placebo)  Basu et al. (2015)93  Cocoa beverage or placebo (480 mg or less than 0.1 mg flavanols)  0, 0.5, 1, 2, 4, 6 h  Diabetic individuals, n = 24  HDL↑ (vs baseline, 1, 4 h), plasma insulin↑ (vs baseline, 0.5, 1, 2, 4, 6 h), insulin resistance ↑ (vs baseline, 4 h), artery elasticity ↑ (vs placebo, 2 h)  Bernardo et al. (2015)97  Cinnamon tea (557 mg of polyphenol)  0, 0.5, 1, 1.5, 2 h  Healthy individuals, n = 15  Plasma glucose in oral glucose tolerance test, Cmax↓, ⊿Cmax ↓ (vs placebo)  Abbreviations: AUC, area under the blood concentration time curve; HDL, high-density lipoprotein. Considerable studies have also assessed repeated treatment with flavan 3-ols in humans. Ingestion of flavan 3-ol–rich food for 4–12 weeks substantially altered plasma lipid concentrations, such as elevating high-density lipoproteins and reducing low-density lipoproteins,12,103,104 or improved insulin resistance.15,30,83,104 These chronic alterations on lipid metabolism and insulin resistance seem to result from the accumulation of postprandial metabolic changes following the ingestion of flavan 3-ols. However, more extensive studies are needed to elucidate the mechanism underlying metabolic alternation by flavan 3-ol ingestion. Nervous system Several studies have been reported regarding the alteration of both the autonomic and central nervous system following the ingestion of flavan 3-ols (Table 345,105–108). Spaak et al.105 reported that the ingestion of red wine elevates plasma adrenaline levels and muscle sympathetic nerve activity, although these effects were not observed when only ethanol was consumed. In addition, working memory was suggested to be improved by the ingestion of chocolate in healthy individuals,106,107 and changes in these cerebral functions are considered to be related to changes in cerebral blood flow. A functional magnetic resonance imaging technique demonstrated that the elevation of blood oxygenation after ingestion of cocoa flavan 3-ols associates with the changes in cerebral blood flow.45 Serial tasks, which are used to assess mental status in suspected cases of dementia, were improved 1 hour after supplementation with cocoa flavan 3-ols.108 Repeated treatment with cocoa flavan 3-ols for 8–12 weeks in elderly individuals improved cognitive function and increased plasma brain-derived neurotrophic factor (BDNF) levels or improved insulin resistance.109,110 Acute and chronic changes in cognitive function seem to be closely associated with each other, and further consideration is thus needed as to how they cooperate in the nervous system. Table 3 Postprandial effects on nervous systems following ingestion of foods rich in flavan 3-ols in intervention trials Reference  Ingestion  Experimental period  Participants  Outcome  Autonomic nervous system   Spaak et al. (2008)105  Red wine, alchol, or water (455 mL)  6 h  Healthy individuals, n = 13  Plasma adrenaline↑ (vs water, alchol), sympathetic nerve activity↑ (vs water, alchol)  Central nervous system   Francis et al. (2006)45  Cocoa flavanol (13, 190 mg)  1.5 h  Healthy individuals, n = 16  Magnetic resonance imaging based on blood oxygenation level-dependent↑ (13 vs 190 mg)   Scholey et al. (2010)108  Cocoa flavanol (control, 520, and 994 mg)  All tasks were carried out for 1h after ingestion  Healthy individuals, n = 30  Serial 3 tasks↑ (520 and 994 mg vs control), serial 7 tasks↓ (994 mg vs control), rapid visual information processing tasks↑ (994 mg vs control), mental fatigue scale↑ (994 mg vs control)   Field et al. (2011)106  35 g of white chocolate or 35 g of dark chocolate (cocoa flavanol 773 mg)  2 h  Healthy individuals, n = 30  Visual spatial working memory↑ (vs white chocolate), choice reaction time↓ (vs white chocolate)   Grassi et al. (2016)107  100 g of flavanol-rich chocolate or flavanol poor chocolate (520 or 88.5 mg)  1.5 h  Healthy individuals, n = 32 (with sleep deprivation)  Working memory accuracy ↑ (woman, rich vs poor)  Reference  Ingestion  Experimental period  Participants  Outcome  Autonomic nervous system   Spaak et al. (2008)105  Red wine, alchol, or water (455 mL)  6 h  Healthy individuals, n = 13  Plasma adrenaline↑ (vs water, alchol), sympathetic nerve activity↑ (vs water, alchol)  Central nervous system   Francis et al. (2006)45  Cocoa flavanol (13, 190 mg)  1.5 h  Healthy individuals, n = 16  Magnetic resonance imaging based on blood oxygenation level-dependent↑ (13 vs 190 mg)   Scholey et al. (2010)108  Cocoa flavanol (control, 520, and 994 mg)  All tasks were carried out for 1h after ingestion  Healthy individuals, n = 30  Serial 3 tasks↑ (520 and 994 mg vs control), serial 7 tasks↓ (994 mg vs control), rapid visual information processing tasks↑ (994 mg vs control), mental fatigue scale↑ (994 mg vs control)   Field et al. (2011)106  35 g of white chocolate or 35 g of dark chocolate (cocoa flavanol 773 mg)  2 h  Healthy individuals, n = 30  Visual spatial working memory↑ (vs white chocolate), choice reaction time↓ (vs white chocolate)   Grassi et al. (2016)107  100 g of flavanol-rich chocolate or flavanol poor chocolate (520 or 88.5 mg)  1.5 h  Healthy individuals, n = 32 (with sleep deprivation)  Working memory accuracy ↑ (woman, rich vs poor)  POSTPRANDIAL EFFECTS OF FLAVAN 3-OLS IN ANIMAL STUDIES Circulatory system Several papers have reported postprandial physiological changes following the ingestion of flavan 3-ol fractions or isolated flavan 3-ol by using experimental animals (Table 4) 111–115,116–119,120,121. These studies suggest that flavan 3-ols alter the level of NO in endothelial cells and influence hemodynamics, such as blood pressure, heart rate, and blood flow, in parallel.111,112 Comparisons of the acute hemodynamic changes by 14 polyphenolic compounds113,114 showed that mean blood pressure, heart rate, and blood flow in cremaster arterioles increase substantially shortly after the administration of a small amount of flavan 3-ol fraction (1–10 mg/kg). These changes are transient, and the increased blood pressure and heart rate return to baseline levels 60 minutes after ingestion. Phosphorylated endothelial nitric oxide synthase (eNOS) levels were substantially increased in aortas dissected 60 minutes after flavan 3-ol fraction ingestion compared with the vehicle treatment group,112 and these effects were greater than those of isolated quercetin, hesperidin, trans-resveratrol, or curcumin.113 As in the FMD intervention studies, flavan 3-ols appear to increase NO production from vascular endothelial cells by inducing eNOS phosphorylation. This effect was not dose-dependent because high amounts of flavan 3-ol fraction (100 mg/kg) did not induce eNOS phosphorylation or changes in blood pressure.115 These results suggest that flavan 3-ols do not induce eNOS expression directly. Table 4 Postprandial physiological effects following ingestion of flavan 3-ols fraction in animal studies Reference  Ingestion  Experimental period  Experimental animals  Outcome  Circulatory system    Ingawaet al. (2014)112  Flavan 3-ols, 10 mg/kg  60 min  Rat  Mean blood pressure↑ (transiently), heart rate↑ (transiently), phosphorylated eNOS↑ (60 min, in aorta)   Aruga et al. (2014)113  Flavan-3-ols, (−)-epicatechin, epigallocatechin gallate, theaflavins, quercetin, cyanidin, hesperidin, daidzein, trans-resveratrol, gnetin C, curcumin, 1 mg/kg p.o.  60 min  Rat  Mean blood pressure↑ (transiently, flavan 3-ols, epicatechin, quercetin, cyanidin, daizein ), heart rate↑ (transiently, flavan 3-ols), blood flow in cremaster arteriole↑ (flavan 3-ols, theaflavins)   Pons et al. (2016)111  250, 375, 500 mg of grape seed extract  2, 4, 6, 8, 24, 48 h   Rat  BP↓ (cafeteria meal–fed rat, 250, 375 vs control)  Metabolic system    Yamashita et al. (2012)116  Flavan 3-ols, 50, 250 mg/kg  15, 30, 60, 90, 120 min  Mice  Plasama glucose↓ (30, 60 min vs control), OGTT (glucose, starch maltose, sucurose)   Yamashita et al. (2013)118  Cinnamtannin A2, 10 μg/kg  60 min  Mice  Plasma insuline↑ (vs control)   Matsumura et al. (2014)119  Flavan 3-ols, 10 mg/kg  0, 1, 2, 5, 20 h  Mice  Energy expenditure, PGC-1α, UCP-3, and AMPK phosphorylation↑ (in gastrocnemius, vs control, 1, 2 h ), UCP-1 and PGC-1 α (in brown adipose, vs control, 1 h ), plasma adrenaline (in brown adipose, vs control, 2, 5 h)   Manzano et al. (2016)117  Apple polyphenol, 150 mg/kg  30, 60, 90, 120, 180, 240 min  Mice  Plasama glucose↓ OGTT(glucose), 30 min  Autonomic nervous system    Tanida et al. (2009)120  Flavangenol, 3 μg (intraduodenal)  60 min  Rat  Sympathetic nerve activity by electro-physiological analysis↑   Saito et al. (2016)114  Theaflavin, 10 mg/kg  60 min  Rat  Mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ±   Saito et al. (2016)115  