These studies suggest that the 2204A>C variant is associated with greater CYP7A1 activity. Increased intestinal bile acids and the resulting enhanced efficient of cholesterol absorption could elucidate why C-allele carriers present enhanced cholesterol-lowering and increased feedback cholesterol synthesis to plant sterol intervention.The metabolic status of subjects has been proposed as the factor that predicts the response of plasma cholesterol to an intervention with plant sterols . Rideout et al. highlighted between-subject differences in LDLresponsiveness to plant sterols that could compromise the overall conclusion on their efficacy. They observed that, in a pooled study population of 113 subjects , 4 wk of a controlled diet supplemented with 2 g plant sterols/d led to a mean decrease in LDL cholesterol concentrations of 7.3%. After this observation, the authors stratified the population cohort into responders and nonresponders and proposed the basal cholesterol fractional synthesis rate as the determinant of the response based on 1) a correlation of FSR with the percentage of change in LDL cholesterol , 2) 23% higher basal FSR values in nonresponders compared with the values of the responders group, 3) after stratification based on basal FSR, subjects in the first quartile showed the best response, with a mean decrease of 12.4% compared with the control period, plants in pots ideas whereas for those in the last quartile, the decrease was only 3.17%.

The same authors have proposed the ratio of lathosterol to cholesterol , a surrogate marker of endogenous cholesterol synthesis, as the predictor of the effects of plant sterols on cholesterol concentrations . In this randomized, single-blind, crossover, placebo-controlled trial, mildly hypercholesterolemic adults were preselected based on their baseline L:C. The participant cohort of 63 individuals consisted of 24 subjects with high endogenous cholesterol synthesis and 39 subjects with low endogenous cholesterol synthesis . In addition to the L:C values, the 2 subgroups were significantly different in terms of body weight, BMI, and HDL cholesterol and TG concentrations, as well as the ratios of plasma phytosterols to cholesterol. After daily consumption of a diet enriched with 2 g plant sterols for 28 d, significant decreases in TG concentrations of 0.40 6 0.07 and 0.09 6 0.09 mmol/L were found in the HECS and LECS groups, respectively, compared with the placebo group, while the decreases in LDL concentrations were 0.29 6 0.05 and 0.05 6 0.07 mmol/L in the HECS and LECS groups, respectively. This work suggests that participants in the HECS group were 3 times more likely to respond to plant sterol supplementation than those in the LECS group. Finally, there was a positive correlation between the L:S and the overall decrease in TGs but not in LDL cholesterol . From these observations the authors suggested that the link between high L:S and the metabolic syndrome indicates that subjects with the metabolic syndrome are responsive to plant sterols. Neither of these 2 articles reported genetic polymorphism as a putative determinant of variation, although it is known that it can influence basal cholesterol synthesis as discussed above.

The effects of an 8-wk consumption of soy nuts on anthropometric variables, blood pressure, lipid concentrations, and inflammatory markers in postmenopausal women were evaluated based on the stratification by metabolic syndrome status . Participants included 60 women, 49 without metabolic syndrome and 11 with metabolic syndrome. In healthy volunteers, the isoflavone-enriched diet, compared with the placebo diet, resulted in a significant decrease in both SBP and DPB, and C-reactive protein . In contrast, in the group of women with the metabolic syndrome the supplemented diet significantly decreased DBP and CRP, as well as the circulating concentrations of TGs and intercellular adhesion molecule 1. Further stratification of the subjects on the ability to produce equol indicated that in women without the metabolic syndrome the changes in SBP were more pronounced in equol producers. Similarly, the DBP decrease was significant only in the equol-producer group. In response to the isoflavone-enriched diet, a significant decrease of CRP was observed only in equol producers. In women with the metabolic syndrome, the observed effects were significant only in the equol-producer group . As a final conclusion, the authors commented that soy consumption induced more pronounced beneficial effects on biomarkers of CVD in women with metabolic syndrome than in healthy women and that the magnitude of the responsiveness was tightly dependent on their ability to produce equol and thereby on the composition of their gut microbiota. However, the low number of subjects, especially after the stratification to equol producers and non-producers with the metabolic syndrome, with 7 and 4 subjects, respectively, makes the conclusion strictly exploratory.

The interindividual variation in response to dietary polyphenol intake depending on the pathophysiological status was also reported. In a crossover, randomized, placebo controlled study, Egert et al. evaluated the effects of a 6-wk quercetin supplementation on blood pressure, lipid concentrations, and inflammatory markers in 93 subjects with central obesity and elevated plasma concentrations of TGs and CRP. In the entire study population, SBP and pulse pressure were significantly lower after quercetin supplementation compared with the baseline values. After subgroup analysis, no effects on either of these variables were observed in the group of normotensive subjects, whereas in the group of hypertensive subjects quercetin supplementation resulted in a significant decrease in SBP. Similarly, the pulse pressure was significantly lower after quercetin treatment compared with baseline without significant effects on both variables after the placebo period. A double-blind, parallel design, randomized controlled study investigated the effects of a 12-wk consumption of catechin-enriched green tea, providing 582.8 mg catechin/d, or green tea, providing 96.3 mg catechin/d, in 43 subjects with type 2 diabetes . In comparison with the effects of standard green tea, catechin-enriched green tea induced a significant decrease in waist circumference and TC concentration and an increase in insulin concentration in the entire population. Further stratification of both groups based on the use of insulinotropic agents as antidiabetic therapy, including either oral sulfonylureas or glinidines, showed that the effect of catechin-enriched green tea on insulin concentrations and glycated hemoglobin was significant only in asubgroup of patients receiving insulinotropic therapy and not in subjects with another type of medication. Both results indicate the potential of catechins to act synergistically with the therapeutics regarding their insulinotropic action, with the ultimate beneficial effects on protein glycation. It should be noted that the number of patients receiving insulinotropic therapy was 17 of 23 in the test group and 16 of 20 in the control group, thus the lack of the effect in the group with non-insulinotropic therapeutics could be because of the low number of participants. Taken together, these few studies suggest that metabolic or disease-related traits of volunteers enrolled in clinical trials can lead to interindividual variation in response to plant-food bio-active intake.Besides the factors discussed above, the bio-availability of plant-food bio-active compounds could be an important factor in determining the interindividual variability in response to their consumption. It could be expected that individuals presenting a higher capacity of absorption and metabolism of these compounds, thus achieving higher concentration of bio-active metabolites in the circulation, would gain greater benefits compared with low absorbers and metabolizers. However, this assumption has been poorly documented so far. Indeed, some studies highlighted in the present review suggest that this is not always the case; for example, container size for blueberries age dependent differences in vascular response were seen despite no age-dependent differences in plasma concentrations of metabolites .

