The bioavailability and tissue distribution of phytochemicals in humans are key factors that need to be clearly established and associated with their biological effects. The fate of phytochemicals in the body, including absorption, metabolism, and distribution, may vary according to the categories of phytochemicals. Ingested polyphenols can be absorbed from the stomach or the small intestine and can undergo conjugation in the intestine and liver to give methyl, glucuronide, and sulfate derivatives . Native polyphenols can also break down, producing smaller phenolic acid derivatives, such as protocatechuic, vanillic, or ferulic acid. These phenolic acids can also undergo phase I and phase II metabolism in the liver . The bioavailability of plant-food bio-active compounds is complex and presents interindividual variation ; however, the extent of such variability and the major determinants involved are currently not established. An example of interindividual variation in the metabolism of plant bio-active compounds is the conversion by the gut microbiota of the soy isoflavone precursors, black plastic nursery pots daidzin and daidzein, to the microbial-derived metabolite equol.
After a soy challenge, 20–30% of Western and 50–60% of Asian populations produce equol. The bacteria involved in the conversion have been identified, but the determinants that govern the daidzein-metabolizing phenotype still have not been fully elucidated. The gut microbiota has also a key role in the metabolism of other plant-food bio-active compounds, such as lignans and ellagitannins . Genetic polymorphisms can also contribute to the interindividual variation in bioavailability. For example, the role of genetic polymorphisms in the interindividual variability in bioavailability of caffeine was demonstrated. Caffeine is mainly metabolized by cytochrome P450 1A2 in the liver, and subjects with the CYP1A2*1F allele variant are considered slow caffeine metabolizers compared with the rapid caffeine metabolizers carrying the wild-type allele . Other factors such as age, sex, and dietary habits may affect the bioavailability of plant-food bio-active compounds. For example, sex differences in the glucuronidation of resveratrol, a polyphenol present in grapes and wine, have recently been observed, which may be explained by sex-specific uridine 59-diphospho–glucuronosyltransferase isoenzyme expression profiles regulated by sex hormones . The existence of an interindividual variability in the bioavailability of plant-food bio-active compounds suggests that there could also exist an interindividual variability in biological response to the consumption of these compounds.
Heterogeneity in the responsiveness to plant bio-active compounds can obscure associations between habitual intakes and health outcomes, resulting in a potential masking of health benefits for specific population groups and thereby limiting our knowledge of the role of the different bio-actives for health. Improving our knowledge of the factors, both genetic and nongenetic [such as age, sex, or genotype], that influence whether plant-food bio-active compounds are more or less effective in individuals will be invaluable to progress in the development of effective and innovative solutions leading to health improvements . However, to date, this interindividual variation in efficacy of plant-food bio-active compounds to modulate physiological outcomes has been little explored. The aim of this review is to provide an overview of the existing studies, both prospective and clinical trials, that has revealed interindividual variability in the responsiveness to the consumption of major plantfood bio-active compounds present in our diet: polyphenols, caffeine, and plant sterols. This review focuses on interindividual variability regarding cardiometabolic outcomes and discloses the potential determinants involved.We identified 6 prospective studies addressing the impact of interindividual variability in biomarkers of cardiometabolic health after habitual intake of a range of different plantbio-active compounds, including coffee and soy .
One area of particular interest relates to the microbially derived soy isoflavone metabolite, equol. In one prospective study, which examined associations between urinary equol excretion, serum lipids, and carotid intima thickness in 572 Chinese participants, 25% were equol excreters on their usual diet. In relation to other characteristics, the number of equol producers was similar between men and women, and there was no significant difference between equol-producer phenotype and age, dietary intakes, blood pressure, or BMI . Equol excreters had significantly lower TG and IMT levels compared to non-equol excreters . Although there was no association between soy isoflavone intake and serum lipids or IMT in the non– equol excreters, equol excreters within the highest quartile of intake had significantly lower IMT and higher HDL cholesterol concentrations than those in the lowest quartile of soy intake. Although this was an Asian population, habitual intakes of isoflavones were low, with a mean intake of 13 mg/d in both the equol- and non–equol-producer groups . The findings are therefore intriguing because data from the extensive literature on soyintervention studies suggest that an isoflavone intake >25 mg/d is required for any biological or clinical effect . The lack of an effect of isoflavone intake on CVD risk in women from the EPIC population was therefore not surprising, given that the median intake of isoflavones was only 0.4 mg/d. This study did not assess equol-producer status, and there was no difference in the association between habitual isoflavone intake and CVD risk when stratified by smoking , BMI, hormone replacement therapy use, age at intake, and hypercholesterolemia . This prospective study also examined associations between habitual lignan intakes and CVD risk in women and observed no association with intake , although the authors suggested a decreased risk of developing CVD in participants who were past smokers and had a higher habitual lignan intake. Therefore, available data on soy and the microbially derived metabolite equol are very limited. The impact of the equol-producer phenotype requires further investigation in population groups in which there is a wide variability in intakes in order to more carefully examine the magnitude of interindividual variability in response to biomarkers of cardiometabolic health and particularly the importance of the microbially derived metabolite equol. Four prospective studies have examined the impact of several factors in explaining the association between coffee intake and CVD risk . Whether polymorphism in the CYP1A2 gene, coding for the main enzyme responsible for the metabolism of caffeine, modulates the association between coffee intake and risk of CVD and related biomarkers was addressed in 3 studies. In one study, the risk of hypertension associated with coffee intake was shown to vary according to CYP1A2 genotype, with carriers of the slow-metabolism *1F allele at increased risk with higher coffee intake but not participants with the fast metabolism *1A/*1A genotype .