Flavan 3-ols, 1, 10, 100 mg/kg  60 min  Rat  mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ± phosphorylated eNOS without adrenaline blocker↑ (60 min, in aorta), with adrenaline blocker ±  Kamio et al. (2015)121  Flavan 3-ols, 10 mg/kg  2 h  Mice  Energy expenditure without adrenaline blocker↑, with adrenaline blocker ± UCP-3, and AMPK phosphorylation without adrenaline blocker↑ (in gastrocnemius), with adrenaline blocker ± UCP-1 and PGC-1 αwithout adrenaline blocker↑ (in brown adipose), with adrenaline blocker ±  Reference  Ingestion  Experimental period  Experimental animals  Outcome  Circulatory system    Ingawaet al. (2014)112  Flavan 3-ols, 10 mg/kg  60 min  Rat  Mean blood pressure↑ (transiently), heart rate↑ (transiently), phosphorylated eNOS↑ (60 min, in aorta)   Aruga et al. (2014)113  Flavan-3-ols, (−)-epicatechin, epigallocatechin gallate, theaflavins, quercetin, cyanidin, hesperidin, daidzein, trans-resveratrol, gnetin C, curcumin, 1 mg/kg p.o.  60 min  Rat  Mean blood pressure↑ (transiently, flavan 3-ols, epicatechin, quercetin, cyanidin, daizein ), heart rate↑ (transiently, flavan 3-ols), blood flow in cremaster arteriole↑ (flavan 3-ols, theaflavins)   Pons et al. (2016)111  250, 375, 500 mg of grape seed extract  2, 4, 6, 8, 24, 48 h   Rat  BP↓ (cafeteria meal–fed rat, 250, 375 vs control)  Metabolic system    Yamashita et al. (2012)116  Flavan 3-ols, 50, 250 mg/kg  15, 30, 60, 90, 120 min  Mice  Plasama glucose↓ (30, 60 min vs control), OGTT (glucose, starch maltose, sucurose)   Yamashita et al. (2013)118  Cinnamtannin A2, 10 μg/kg  60 min  Mice  Plasma insuline↑ (vs control)   Matsumura et al. (2014)119  Flavan 3-ols, 10 mg/kg  0, 1, 2, 5, 20 h  Mice  Energy expenditure, PGC-1α, UCP-3, and AMPK phosphorylation↑ (in gastrocnemius, vs control, 1, 2 h ), UCP-1 and PGC-1 α (in brown adipose, vs control, 1 h ), plasma adrenaline (in brown adipose, vs control, 2, 5 h)   Manzano et al. (2016)117  Apple polyphenol, 150 mg/kg  30, 60, 90, 120, 180, 240 min  Mice  Plasama glucose↓ OGTT(glucose), 30 min  Autonomic nervous system    Tanida et al. (2009)120  Flavangenol, 3 μg (intraduodenal)  60 min  Rat  Sympathetic nerve activity by electro-physiological analysis↑   Saito et al. (2016)114  Theaflavin, 10 mg/kg  60 min  Rat  Mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ±   Saito et al. (2016)115  Flavan 3-ols, 1, 10, 100 mg/kg  60 min  Rat  mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ± phosphorylated eNOS without adrenaline blocker↑ (60 min, in aorta), with adrenaline blocker ±  Kamio et al. (2015)121  Flavan 3-ols, 10 mg/kg  2 h  Mice  Energy expenditure without adrenaline blocker↑, with adrenaline blocker ± UCP-3, and AMPK phosphorylation without adrenaline blocker↑ (in gastrocnemius), with adrenaline blocker ± UCP-1 and PGC-1 αwithout adrenaline blocker↑ (in brown adipose), with adrenaline blocker ±  Abbreviations: AMPK, 5' AMP-activated protein kinase; BP, blood pressure; eNOS, endothelial nitric oxide synthase; OGTT, oral glucose tolerance test; PGC, peroxisome proliferator–activated receptor γ; UCP, uncoupling protein. Vascular endothelial cells are continuously exposed to shear stress caused by blood flow, which activates several endothelial surface molecules, including platelet endothelial cell adhesion molecule (PECAM)-1, integrins, ion channels, and tyrosine kinase receptors.122,123 Shear stress can further promote phosphorylation of eNOS at Ser 1179 to directly activate eNOS and enhance NO production. Therefore, changes in NO levels induced by flavan 3-ols could affect systemic circulation in response to increased shear stress. Metabolic system Postprandial metabolic changes have also been reported in animal experiments (Table 4). Insulin sensitivity detected after oral glucose or meal tolerance tests increased following the ingestion of flavan 3-ols derived from cocoa116 and apples.96,117 In mice, the area under the plasma glucose curve after consumption of a meal or glucose alone (0–120 or 180 min) was reduced with preliminary supplementation of flavan 3-ols at a dose of 50–250 mg/kg. Interestingly, supplementation with 10 μg/kg of cinnamtannin A2 as a tetramer (−)-epicatechin substantially increased plasma insulin levels 60 minutes after ingestion.118 This result suggests differences between flavan 3-ol constituents in terms of their ability to affect metabolism. Alterations in the glycemic response after ingestion of flavan 3-ols have been suggested to inhibit the expression of sodium-dependent glucose cotransporters (SGLUT) in the intestine96 while enhancing the secretion of glucagon-like peptide-1 (GLP-1)118 and accelerating glucose transporter-4 (GLUT-4) translocation in skeletal muscle.116 It was found that flavan 3-ols enhance energy expenditure in mice,119 with an elevation of phosphorylated AMP kinase (AMPK) in skeletal muscle and the messenger RNA expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein 1 (UCP-1) in brown adipose tissue (BAT). These metabolic changes may lead to a reduction in risk of chronic metabolic diseases, such as dyslipidemia and diabetes. Nervous system Several animal studies have suggested a beneficial effect of flavan 3-ols on the central nervous system, such as on memory or cognitive function, after repeated treatment with flavan 3-ols.124–126 These studies also indicate improved brain function by the ingestion of flavan 3-ols, which results in elevation of BDNF, decrease of monoamine metabolism, the downregulation of neurodegeneration genes in the hippocampus, and/or increase of cerebral blood flow. However, the postprandial alteration of these events by flavan 3-ols may be little as compared with the changes of the central nervous system following chronic ingestion of flavan 3-ols. Several murine studies have evaluated the changes in the autonomic nervous system brought on by ingestion of flavan 3-ols. Tanida et al.120 reported that the activity of sympathetic nerves innervating BAT substantially enhances increased BAT thermogenesis soon after intraduodenal injection of flavangenol as a flavan 3-ol–rich supplement. The stimulation of sympathetic nerves enhances the release of catecholamines (CA) from the terminal of the sympathetic nerve to the target organ, such as BAT, and from the adrenal medulla to the circulatory blood flow.127,128 Transient elevation of plasma adrenaline levels was also observed after ingestion of flavan 3-ol fraction.119 Hemodynamics129 and energy metabolism130 are tightly controlled by the autonomic nervous system. Neural adrenergic factors regulate metabolic pathways, such as glycolysis in the liver via the β2 adrenergic receptor (AR)131,132 or thermogenesis in BAT via the β3 AR.133 The β3 AR is expressed in adipose tissue, particularly BAT, and directly induces UCP-1 via PGC-1α.134,135 Stable blood pressure and heart rate can be maintained through rapid hemodynamic changes regulated by ARs.136 Plasma adrenaline secreted from the adrenal medulla also indirectly induces changes in skeletal muscle metabolism via the β2 AR. The β2 AR expressed in skeletal muscle regulates glycolysis through AMPKα phosphorylation, followed by GLUT-4 translocation,137,138 and lipolysis through PGC-1α upregulation.139,140 In addition, β2 AR agonists, including clenbuterol141 and formoterol,142 can improve muscle metabolism by upregulating PGC-1α expression and activating Akt/mTOR pathways. Given these roles, whether AR activity is involved in the postprandial physiological changes that occur after the ingestion of flavan 3-ols was examined. In the metabolic study, pretreatment of mice with β2 AR blocker butoxamine before the consumption of 10 mg/kg of flavan 3-ols prevented an increase in energy expenditure and levels of phosphorylated AMPKα in the gastrocnemius.121 Furthermore, the β3AR blocker SR52930 suppressed flavan 3-ol–induced increases in PGC-1α or UCP-1 expression in BAT. In the hemodynamic study, small amounts of flavan 3-ols (1–10 mg/kg) transiently increased blood pressure and heart rate, but high doses (100 mg/kg) did not. Pretreatment of mice with a nonspecific adrenaline blocker, such as carvedilol, reduced the changes induced by low doses of flavan 3-ols. Therefore, the hemodynamic changes following the consumption of low doses of flavan 3-ols could be attributed to adrenomimetic effects.114 The treatment of rats with a combination of 100 mg/kg of flavan 3-ols and α2 adrenergic blocker yohimbine, which inhibits excessive sympathetic nerve stimulation of the vasomotor center in the medulla oblongata, caused a noticeable increase in hemodynamic changes, such as elevated blood pressure and heart rate. These results may suggest that the consumption of high amounts of flavan 3-ols (100 