Another important issue in this context is that it is not currently known which of the main bio-active metabolites present in circulation after plant-food consumption are those responsible for the observed effects and which concentrations are required to induce optimal benefits for different subgroups. A few studies have shown correlations and temporal associations between vascular outcomes and specific circulating polyphenol metabolites , which is one step further in establishing a relation between certain bio-active metabolites and health outcomes. Hence, future clinical trials with plant foods should measure circulating concentrations of individual metabolites, demonstrate the existence of a correlation between them and their biological impacts, and report the variabilities in both ADME and biological responses. Gut microbiota metabolism of food phytochemicals, and particularly polyphenols, has been identified as a relevant source of interindividual variability in ADME , and this can be the result of differences in the microbial ecosystems that colonize the human gut and to the gut microbiome richness . These differences in gut microbial metabolism may also affect the health effects of dietary phytochemicals and be responsible for variability in biological response. Six clinical studies have examined the role of gut microbiota metabolism in explaining interindividual variation in response to the consumption of polyphenols on cardiometabolic disease biomarkers . These studies are all related to soy isoflavones, daidzein, the precursor of the microbial-derived metabolite, and equol, which is known to have a higher bioactivity than daidzein itself. In a clinical study assessing the effect of soy intake on cardiovascular health in postmenopausal women , it was demonstrated that changes in endothelial function and blood pressure were not significantly different between the soy and the placebo groups. In the soy group, however, stratification by equol-producer status suggested that endothelial function and blood pressure were improved only in equol producers . Another study on hypercholesterolemic men and postmenopausal women showed that the beneficial effects of soy intake on plasma LDL cholesterol, HDL, and apo1 concentrations occurred only in equol producers . In women with the metabolic syndrome, soy intake only reduced blood pressure, TGs, CRP, and soluble intercellular adhesion molecules in equol producers . Thus, these studies suggest that the microbiota profile responsible for the production of equol is a determinant of the variability in response to the consumption of soy protein–containing isoflavones. Several studies have also explored whether equol is the active metabolite after soy isoflavone intake by supplying S-equol orally. Some controversial results were found. Consumption of S-equol decreased LDL cholesterol and the cardio-ankle vascular index in overweight or obese Japanese subjects, with the effects being more prominent in the subgroup of female nonproducers . In contrast, a recent study evaluated the effect of S-equol on prospectively recruited equol and non–equol producers, and although soy intake improved carotidfemoral PWV in equol producers, a single dose of S-equol had no cardiovascular benefits in non–equol producers . This study suggests that the equol-producer phenotype is critical in explaining the vascular benefits of equol, but more studies are necessary to confirm these findings. There is growing evidence that gut microbiota speciation correlates with the risk of CVD, obesity, and type 2 diabetes , and some studies also suggest a relation between gut microbiota, diet, obesity , and atherosclerosis . Interestingly, the equol-producing bacteria identified so far include species of the genera Adlercreutzia, Eggerthella, Paraeggerthella, and Slackia, all of them belonging to Coriobacteriaceae, a family that has been associated with beneficial metabolic processes in obesity and diabetes . Therefore, the occurrence of these bacterial species responsible for equol production can be an indication of a potential beneficial response to the consumption of plant-food bio-active compounds regarding cardiometabolic diseases. It is well established that ellagic acid is converted to urolithins by the colon microbiota, and 3 different and consistent urolithin phenotypes were observed in various clinical intervention studies with ellagitannins, urolithin B being more frequently observed in subjects with metabolic syndrome . Supporting these findings, urolithin A was inversely correlated with the severity of metabolicsyndrome and obesity . Thus, the correlation of these phenotypes with cardiovascular health deserves further investigation.In this review, we have highlighted the limited existing data and summarized the available clinical and prospective studies that have investigated, to some extent, the interindividual variability in the biological response to the consumption of plant-food bio-active compounds. These studies suggest that some individuals may benefit more from the health effects of these bio-actives than others, and genetic and non-genetic factors may be important ones contributing to the variability in biological effects observed between individuals . Nevertheless, there are still very few studies robustly assessing determinants of this between-subject variability, with <25 clinical studies identified to date . Each of them examined different biomarkers and different bio-active compounds, which precludes the pooling of data from available studies. With such wide heterogeneity in studied food bio-active compounds, cardiometabolic biomarkers, study populations, and study designs, it is not yet possible to draw conclusions based on sound scientific results.