In a more recent study from this same hypertensive cohort, the association between coffee intake and impaired fasting glucose was stronger in carriers of the *1F variant, with the highest risk in heavy drinkers [$4 cups/d ] . In relation to myocardial infarction, 30 plant pot in a case-control study coffee intake was only associated with an increased risk of nonfatal myocardial infarction among participants with slow-caffeine metabolism . Only one study examined whether the relation between coffee intake and incident of coronary artery disease is dependent on the metabolism of catecholamines, specifically polymorphisms of the catechol-Omethyltransferase gene. In a cohort of 773 men, the relation between consumption of caffeinated coffee and the incidence of fatal and nonfatal CAD was dependent on COMT genotype. In men who were either homozygous for the high-activity COMT allele or heterozygous, substantial coffee intake did not increase the incidence of acute coronary events. However, for those who were homozygous for the low-activity COMT allele, heavy coffee consumption was associated with a higher incidence of acute coronary events, and the relative CAD incidence was >200% higher among drinkers of >6.5 cups of coffee/d after multivariable adjustment . Taken together, these few prospective studies have shown that there is interindividual variability in response to the consumption of plant-food bio-active compounds and that individuals do not equally benefit from the consumption of these phytochemicals. Different determinants, such as gut microbiota, genetic polymorphism, or smoking, have been suggested to be involved in these between-subject variations. It should also be noted that coffee is a source of not only caffeine, the amount of which can vary depending on brewing , but also of other micronutrients, such as chlorogenic acid, which has been shown to mediate the blood pressure rise caused by coffee intake .Age is the strongest independent cardiovascular risk factor for CVD, as indicated in most methods of risk scoring, such as the Framingham risk score or the European Society of Cardiology SCORE system . Aging is also associated with increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension . All these age-associated changes in the vascular system are known to have an effect on the bioactivity of some drugs, such as verapamil, albuterol, or benzodiazepines , and potentially could also have an effect on the bioactivity of plant-food bio-actives, which undergo the same conjugation pathways when absorbed.To date, few studies have examined the effects of age on the cardiometabolic effects of food bio-active compounds . Three studies have investigated age-dependent effects of cocoa flavanols on vascular function , with conflicting results. However, only one of them was a controlled study specifically designed to investigate the effects of flavanols in the context of the aged cardiovascular system. A double-blind RCT demonstrated that consumption of a flavanol-rich drink 2 times/d for 2 wk reversed age-related increases in blood pressure together with vascular stiffness in healthy elderly men. CF-intake–associated improvements in the compliance of large arteries were complemented by a decrease in pulse wave velocity and aortic augmentation of systolic blood pressure . Endothelial function in large conduit arteries was also significantly improved in healthy young and elderly individuals. These beneficial effects were associated with an improved dilatory capacity of resistance arteries, lower diastolic blood pressure , and increases in microcirculatory perfusion and RBC deformability. Cardiac output was not affected by CFs. Importantly, despite age-dependent differences in baseline flow-mediated dilatation , PWV, and DBP, the magnitude of the changes in the vascular response to CFs was not significantly different between the young and the elderly. In contrast, flavanol consumption improved only SBP and the augmentation index in the elderly group . This is probably because SBP is slightly higher in the elderly, mainly caused by stiffer arteries. Plasma concentrations of flavanol metabolites were not significantly different between young and elderly individuals, suggesting that differences in bioavailability could not explain the differences observed in biological responses. Of note, endothelial dysfunction is a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis. The measurement of ultrasound-based endothelium dependent FMD in the brachial artery is the more widely used noninvasive measure of endothelial function and constitutes a clinical surrogate marker of vascular health . This technique consists of assessing the change in the diameter of the brachial artery after the increase in shear stress induced by a reactive hyperemia, with the degree of dilatation reflecting arterial endothelial NO release . The aortic AIX is closely related to wave reflections and constitutes a surrogate marker of arterial stiffness . In agreement with previous data, a recent study showed that the absorption, distribution, metabolism, and excretion of CFs was not significantly different between young and elderly healthy subjects after consumption of a similar amount of CFs . However, small but significant differences in metabolism were reported at a higher intake amount of CFs , with higher glucuronidation, lower methylsulfation, and lower urinary excretion of gut microbial g-valerolactone metabolites observed in the elderly. This observation suggests that dose-response studies covering the amounts of bio-active intake that can be achievable through a normal diet are necessary when investigating the interindividual variability in the ADME of plant-food bio-active compounds. A study also investigated whether the consumption of a flavanol-rich cocoa drink could improve blood pressure and endothelial function in healthy young and elderly men . No changes in blood pressure or endothelial function were observed in any group after 4–6 d of daily CF consumption. However, an effect on the last day of the study was seen in both groups after 90–180 min of CF consumption, and when compared with baseline values of day 1, the effect was higher for the elderly volunteers. Pulse wave analysis showed a similar pattern, with higher vascular responses in the elderly after acute consumption. The authors attributed these effects to an increase in NO production because responses to the endothelial NO synthase inhibitor L-nitroarginine-methyl-ester were also greater in the elderly. Nevertheless, the relevance of comparing changes in vascular function after acute consumption on days 4–6 with baseline levels on day 1 remains to be established.