mg/kg) can induce excessive neural stimulation, resulting in negative feedback to the vasomotor center to reduce peripheral changes, such as transient increases in blood pressure and heart rate. These observations indicate that neural adrenergic factors are essential mediators of the postprandial physiological alterations induced by flavan 3-ol consumption (Figure 3). Flavan 3-ols stimulate sympathetic nerves through the central nervous system while passing through the gut. Consequently, noradrenaline is secreted from the sympathetic nerve to the target organ, such as peripheral arteries, the heart, or BAT. The resulting activation of ARs expressed in each organ dynamically induces hemodynamic and metabolic changes. Sympathomimetic action also increases CA secretion from the adrenal medulla into the bloodstream. In skeletal muscle, βAR is activated, resulting in metabolic changes. Moreover, excessive sympathetic nerve stimulation induced by high doses of flavan 3-ols is suppressed by the negative feedback system in the central nervous system. However, the mechanism through which flavan 3-ol ingestion stimulates sympathetic nerve activity is unknown. Further studies are required to clarify the mechanisms involved, including brain-gastrointestinal axis stimulation by flavan 3-ols. Figure 3 View largeDownload slide Possible mechanisms of postprandial physiological alteration following flavan 3-ol ingestion. Flavan 3-ols stimulate sympathetic nerves through the central nervous system while passing through the gut. Consequently, noradrenaline is secreted from the sympathetic nerve to the target organ, such as peripheral arteries, the heart, or brown adipose tissue (BAT). The resulting activation of adrenergic receptors (ARs) expressed in each organ dynamically induces hemodynamic and metabolic changes. Sympathomimetic action also increases CA secretion from the adrenal medulla into the bloodstream. In skeletal muscle, βAR is activated and increases metabolic changes. Moreover, excessive sympathetic nerve stimulation induced by high doses of flavan 3-ols is suppressed by the negative feedback system in the central nervous system. Abbreviations: AMPK, AMP kinase; eNOS, endothelium nitric oxide synthase; GLUT-4, glucose transpoter-4; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1 α; UCP-1, uncoupling protein-1. Figure 3 View largeDownload slide Possible mechanisms of postprandial physiological alteration following flavan 3-ol ingestion. Flavan 3-ols stimulate sympathetic nerves through the central nervous system while passing through the gut. Consequently, noradrenaline is secreted from the sympathetic nerve to the target organ, such as peripheral arteries, the heart, or brown adipose tissue (BAT). The resulting activation of adrenergic receptors (ARs) expressed in each organ dynamically induces hemodynamic and metabolic changes. Sympathomimetic action also increases CA secretion from the adrenal medulla into the bloodstream. In skeletal muscle, βAR is activated and increases metabolic changes. Moreover, excessive sympathetic nerve stimulation induced by high doses of flavan 3-ols is suppressed by the negative feedback system in the central nervous system. Abbreviations: AMPK, AMP kinase; eNOS, endothelium nitric oxide synthase; GLUT-4, glucose transpoter-4; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1 α; UCP-1, uncoupling protein-1. CONCLUSION The stimulation of sympathetic nerve activity seems to be involved in postprandial hemodynamic, metabolic, and nervous system alteration following the ingestion of flavan 3-ols. All of the postprandial actions of flavan 3-ols in these systems are likely to lead to beneficial effect in chronic impairment, such as reduced cardiovascular and metabolic diseases, and possibly a reduction in the decline of cognitive function. Sympathetic nervous stimulation has been well documented to be induced by the response against physical stress, such as cold143,144 and exercise.145,146 Transient cold exposure induces BAT thermogenesis via β3 AR.147 The duration of cold exposure promotes not only the activation of BAT but also the differentiation from white adipose to beige adipose.148 Both adipose tissue types are suggested to be important in regulating body temperature and body weight because of the expenditure of chemical energy to produce heat. In addition, at the beginning of exercise, transient hemodynamic changes, such as elevation of blood pressure, heart rate, and blood flow, along with shear stress to arterioles, are induced.149 Repeating these hemodynamic events produces vascular reconstruction and hypotension via the induction of eNOS expression and the secretion of vascular endothelial growth factor.146 The hypotensive effect of exercise is attributable to these mechanisms. Moreover, recent evidence suggests that enhancement of cerebral blood flow by exercise increases the release of BDNF from the brain, consequently conveying a protective effect against the decline of cognitive function.150,151 Therefore, it is rational to believe that these hemodynamic, metabolic, and nervous system changes occur cooperatively rather than independently. Activation of the brain-gastrointestinal axis may play a part in this postprandial change after the ingestion of flavan 3-ols because flavan 3-ols can reach functional proteins located in the gastrointestinal mucosal cells despite little transfer into the circulation. Studies of the interaction between flavan 3-ols and the gut should be evaluated to identify the target sites of flavan 3-ols in the digestive tract. Acknowledgments Author contributions. N. Osakabe performed the data searches and data extraction and conducted the data analysis and wrote the article. All authors contributed to the editing of the manuscript and share responsibility for the final content. All authors read and approved the final manuscript. Funding. This work was supported by a grant from the Urgent Project for Development and Diffusion of Innovative Technology towards Realization of the Aggressive Agriculture, Forestry, and Fisheries from the Cross-Ministerial Strategic Innovation Promotion Program (SIP), Council for Science, Technology and Innovation, Cabinet Office, Government of Japan. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript Declaration of interest. The authors have no relevant interests to declare. References 1 Clifford MN, van der Hooft JJ, Crozier A. Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols. Am J Clin Nutr.  2013; 98: 1619s– 1630s. 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Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nutrition Reviews Oxford University Press

Possible mechanisms of postprandial physiological alterations following flavan 3-ol ingestion

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Abstract

Abstract Foods rich in flavan 3-ols are known to prevent cardiovascular diseases by reducing metabolic syndrome risks, such as hypertension, hyperglycemia, and dyslipidemia. However, the mechanisms involved in this reduction are unclear, particularly because of the poor bioavailability of flavan 3-ols. Recent metabolome analyses of feces produced after repeated ingestion of foods rich in flavan 3-ols may provide insight into the chronic physiological changes associated with the intake of flavan 3-ols. Substantial postprandial changes have been reported after flavan 3-ol ingestion, including hemodynamic and metabolic changes as well as autonomic and central nervous alterations. Taken together, the evidence suggests that flavan 3-ols have both postprandial and chronic effects, which could involve different or common mechanisms. In general, the accumulation of acute functional changes induces chronic physiological alteration. Therefore, this review highlights the postprandial action of flavan 3-ols in order to address the yet unknown mechanism(s) for their physiological function. autonomic, central nervous system, flavan 3-ols, hemodynamics, metabolic, postprandial INTRODUCTION Flavan 3-ols are a subclass of plant flavonoids that possess a diphenylpropane structure and are categorized as monomeric [eg, (+)-catechin or (−)-epicatechin and its gallate type] or oligomeric catechins (eg, theaflavin and procyanidins). Extensive studies have been performed on the bioavailability and vascular functions of monomeric catechins in relation to their antiatherosclerotic effects.1–3 The present review focuses mainly on oligomeric procyanidins because the physiological function of oligomeric procyanidins has attracted considerable attention in recent years. Foods rich in flavan 3-ols, such as tea, cocoa, red wine, grapes, and apples, could have substantial potential for managing cardiovascular health.4–6 Recent meta-analyses have suggested that flavan 3-ol consumption reduces the risk of cardiovascular diseases, including coronary heart disease, myocardial infarction, and stroke.7–9 In addition, numerous randomized controlled trials confirmed that dark chocolate containing large amounts of flavan 3-ols improves several conditions that contribute to metabolic syndrome, including hypertension,10,11 dyslipidemia,12,13 and glucose intolerance,14,15 and subsequent meta-analyses confirmed that dark chocolate can reduce the risk of cardiovascular disease.16–20 In vitro evidence supports previous clinical data showing that flavan 3-ols affect nitric oxide (NO) production or breakdown,21–23 as well as lipid metabolism24,25 and platelet function.26,27 Ingestion of flavan 3-ols has also been suggested to be inversely associated with diabetes risk.28 The ingestion of flavan 3-ols has been reported to reduce peripheral insulin or glucose resistance in postmenopausal women,29 hypertensive patients with impaired glucose tolerance,15 and healthy volunteers.30,31 In addition, several animal studies have suggested that treatment with flavan 3-ols attenuates the risk factors for diabetes.32–34 Recent reports imply that flavan 3-ols attenuate mood disorders and cognitive impairment in elder healthy volunteers,35 although the mechanisms underlying the beneficial effect of flavan 3-ols is not well understood. A recent comprehensive review on polyphenol and human health suggested that the mechanism for beneficial effect of flavan 3-ols has not been fully elucidated because of their poor bioavailability.36 (+)-Catechin and (−)-epicatechin are more readily absorbed than the other flavan 3-ols from the gastrointestinal tract, and almost all catechins are metabolized; therefore, unchanged forms are nearly absent in blood.37 In contrast, other flavan 3-ols, including gallate-type catechins and oligomeric catechins, are rarely absorbed from the gut into the blood.38–40 Consequently, flavan 3-ols pass from the upper digestive tract to the colon and are metabolized by gut microbiota to produce metabolites, primarily lactones and aromatic acids.41 Flavan 3-ol metabolites could be absorbed into the systemic circulation and are expected to play a role in the physiological changes that occur in response to frequent consumption of flavan 3-ols.42 In contrast, other studies have shown that flavan 3-ols exert postprandial actions on the hemodynamic,43 metabolic,44 and nervous systems,45 which seem to be unrelated to their metabolites when the passage time in the intestine is taken into account. As such, flavan 3-ols may have both postprandial and chronic activities, and different or common mechanisms may underlie these effects. In general, the accumulation of acute functional changes induces chronic physiological alterations. Moreover, these hemodynamic, metabolic, and nervous system changes following the ingestion of flavan 3-ols are likely to occur cooperatively, not independently. Therefore, this review highlights the postprandial action of flavan 3-ols in order to address yet unknown mechanisms for the beneficial effect in human health. FLAVAN 3-OLS AND BIOAVAILABILITY IN HUMANS Flavan 3-ols are a subclass of plant flavonoids possessing a diphenylpropane structure and are categorized as monomers [eg, (+)-catechin or (−)-epicatechin and its gallate type] or oligomers (eg, theaflavin and procyanidins) (Figure 1). They are included as antioxidants found in several plant-derived foods, such as tea, cocoa beans, grape (red wine), and apples.39,46–49 Figure 1 View largeDownload slide Flavan 3-ol subclasses, prominent chemicals, and typical food sources. Figure 1 View largeDownload slide Flavan 3-ol subclasses, prominent chemicals, and typical food sources. Nongallate type catechins such as (−)-epicatechin are absorbed via the gastrointestinal tract and exist in the blood primarily as metabolites, often as conjugates with glucuronide and/or sulfate50,51 (Figure 2). Approximately 20% of consumed (−)-epicatechin is absorbed, but unmetabolized (−)-epicatechin is nearly absent in the blood. The chemical structure of plasma (−)-epicatechin glucuronide differs between humans and murine animals52; (−)-epicatechin glucuronides isolated from human plasma have lower antioxidative activity than those isolated from rat plasma.52–54 Other flavan 3-ols (ie, gallate-type catechins and oligomeric catechins) are poorly absorbed in the gastrointestinal tract, because ATP-binding cassette (ABC) transporters, such as P-glycoprotein or a multidrug resistance protein (MRP), are involved in the elimination of flavan 3-ols from intestinal epithelial cells55 (Figure 2). In turn, gallate-type catechins and oligomeric catechins are present in the blood at very low concentrations.37–40,56–57 Figure 2 View largeDownload slide Absorption of flavan 3-ols from the digestive tract. Abbreviation: MRP, multidrug resistant protein. Figure 2 View largeDownload slide Absorption of flavan 3-ols from the digestive tract. Abbreviation: MRP, multidrug resistant protein. The bioavailability of flavan 3-ols may also be affected by the food matrix. Several previous studies reported that sugars enhance the absorption of flavan 3-ols in humans,58–60 with the different sugar types that coexist with flavan 3-ols affecting the absorption rate. Whether the interaction of flavan 3-ols and protein affects the bioavailability of flavan 3-ols is still controversial.61 Several in vitro studies have shown that several proteins, such as the major milk protein β-lactoglobulin62 and albumin,63 bind to flavan 3-ols tightly via covalent bonding. Serafini et al.64 reported that milk protein reduces the intestinal absorption of flavan 3-ols. However, other studies have shown that they do not inhibit flavan 3-ol absorption.59,65,66 Most of the remaining flavan 3-ols are metabolized by gut microbiota after passing from the upper digestive tract into the colon41 (Figure 2). A recent radiolabel study in rats reported that procyanidin B2 metabolite is absorbed into the systemic circulation, with peak levels 5–7 hours after oral administration.67 This finding is consistent with a study of the pig cecum system that demonstrated the degradation of procyanidins by microbiota 4–8 hours after consumption.68,69 Some of the main flavan 3-ol metabolites in humans are valerolactones, such as δ-(3, 4-dihydroxyphenyl)-γ-valerolactone, δ-(3-hydroxyphenyl)-γ-valerolactone,70 5-(3,4-dihydroxyphenyl)- γ-valerolactone, and 5-phenyl-γ-valerolactone.71 Phenolic acids, such as m-hydroxyphenylpropionic acid,70 3-hydroxyphenyl propionic acid, 3-phenylpropionic acid,72 hydroxyphenylpropionic acid, ferulic acid, 3,4-dihydroxyphenylacetic acid, m-hydroxyphenylacetic acid, vanillic acid, and m-hydroxybenzoic acid,73 are also flavan 3-ol metabolites detected in extracts derived from human samples. POSTPRANDIAL EFFECTS OF FLAVAN 3-OLS IN INTERVENTION TRIALS Circulatory system Several studies have described postprandial endothelial changes following the consumption of foods rich in flavan 3-ols. The elevation of flow-mediated dilatation (FMD), which occurs following the generation of endothelial-derived nitric oxide induced by shear stress, has been studied extensively.74 In various studies, FMD was measured after the consumption of flavan 3-ol–rich foods for a specified period in healthy volunteers,75–80 smokers,81,82 obese individuals,83,84 and patients with cardiovascular risk43,85–89 or end-stage renal disease90 (Table 143,75–90,91,92). In 19 trials and all but 2 reports,85,87 FMD substantially increased between 1 and 2 hours after the ingestion of flavan 3-ol–rich foods, including dark chocolate, red wine, and pure (−)-epicatechin. The flavan 3-ol dose in these studies varied widely, from 176 mg43 to 963 mg.88 The activity of pure (−)-epicatechin was described in the 2 papers with contrasting conclusions, and thus the activity of (−)-epicatechin remains poorly understood.93 In addition, portal or hepatic blood flow91 and cerebral blood flow92 have been reported to increase after the ingestion of flavan 3-ol–rich foods. A transient increase in blood pressure was demonstrated in the hepatic blood flow study.91 These results indicate that oral administration of flavan 3-ols increases NO production by vascular endothelial cells directly, or indirectly through blood flow that transmits shear stress to the endothelium. Table 1 Postprandial effects on circulation following ingestion of foods rich in flavan 3-ols in intervention trials Reference  Ingestion  Experimental period  Participants  Outcome  Heiss et al. (2003)43  Flavanol drink (10 or 176 mg )  2 h  Individuals with cardiovascular risk, n = 26  FMD↑ (vs baseline)  Vlachopoulos et al. (2005)75  1000 g of dark chocolate (>74% cocoa)  0.5, 1, 2,1.5, 3, 2.5, 3 h  Healthy individuals, n = 17  FMD↑ (vs baseline, 1 h)  Heiss et al. (2005)81  Flavanol drink (88–370 mg )  2 h  Smokers, n = 11  FMD↑ (176 or 370 mg vs baseline), RXNO↑ (176 or 370 mg vs baseline)  Farouque et al. (2006)85  Chocolate bar or placebo (444 or 19.6 mg)  90 min  Individuals with cardiovascular risk, n = 45  FMD ± (vs placebo, 90 min)  Schroeter et al. (2006)76  Flavanol drink (37 or 917 mg) 1 or 2 mg/kg of epicatechin  1, 2, 3, 4 h  Healthy individuals, n = 16 (flavanol drink study), n = 6 (epicatechin study)  FMD↑ (vs baseline, flavanol study, epicatechin study, 2, 4 h)  Hermann et al. (2006)82  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2, 4, 8, 24 h  Smokers, n = 25  FMD↑ (vs baseline, 2 h), platelet adhesion↓ (vs baseline, 2 h)  Balzer et al. (2008)88  Cocoa containing increasing concentrations of flavanols (75, 371, and 963 mg)  1, 2, 3, 4, 6 h  Individuals with cardiovascular risk, n = 10  FMD↑ (963 mg vs 75 mg flavanol)  Davison et al. (2008)83  Cocoa (36 and 902 mg)  2 h  Obese individuals, n = 49  FMD↑ (vs baseline)  Faridi et al. (2008)77  Cocoa powder or placebo  2 h  Healthy individuals, n = 45  FMD↑ (vs placebo)  Berry et al. (2010)84  Cocoa beverage powder (22 mg or 701 mg)  2 h  Obese individuals, n = 21  FMD↑ (701 mg vs 22 mg flavanol)  Westphal and Luley (2011)78  Flavanol drink (918 mg)  0, 2, 4, 6 h  Healthy individuals, n = 18  FMD↑ (vs control, 2, 4 h)  De Gottardi et al. (2012)91  Chocolate (>85%, 0.55 g/kg of body weight) or white chocolate  0, 0.5 h  Cirrhotic patients, n = 22  Hepatic venous pressure gradient↑ (vs white chocolate, 0.5 h), portal blood flow↑ (vs white chocolate, 0.5 h), blood pressure (vs white chocolate , 0.5 h)  Loffredo et al. (2014)86  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2 h  Individuals with cardiovascular risk, n = 20  FMD↑ (vs milk chocolate, 2 h), isoprostanes↓ (vs milk chocolate, 2 h), nitrite/nitrate (NOx)↑ (vs milk chocolate, 2 h), sNOX2‐dp↓ (vs milk chocolate, 2 h), maximal walking distance ↑ (vs milk chocolate, 2 h), and maximal walking time ↑ (vs milk chocolate, 2 h)  Hammer et al. (2015)87  50 g of dark chocolate or 50 g of white chocolate  2 h  Individuals with cardiovascular risk, n = 21  FMD ±  Lamport et al. (2015)92  Flavanol drink (494 mg or 23 mg)  2 h  Healthy individuals, n = 18  Cerebral blood flow↑  Rodriguez-Mateos et al. (2015)89  1.4, 2.7, 5.5, 10.9 mg/kg of cacao flavanol drink  1, 2, 3, 4 h  Healthy individuals, n = 15  ⊿FMD↑ (2.7, 5.5, 10.9 vs 1.4 mg/kg)  Dower et al. (2016)79  75 g of dark chocolate with placebo (150 mg of epicatechin) or 75 g of white chocolate with 100 mg of epicatechin or 75 g of white chocolate with placebo  2 h  Healthy individuals, n = 20  FMD↑ (dark chocolate vs white chocolate with placebo) FMD ± (white chocolate with epicatechin vs white chocolate with placebo)  Rassaf et al. (2016)90  Cocoa flavanol drink (900 mg) or placebo  1, 2, 3, 4, 5 h  Individuals with end-stage renal disease, n = 57  FMD↑ (vs placebo, 1, 2 h)  Sansone et al. (2017)80  0–880 mg of flavanol or 0–220 mg of methylxanthin  2 h  Healthy individuals, n = 47  FMD↑  Reference  Ingestion  Experimental period  Participants  Outcome  Heiss et al. (2003)43  Flavanol drink (10 or 176 mg )  2 h  Individuals with cardiovascular risk, n = 26  FMD↑ (vs baseline)  Vlachopoulos et al. (2005)75  1000 g of dark chocolate (>74% cocoa)  0.5, 1, 2,1.5, 3, 2.5, 3 h  Healthy individuals, n = 17  FMD↑ (vs baseline, 1 h)  Heiss et al. (2005)81  Flavanol drink (88–370 mg )  2 h  Smokers, n = 11  FMD↑ (176 or 370 mg vs baseline), RXNO↑ (176 or 370 mg vs baseline)  Farouque et al. (2006)85  Chocolate bar or placebo (444 or 19.6 mg)  90 min  Individuals with cardiovascular risk, n = 45  FMD ± (vs placebo, 90 min)  Schroeter et al. (2006)76  Flavanol drink (37 or 917 mg) 1 or 2 mg/kg of epicatechin  1, 2, 3, 4 h  Healthy individuals, n = 16 (flavanol drink study), n = 6 (epicatechin study)  FMD↑ (vs baseline, flavanol study, epicatechin study, 2, 4 h)  Hermann et al. (2006)82  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2, 4, 8, 24 h  Smokers, n = 25  FMD↑ (vs baseline, 2 h), platelet adhesion↓ (vs baseline, 2 h)  Balzer et al. (2008)88  Cocoa containing increasing concentrations of flavanols (75, 371, and 963 mg)  1, 2, 3, 4, 6 h  Individuals with cardiovascular risk, n = 10  FMD↑ (963 mg vs 75 mg flavanol)  Davison et al. (2008)83  Cocoa (36 and 902 mg)  2 h  Obese individuals, n = 49  FMD↑ (vs baseline)  Faridi et al. (2008)77  Cocoa powder or placebo  2 h  Healthy individuals, n = 45  FMD↑ (vs placebo)  Berry et al. (2010)84  Cocoa beverage powder (22 mg or 701 mg)  2 h  Obese individuals, n = 21  FMD↑ (701 mg vs 22 mg flavanol)  Westphal and Luley (2011)78  Flavanol drink (918 mg)  0, 2, 4, 6 h  Healthy individuals, n = 18  FMD↑ (vs control, 2, 4 h)  De Gottardi et al. (2012)91  Chocolate (>85%, 0.55 g/kg of body weight) or white chocolate  0, 0.5 h  Cirrhotic patients, n = 22  Hepatic venous pressure gradient↑ (vs white chocolate, 0.5 h), portal blood flow↑ (vs white chocolate, 0.5 h), blood pressure (vs white chocolate , 0.5 h)  Loffredo et al. (2014)86  40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa)  2 h  Individuals with cardiovascular risk, n = 20  FMD↑ (vs milk chocolate, 2 h), isoprostanes↓ (vs milk chocolate, 2 h), nitrite/nitrate (NOx)↑ (vs milk chocolate, 2 h), sNOX2‐dp↓ (vs milk chocolate, 2 h), maximal walking distance ↑ (vs milk chocolate, 2 h), and maximal walking time ↑ (vs milk chocolate, 2 h)  Hammer et al. (2015)87  50 g of dark chocolate or 50 g of white chocolate  2 h  Individuals with cardiovascular risk, n = 21  FMD ±  Lamport et al. (2015)92  Flavanol drink (494 mg or 23 mg)  2 h  Healthy individuals, n = 18  Cerebral blood flow↑  Rodriguez-Mateos et al. (2015)89  1.4, 2.7, 5.5, 10.9 mg/kg of cacao flavanol drink  1, 2, 3, 4 h  Healthy individuals, n = 15  ⊿FMD↑ (2.7, 5.5, 10.9 vs 1.4 mg/kg)  Dower et al. (2016)79  75 g of dark chocolate with placebo (150 mg of epicatechin) or 75 g of white chocolate with 100 mg of epicatechin or 75 g of white chocolate with placebo  2 h  Healthy individuals, n = 20  FMD↑ (dark chocolate vs white chocolate with placebo) FMD ± (white chocolate with epicatechin vs white chocolate with placebo)  Rassaf et al. (2016)90  Cocoa flavanol drink (900 mg) or placebo  1, 2, 3, 4, 5 h  Individuals with end-stage renal disease, n = 57  FMD↑ (vs placebo, 1, 2 h)  Sansone et al. (2017)80  0–880 mg of flavanol or 0–220 mg of methylxanthin  2 h  Healthy individuals, n = 47  FMD↑  Abbreviation: FMD, flow-mediated dilation. Two meta-analyses of randomized control intervention studies examining postprandial FMD alteration after ingestion of flavan 3-ols are available in the literature.19,94 These papers confirmed the postprandial increase in FMD following the ingestion of foods rich in flavan 3-ols. Interestingly, these papers also reported on medium- to long-term supplementation trials that suggested that changes in FMD were greater following a single oral administration than repeated ingestion of flavan 3-ol–rich foods. In contrast, recent meta-analyses have indicated that flavan 3-ol–rich food consumption for 2–18 weeks substantially reduces blood pressure in healthy volunteers or patients with moderate hypertension.95 This hypotensive activity of flavan 3-ols seems to be reflected in the initial hemodynamic changes, but further studies are needed to explain the relevance of the acute and chronic effects of flavan 3-ols on the systemic circulation or microcirculation. Metabolic system In oral glucose or meal tolerance tests44,93,96,97 in healthy individuals, postmenopausal woman, and diabetic patients, flavan 3-ols were reported to induce postprandial metabolic changes such as improvement of glucose or insulin tolerance (Table 244,93,96–98). In addition, energy expenditure as measured by respiratory analysis was substantially increased after obese individuals ingested 1 mg/kg body weight (−)-epicatechin.98 These rapid metabolic changes were also observed 2–4 hours after ingestion of food rich in flavan 3-ol, and several in vitro studies found that high concentrations of flavan 3-ols pulled down in micelles99,100 consisted of dietary fat and bile acid or inhibited glycolytic digestive enzymes.101,102 These actions observed in in vitro studies may reduce the increase in blood glucose or insulin. Table 2 Postprandial effects on metabolic system following ingestion of foods rich in flavan 3-ols in intervention trials Reference  Ingestion  Experimental period  Participants  Outcome  Naissides et al. (2004)44  400 mL of red wine (2.2 g/L of total polyphenols)  0, 1, 2, 3, 4, 5, 6 h  Postmenoposal women, n = 17  Plasma insulin in oral glucose tolerance test, AUC↑ (vs placebo), plasma triglyceride in oral lipid tolerance test, AUC↑ (vs placebo)  Gutierrez-Salmean et al. (2014)98  Epicatechin 1mg/kg  0, 2, 4 h  Obese individuals, n = 24  Respiratory quotient↑ (vs, baseline, 2 h), plasma glucose↓(vs, control, 4 h)  Schulze et al. (2014)96  2.8 g of apple extract  0, 15, 30, 45, 60, 90, 120, 180 min  Healthy individuals, n = 10  Plasma glucose in oral glucose tolerance test, AUC↓, plasma glucose in oral glucose tolerance test, AUC↓, urine glucose excretion ↑ (0–3 h, vs placebo)  Basu et al. (2015)93  Cocoa beverage or placebo (480 mg or less than 0.1 mg flavanols)  0, 0.5, 1, 2, 4, 6 h  Diabetic individuals, n = 24  HDL↑ (vs baseline, 1, 4 h), plasma insulin↑ (vs baseline, 0.5, 1, 2, 4, 6 h), insulin resistance ↑ (vs baseline, 4 h), artery elasticity ↑ (vs placebo, 2 h)  Bernardo et al. (2015)97  Cinnamon tea (557 mg of polyphenol)  0, 0.5, 1, 1.5, 2 h  Healthy individuals, n = 15  Plasma glucose in oral glucose tolerance test, Cmax↓, ⊿Cmax ↓ (vs placebo)  Reference  Ingestion  Experimental period  Participants  Outcome  Naissides et al. (2004)44  400 mL of red wine (2.2 g/L of total polyphenols)  0, 1, 2, 3, 4, 5, 6 h  Postmenoposal women, n = 17  Plasma insulin in oral glucose tolerance test, AUC↑ (vs placebo), plasma triglyceride in oral lipid tolerance test, AUC↑ (vs placebo)  Gutierrez-Salmean et al. (2014)98  Epicatechin 1mg/kg  0, 2, 4 h  Obese individuals, n = 24  Respiratory quotient↑ (vs, baseline, 2 h), plasma glucose↓(vs, control, 4 h)  Schulze et al. (2014)96  2.8 g of apple extract  0, 15, 30, 45, 60, 90, 120, 180 min  Healthy individuals, n = 10  Plasma glucose in oral glucose tolerance test, AUC↓, plasma glucose in oral glucose tolerance test, AUC↓, urine glucose excretion ↑ (0–3 h, vs placebo)  Basu et al. (2015)93  Cocoa beverage or placebo (480 mg or less than 0.1 mg flavanols)  0, 0.5, 1, 2, 4, 6 h  Diabetic individuals, n = 24  HDL↑ (vs baseline, 1, 4 h), plasma insulin↑ (vs baseline, 0.5, 1, 2, 4, 6 h), insulin resistance ↑ (vs baseline, 4 h), artery elasticity ↑ (vs placebo, 2 h)  Bernardo et al. (2015)97  Cinnamon tea (557 mg of polyphenol)  0, 0.5, 1, 1.5, 2 h  Healthy individuals, n = 15  Plasma glucose in oral glucose tolerance test, Cmax↓, ⊿Cmax ↓ (vs placebo)  Abbreviations: AUC, area under the blood concentration time curve; HDL, high-density lipoprotein. Considerable studies have also assessed repeated treatment with flavan 3-ols in humans. Ingestion of flavan 3-ol–rich food for 4–12 weeks substantially altered plasma lipid concentrations, such as elevating high-density lipoproteins and reducing low-density lipoproteins,12,103,104 or improved insulin resistance.15,30,83,104 These chronic alterations on lipid metabolism and insulin resistance seem to result from the accumulation of postprandial metabolic changes following the ingestion of flavan 3-ols. However, more extensive studies are needed to elucidate the mechanism underlying metabolic alternation by flavan 3-ol ingestion. Nervous system Several studies have been reported regarding the alteration of both the autonomic and central nervous system following the ingestion of flavan 3-ols (Table 345,105–108). Spaak et al.105 reported that the ingestion of red wine elevates plasma adrenaline levels and muscle sympathetic nerve activity, although these effects were not observed when only ethanol was consumed. In addition, working memory was suggested to be improved by the ingestion of chocolate in healthy individuals,106,107 and changes in these cerebral functions are considered to be related to changes in cerebral blood flow. A functional magnetic resonance imaging technique demonstrated that the elevation of blood oxygenation after ingestion of cocoa flavan 3-ols associates with the changes in cerebral blood flow.45 Serial tasks, which are used to assess mental status in suspected cases of dementia, were improved 1 hour after supplementation with cocoa flavan 3-ols.108 Repeated treatment with cocoa flavan 3-ols for 8–12 weeks in elderly individuals improved cognitive function and increased plasma brain-derived neurotrophic factor (BDNF) levels or improved insulin resistance.109,110 Acute and chronic changes in cognitive function seem to be closely associated with each other, and further consideration is thus needed as to how they cooperate in the nervous system. Table 3 Postprandial effects on nervous systems following ingestion of foods rich in flavan 3-ols in intervention trials Reference  Ingestion  Experimental period  Participants  Outcome  Autonomic nervous system   Spaak et al. (2008)105  Red wine, alchol, or water (455 mL)  6 h  Healthy individuals, n = 13  Plasma adrenaline↑ (vs water, alchol), sympathetic nerve activity↑ (vs water, alchol)  Central nervous system   Francis et al. (2006)45  Cocoa flavanol (13, 190 mg)  1.5 h  Healthy individuals, n = 16  Magnetic resonance imaging based on blood oxygenation level-dependent↑ (13 vs 190 mg)   Scholey et al. (2010)108  Cocoa flavanol (control, 520, and 994 mg)  All tasks were carried out for 1h after ingestion  Healthy individuals, n = 30  Serial 3 tasks↑ (520 and 994 mg vs control), serial 7 tasks↓ (994 mg vs control), rapid visual information processing tasks↑ (994 mg vs control), mental fatigue scale↑ (994 mg vs control)   Field et al. (2011)106  35 g of white chocolate or 35 g of dark chocolate (cocoa flavanol 773 mg)  2 h  Healthy individuals, n = 30  Visual spatial working memory↑ (vs white chocolate), choice reaction time↓ (vs white chocolate)   Grassi et al. (2016)107  100 g of flavanol-rich chocolate or flavanol poor chocolate (520 or 88.5 mg)  1.5 h  Healthy individuals, n = 32 (with sleep deprivation)  Working memory accuracy ↑ (woman, rich vs poor)  Reference  Ingestion  Experimental period  Participants  Outcome  Autonomic nervous system   Spaak et al. (2008)105  Red wine, alchol, or water (455 mL)  6 h  Healthy individuals, n = 13  Plasma adrenaline↑ (vs water, alchol), sympathetic nerve activity↑ (vs water, alchol)  Central nervous system   Francis et al. (2006)45  Cocoa flavanol (13, 190 mg)  1.5 h  Healthy individuals, n = 16  Magnetic resonance imaging based on blood oxygenation level-dependent↑ (13 vs 190 mg)   Scholey et al. (2010)108  Cocoa flavanol (control, 520, and 994 mg)  All tasks were carried out for 1h after ingestion  Healthy individuals, n = 30  Serial 3 tasks↑ (520 and 994 mg vs control), serial 7 tasks↓ (994 mg vs control), rapid visual information processing tasks↑ (994 mg vs control), mental fatigue scale↑ (994 mg vs control)   Field et al. (2011)106  35 g of white chocolate or 35 g of dark chocolate (cocoa flavanol 773 mg)  2 h  Healthy individuals, n = 30  Visual spatial working memory↑ (vs white chocolate), choice reaction time↓ (vs white chocolate)   Grassi et al. (2016)107  100 g of flavanol-rich chocolate or flavanol poor chocolate (520 or 88.5 mg)  1.5 h  Healthy individuals, n = 32 (with sleep deprivation)  Working memory accuracy ↑ (woman, rich vs poor)  POSTPRANDIAL EFFECTS OF FLAVAN 3-OLS IN ANIMAL STUDIES Circulatory system Several papers have reported postprandial physiological changes following the ingestion of flavan 3-ol fractions or isolated flavan 3-ol by using experimental animals (Table 4) 111–115,116–119,120,121. These studies suggest that flavan 3-ols alter the level of NO in endothelial cells and influence hemodynamics, such as blood pressure, heart rate, and blood flow, in parallel.111,112 Comparisons of the acute hemodynamic changes by 14 polyphenolic compounds113,114 showed that mean blood pressure, heart rate, and blood flow in cremaster arterioles increase substantially shortly after the administration of a small amount of flavan 3-ol fraction (1–10 mg/kg). These changes are transient, and the increased blood pressure and heart rate return to baseline levels 60 minutes after ingestion. Phosphorylated endothelial nitric oxide synthase (eNOS) levels were substantially increased in aortas dissected 60 minutes after flavan 3-ol fraction ingestion compared with the vehicle treatment group,112 and these effects were greater than those of isolated quercetin, hesperidin, trans-resveratrol, or curcumin.113 As in the FMD intervention studies, flavan 3-ols appear to increase NO production from vascular endothelial cells by inducing eNOS phosphorylation. This effect was not dose-dependent because high amounts of flavan 3-ol fraction (100 mg/kg) did not induce eNOS phosphorylation or changes in blood pressure.115 These results suggest that flavan 3-ols do not induce eNOS expression directly. Table 4 Postprandial physiological effects following ingestion of flavan 3-ols fraction in animal studies Reference  Ingestion  Experimental period  Experimental animals  Outcome  Circulatory system    Ingawaet al. (2014)112  Flavan 3-ols, 10 mg/kg  60 min  Rat  Mean blood pressure↑ (transiently), heart rate↑ (transiently), phosphorylated eNOS↑ (60 min, in aorta)   Aruga et al. (2014)113  Flavan-3-ols, (−)-epicatechin, epigallocatechin gallate, theaflavins, quercetin, cyanidin, hesperidin, daidzein, trans-resveratrol, gnetin C, curcumin, 1 mg/kg p.o.  60 min  Rat  Mean blood pressure↑ (transiently, flavan 3-ols, epicatechin, quercetin, cyanidin, daizein ), heart rate↑ (transiently, flavan 3-ols), blood flow in cremaster arteriole↑ (flavan 3-ols, theaflavins)   Pons et al. (2016)111  250, 375, 500 mg of grape seed extract  2, 4, 6, 8, 24, 48 h   Rat  BP↓ (cafeteria meal–fed rat, 250, 375 vs control)  Metabolic system    Yamashita et al. (2012)116  Flavan 3-ols, 50, 250 mg/kg  15, 30, 60, 90, 120 min  Mice  Plasama glucose↓ (30, 60 min vs control), OGTT (glucose, starch maltose, sucurose)   Yamashita et al. (2013)118  Cinnamtannin A2, 10 μg/kg  60 min  Mice  Plasma insuline↑ (vs control)   Matsumura et al. (2014)119  Flavan 3-ols, 10 mg/kg  0, 1, 2, 5, 20 h  Mice  Energy expenditure, PGC-1α, UCP-3, and AMPK phosphorylation↑ (in gastrocnemius, vs control, 1, 2 h ), UCP-1 and PGC-1 α (in brown adipose, vs control, 1 h ), plasma adrenaline (in brown adipose, vs control, 2, 5 h)   Manzano et al. (2016)117  Apple polyphenol, 150 mg/kg  30, 60, 90, 120, 180, 240 min  Mice  Plasama glucose↓ OGTT(glucose), 30 min  Autonomic nervous system    Tanida et al. (2009)120  Flavangenol, 3 μg (intraduodenal)  60 min  Rat  Sympathetic nerve activity by electro-physiological analysis↑   Saito et al. (2016)114  Theaflavin, 10 mg/kg  60 min  Rat  Mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ±   Saito et al. (2016)115  Flavan 3-ols, 1, 10, 100 mg/kg  60 min  Rat  mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ± phosphorylated eNOS without adrenaline blocker↑ (60 min, in aorta), with adrenaline blocker ±  Kamio et al. (2015)121  Flavan 3-ols, 10 mg/kg  2 h  Mice  Energy expenditure without adrenaline blocker↑, with adrenaline blocker ± UCP-3, and AMPK phosphorylation without adrenaline blocker↑ (in gastrocnemius), with adrenaline blocker ± UCP-1 and PGC-1 αwithout adrenaline blocker↑ (in brown adipose), with adrenaline blocker ±  Reference  Ingestion  Experimental period  Experimental animals  Outcome  Circulatory system    Ingawaet al. (2014)112  Flavan 3-ols, 10 mg/kg  60 min  Rat  Mean blood pressure↑ (transiently), heart rate↑ (transiently), phosphorylated eNOS↑ (60 min, in aorta)   Aruga et al. (2014)113  Flavan-3-ols, (−)-epicatechin, epigallocatechin gallate, theaflavins, quercetin, cyanidin, hesperidin, daidzein, trans-resveratrol, gnetin C, curcumin, 1 mg/kg p.o.  60 min  Rat  Mean blood pressure↑ (transiently, flavan 3-ols, epicatechin, quercetin, cyanidin, daizein ), heart rate↑ (transiently, flavan 3-ols), blood flow in cremaster arteriole↑ (flavan 3-ols, theaflavins)   Pons et al. (2016)111  250, 375, 500 mg of grape seed extract  2, 4, 6, 8, 24, 48 h   Rat  BP↓ (cafeteria meal–fed rat, 250, 375 vs control)  Metabolic system    Yamashita et al. (2012)116  Flavan 3-ols, 50, 250 mg/kg  15, 30, 60, 90, 120 min  Mice  Plasama glucose↓ (30, 60 min vs control), OGTT (glucose, starch maltose, sucurose)   Yamashita et al. (2013)118  Cinnamtannin A2, 10 μg/kg  60 min  Mice  Plasma insuline↑ (vs control)   Matsumura et al. (2014)119  Flavan 3-ols, 10 mg/kg  0, 1, 2, 5, 20 h  Mice  Energy expenditure, PGC-1α, UCP-3, and AMPK phosphorylation↑ (in gastrocnemius, vs control, 1, 2 h ), UCP-1 and PGC-1 α (in brown adipose, vs control, 1 h ), plasma adrenaline (in brown adipose, vs control, 2, 5 h)   Manzano et al. (2016)117  Apple polyphenol, 150 mg/kg  30, 60, 90, 120, 180, 240 min  Mice  Plasama glucose↓ OGTT(glucose), 30 min  Autonomic nervous system    Tanida et al. (2009)120  Flavangenol, 3 μg (intraduodenal)  60 min  Rat  Sympathetic nerve activity by electro-physiological analysis↑   Saito et al. (2016)114  Theaflavin, 10 mg/kg  60 min  Rat  Mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ±   Saito et al. (2016)115  Flavan 3-ols, 1, 10, 100 mg/kg  60 min  Rat  mean blood pressure without adrenaline blocker↑ (transiently), with adrenaline blocker ± heart rate without adrenaline blocker↑ (transiently), with adrenaline blocker ± phosphorylated eNOS without adrenaline blocker↑ (60 min, in aorta), with adrenaline blocker ±  Kamio et al. (2015)121  Flavan 3-ols, 10 mg/kg  2 h  Mice  Energy expenditure without adrenaline blocker↑, with adrenaline blocker ± UCP-3, and AMPK phosphorylation without adrenaline blocker↑ (in gastrocnemius), with adrenaline blocker ± UCP-1 and PGC-1 αwithout adrenaline blocker↑ (in brown adipose), with adrenaline blocker ±  Abbreviations: AMPK, 5' AMP-activated protein kinase; BP, blood pressure; eNOS, endothelial nitric oxide synthase; OGTT, oral glucose tolerance test; PGC, peroxisome proliferator–activated receptor γ; UCP, uncoupling protein. Vascular endothelial cells are continuously exposed to shear stress caused by blood flow, which activates several endothelial surface molecules, including platelet endothelial cell adhesion molecule (PECAM)-1, integrins, ion channels, and tyrosine kinase receptors.122,123 Shear stress can further promote phosphorylation of eNOS at Ser 1179 to directly activate eNOS and enhance NO production. Therefore, changes in NO levels induced by flavan 3-ols could affect systemic circulation in response to increased shear stress. Metabolic system Postprandial metabolic changes have also been reported in animal experiments (Table 4). Insulin sensitivity detected after oral glucose or meal tolerance tests increased following the ingestion of flavan 3-ols derived from cocoa116 and apples.96,117 In mice, the area under the plasma glucose curve after consumption of a meal or glucose alone (0–120 or 180 min) was reduced with preliminary supplementation of flavan 3-ols at a dose of 50–250 mg/kg. Interestingly, supplementation with 10 μg/kg of cinnamtannin A2 as a tetramer (−)-epicatechin substantially increased plasma insulin levels 60 minutes after ingestion.118 This result suggests differences between flavan 3-ol constituents in terms of their ability to affect metabolism. Alterations in the glycemic response after ingestion of flavan 3-ols have been suggested to inhibit the expression of sodium-dependent glucose cotransporters (SGLUT) in the intestine96 while enhancing the secretion of glucagon-like peptide-1 (GLP-1)118 and accelerating glucose transporter-4 (GLUT-4) translocation in skeletal muscle.116 It was found that flavan 3-ols enhance energy expenditure in mice,119 with an elevation of phosphorylated AMP kinase (AMPK) in skeletal muscle and the messenger RNA expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein 1 (UCP-1) in brown adipose tissue (BAT). These metabolic changes may lead to a reduction in risk of chronic metabolic diseases, such as dyslipidemia and diabetes. Nervous system Several animal studies have suggested a beneficial effect of flavan 3-ols on the central nervous system, such as on memory or cognitive function, after repeated treatment with flavan 3-ols.124–126 These studies also indicate improved brain function by the ingestion of flavan 3-ols, which results in elevation of BDNF, decrease of monoamine metabolism, the downregulation of neurodegeneration genes in the hippocampus, and/or increase of cerebral blood flow. However, the postprandial alteration of these events by flavan 3-ols may be little as compared with the changes of the central nervous system following chronic ingestion of flavan 3-ols. Several murine studies have evaluated the changes in the autonomic nervous system brought on by ingestion of flavan 3-ols. Tanida et al.120 reported that the activity of sympathetic nerves innervating BAT substantially enhances increased BAT thermogenesis soon after intraduodenal injection of flavangenol as a flavan 3-ol–rich supplement. The stimulation of sympathetic nerves enhances the release of catecholamines (CA) from the terminal of the sympathetic nerve to the target organ, such as BAT, and from the adrenal medulla to the circulatory blood flow.127,128 Transient elevation of plasma adrenaline levels was also observed after ingestion of flavan 3-ol fraction.119 Hemodynamics129 and energy metabolism130 are tightly controlled by the autonomic nervous system. Neural adrenergic factors regulate metabolic pathways, such as glycolysis in the liver via the β2 adrenergic receptor (AR)131,132 or thermogenesis in BAT via the β3 AR.133 The β3 AR is expressed in adipose tissue, particularly BAT, and directly induces UCP-1 via PGC-1α.134,135 Stable blood pressure and heart rate can be maintained through rapid hemodynamic changes regulated by ARs.136 Plasma adrenaline secreted from the adrenal medulla also indirectly induces changes in skeletal muscle metabolism via the β2 AR. The β2 AR expressed in skeletal muscle regulates glycolysis through AMPKα phosphorylation, followed by GLUT-4 translocation,137,138 and lipolysis through PGC-1α upregulation.139,140 In addition, β2 AR agonists, including clenbuterol141 and formoterol,142 can improve muscle metabolism by upregulating PGC-1α expression and activating Akt/mTOR pathways. Given these roles, whether AR activity is involved in the postprandial physiological changes that occur after the ingestion of flavan 3-ols was examined. In the metabolic study, pretreatment of mice with β2 AR blocker butoxamine before the consumption of 10 mg/kg of flavan 3-ols prevented an increase in energy expenditure and levels of phosphorylated AMPKα in the gastrocnemius.121 Furthermore, the β3AR blocker SR52930 suppressed flavan 3-ol–induced increases in PGC-1α or UCP-1 expression in BAT. In the hemodynamic study, small amounts of flavan 3-ols (1–10 mg/kg) transiently increased blood pressure and heart rate, but high doses (100 mg/kg) did not. Pretreatment of mice with a nonspecific adrenaline blocker, such as carvedilol, reduced the changes induced by low doses of flavan 3-ols. Therefore, the hemodynamic changes following the consumption of low doses of flavan 3-ols could be attributed to adrenomimetic effects.114 The treatment of rats with a combination of 100 mg/kg of flavan 3-ols and α2 adrenergic blocker yohimbine, which inhibits excessive sympathetic nerve stimulation of the vasomotor center in the medulla oblongata, caused a noticeable increase in hemodynamic changes, such as elevated blood pressure and heart rate. These results may suggest that the consumption of high amounts of flavan 3-ols (100 mg/kg) can induce excessive neural stimulation, resulting in negative feedback to the vasomotor center to reduce peripheral changes, such as transient increases in blood pressure and heart rate. These observations indicate that neural adrenergic factors are essential mediators of the postprandial physiological alterations induced by flavan 3-ol consumption (Figure 3). Flavan 3-ols stimulate sympathetic nerves through the central nervous system while passing through the gut. Consequently, noradrenaline is secreted from the sympathetic nerve to the target organ, such as peripheral arteries, the heart, or BAT. The resulting activation of ARs expressed in each organ dynamically induces hemodynamic and metabolic changes. Sympathomimetic action also increases CA secretion from the adrenal medulla into the bloodstream. In skeletal muscle, βAR is activated, resulting in metabolic changes. Moreover, excessive sympathetic nerve stimulation induced by high doses of flavan 3-ols is suppressed by the negative feedback system in the central nervous system. However, the mechanism through which flavan 3-ol ingestion stimulates sympathetic nerve activity is unknown. Further studies are required to clarify the mechanisms involved, including brain-gastrointestinal axis stimulation by flavan 3-ols. Figure 3 View largeDownload slide Possible mechanisms of postprandial physiological alteration following flavan 3-ol ingestion. Flavan 3-ols stimulate sympathetic nerves through the central nervous system while passing through the gut. Consequently, noradrenaline is secreted from the sympathetic nerve to the target organ, such as peripheral arteries, the heart, or brown adipose tissue (BAT). The resulting activation of adrenergic receptors (ARs) expressed in each organ dynamically induces hemodynamic and metabolic changes. Sympathomimetic action also increases CA secretion from the adrenal medulla into the bloodstream. In skeletal muscle, βAR is activated and increases metabolic changes. Moreover, excessive sympathetic nerve stimulation induced by high doses of flavan 3-ols is suppressed by the negative feedback system in the central nervous system. Abbreviations: AMPK, AMP kinase; eNOS, endothelium nitric oxide synthase; GLUT-4, glucose transpoter-4; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1 α; UCP-1, uncoupling protein-1. Figure 3 View largeDownload slide Possible mechanisms of postprandial physiological alteration following flavan 3-ol ingestion. Flavan 3-ols stimulate sympathetic nerves through the central nervous system while passing through the gut. Consequently, noradrenaline is secreted from the sympathetic nerve to the target organ, such as peripheral arteries, the heart, or brown adipose tissue (BAT). The resulting activation of adrenergic receptors (ARs) expressed in each organ dynamically induces hemodynamic and metabolic changes. Sympathomimetic action also increases CA secretion from the adrenal medulla into the bloodstream. In skeletal muscle, βAR is activated and increases metabolic changes. Moreover, excessive sympathetic nerve stimulation induced by high doses of flavan 3-ols is suppressed by the negative feedback system in the central nervous system. Abbreviations: AMPK, AMP kinase; eNOS, endothelium nitric oxide synthase; GLUT-4, glucose transpoter-4; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1 α; UCP-1, uncoupling protein-1. CONCLUSION The stimulation of sympathetic nerve activity seems to be involved in postprandial hemodynamic, metabolic, and nervous system alteration following the ingestion of flavan 3-ols. All of the postprandial actions of flavan 3-ols in these systems are likely to lead to beneficial effect in chronic impairment, such as reduced cardiovascular and metabolic diseases, and possibly a reduction in the decline of cognitive function. Sympathetic nervous stimulation has been well documented to be induced by the response against physical stress, such as cold143,144 and exercise.145,146 Transient cold exposure induces BAT thermogenesis via β3 AR.147 The duration of cold exposure promotes not only the activation of BAT but also the differentiation from white adipose to beige adipose.148 Both adipose tissue types are suggested to be important in regulating body temperature and body weight because of the expenditure of chemical energy to produce heat. In addition, at the beginning of exercise, transient hemodynamic changes, such as elevation of blood pressure, heart rate, and blood flow, along with shear stress to arterioles, are induced.149 Repeating these hemodynamic events produces vascular reconstruction and hypotension via the induction of eNOS expression and the secretion of vascular endothelial growth factor.146 The hypotensive effect of exercise is attributable to these mechanisms. Moreover, recent evidence suggests that enhancement of cerebral blood flow by exercise increases the release of BDNF from the brain, consequently conveying a protective effect against the decline of cognitive function.150,151 Therefore, it is rational to believe that these hemodynamic, metabolic, and nervous system changes occur cooperatively rather than independently. Activation of the brain-gastrointestinal axis may play a part in this postprandial change after the ingestion of flavan 3-ols because flavan 3-ols can reach functional proteins located in the gastrointestinal mucosal cells despite little transfer into the circulation. Studies of the interaction between flavan 3-ols and the gut should be evaluated to identify the target sites of flavan 3-ols in the digestive tract. Acknowledgments Author contributions. N. Osakabe performed the data searches and data extraction and conducted the data analysis and wrote the article. All authors contributed to the editing of the manuscript and share responsibility for the final content. All authors read and approved the final manuscript. Funding. This work was supported by a grant from the Urgent Project for Development and Diffusion of Innovative Technology towards Realization of the Aggressive Agriculture, Forestry, and Fisheries from the Cross-Ministerial Strategic Innovation Promotion Program (SIP), Council for Science, Technology and Innovation, Cabinet Office, Government of Japan. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript Declaration of interest. The authors have no relevant interests to declare. References 1 Clifford MN, van der Hooft JJ, Crozier A. Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols. Am J Clin Nutr.  2013; 98: 1619s– 1630s. 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Nutrition ReviewsOxford University Press

Published: Mar 1, 2018

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