The Gut Microbiota: Its Key Features and Implications for the Function of the Central Nervous System
November 7, 2021Hydrogen-Rich-Water And Gut Microbiome
November 26, 2021The Role of Phytochemicals in Health
Beyond vitamins, minerals, and fiber there are bioactive compounds in foods called phytochemicals (or phytonutrients) that confer nutrigenomic (gene-nutrient interactions) effects, and play an important role in human health. Tens of thousands of phytochemicals have been identified, and there are likely many more that have yet to be illuminated. They are classified according to their chemical structures and functional properties, which influence their metabolic fate.
Some major classes of phytochemicals are polyphenols, phytosterols, terpenoids, alkaloids, glucosinolates, saponins, and many more. Each of these classes have potent biological activities and can modulate various molecular targets. Plants produce these bitter-tasting compounds as a protective mechanism to dissuade predators, pathogens and other environmental stressors. As such, they exhibit low levels of stressors that, when consumed by humans, can stimulate a hormetic response and bolster cellular resistance much in the same way that exercise, fasting, and hydrogen water does.
Photo credit: Bellik et al., 2012.
The Unique Metabolism of Phytonutrients
Within the parent compounds are a number of subclasses and the multiplicity of metabolites they produce. Their metabolism is intrinsically linked to their mechanisms of action, which is characteristic of that of xenobiotics–they are essentially treated by the body as drugs. The bioavailability of the most abundant phytochemicals is low and their half-life has been shown to be transient at about 90 minutes. Bioavailability means the rate and extent to which something is able to exert its beneficial effects in target tissues.
So then how are they conferring all of these chronic health benefits that we see in long-term, large prospective cohort studies and randomized control trials (RCTs)? Some phytonutrients may get taken up in the small intestine and subsequently undergo first pass metabolism in the liver. The phytonutrients that are not absorbed in the small intestine pass through the colon and undergo degradation by colonic bacteria into microbial metabolites which are then released back into the circulation and absorbed in quantities far greater than the parent compound itself. A multitude of metabolites are generated and exert numerous biological effects. These metabolites can continue to be recycled extensively – even up to 20 times, and they are up to 100-fold greater in concentration in the circulation than the parent compounds themselves, having significantly higher bioavailability (Luca et al., 2019; Rathaur & S R, 2019; Selby-Fam, et al., 2017).
Mechanisms of Action of Phytonutrients
Like hydrogen water, phytonutrients have pleiotropic effects on cellular physiology that extend far beyond direct antioxidant activity. They address numerous mechanisms simultaneously, ultimately resulting in a multitude of downstream health benefits.
Let’s take flavonoids, for example, which are one of the most studied and varied subclass of polyphenols. Flavonoids are categorized in different subtypes including flavones, isoflavonoids, flavanones, flavanols, catechins or flavonols, anthocyanins and chalcones. Within each of those categories are numerous other subtypes (i.e., quercetin and kaempferol are types of catechins), each of which produce an array of metabolites.
One of the mechanisms by which flavonoids exert their beneficial health effects are through nitric oxide (NO) production and activity. Flavonoids inhibit inducible nitric oxide synthase (iNOS) and activate endothelial nitric oxide synthase (eNOS). Excess iNOS activity can have deleterious effects on vascular function including inhibition of mitochondrial respiration, hypotension, and necrosis (premature death of cells). Conversely, increased eNOS promotes increased vasodilation, angiogenesis, and beneficial endothelial and vascular effects.
NO has anti-atherogenic, anti-thrombotic, anti-inflammatory, and anti-proliferative properties that play a pivotal role in vascular homeostasis and integrity. Decreased bioavailability and or production of NO is associated with endothelial dysfunction and a vascular phenotype that is more susceptible to atherogenesis. NO suppresses platelet aggregation, cellular migration and adhesion to the endothelium and smooth muscle cell proliferation. This mechanism overlaps with the Nitrosigine in BOOST which stimulates NO production. What’s good for the heart is good for the brain. There is overlap between the mechanisms by which polyphenols exhibit positive effects on the brain and the cardiovascular system.
Quercetin and apigenin are among the most studied flavonoids which have been known to exhibit antibacterial and antiviral activities by antagonizing the replication and infectivity of certain RNA and DNA viruses. Furthermore, flavonoids help in the production of enzymes such as glutathione-S-transferase, quinone reductase and uridine 5-diphospho-glucuronyl transferase by which carcinogens are detoxified and excreted from the body.
Flavonoids have been shown to modify lipid and glucose metabolism in both the fasted state and post-prandial. Post-prandial means after you’ve eaten—it is defined as “the period after a meal.” Their ability to act on dysfunctional processes related to glucose and lipid metabolism impact several biological systems. The mechanisms are not fully elucidated, but they may inhibit fat absorption at the level of the gut or possibly influence cholesterol and triacylglycerol transport in lipoproteins.
Similar to the ageless defense formula, phytochemicals can prevent the formation of advance glycation end products (AGEs) and other complications (i.e., diabetic) associated with high oxidative stress conditions (Bacanli et al., 2019).
Factors That Influence the Bioavailability of Phytonutrients
There is so much nuance and so many factors that influence the bioavailability of phytonutrients and subsequent biological effects they exert on the individual—both external and internal. This is very important to consider, because it’s not what we consume, but what we absorb and how it gets utilized by our bodies that matters. Let’s discuss what some of those factors are.
Food processing related factors: Storage, cooking and culinary preparation methods, thermal treatments, homogenization, lyophilization (freeze drying) (D’Archivio et al., 2010).
For example, thermal treatment has been shown to significantly reduce total phenolic content in extra virgin olive oil, beans and legumes (D’Archivio et al., 2010).
For red wine that was produced with Cabernet Sauvignon grapes in Napa Valley (California, USA) the 1989 vintage contained 0.09 mg/L resveratrol whereas the 1994 vintage contained as much as 8.9 mg/L (D’Archivio et al., 2010). Unfortunately, the amount of resveratrol in food (like the skins of grapes) and red wine is paltry and you would have to consume barrels of wine (not a good idea) and copious, unrealistic amounts of grape skins to obtain the amount that would be effective. Having said that, it would behoove us to rely on supplements to get a meaningful dose of resveratrol in conjunction with the appropriate ratios of other ingredients.
Environmental factors: Sun exposure, the soil the food was grown in, degree of ripeness, and rainfall.
Food matrix–the configuration of and presence of other constituents in the food, or combinations with other compounds: Bioactive compound mixtures may produce a biological effect higher or lower than the summative effects of each single component and interfere with intestinal absorption of other compounds. There could be synergistic (the presence of two or more bioactive compounds enhancing the other), potentiation (inactive compounds enhancing the potency of active ones), and antagonism (lowering the bioavailability of each other). There is a composite of numerous phytochemicals and other components (i.e., different types of fiber, macronutrients, minerals, vitamins) in a single food or beverage. Concurrently consumed bioactive compounds may affect the intestinal absorption of each other.
A few examples to illustrate this point: The combinations in particular ratios of resveratrol with quercetin and/or genistein enhanced the suppression of adipogenesis more than each of the isolated compounds alone in both human and mouse fat cells (in vitro/cell culture). a-tocopherol mixed with a flavonol (kaempferol or myricetin) was shown to be more effective in inhibiting lipid oxidation induced by free radicals than each component alone or the mixture of resveratrol, chrysin, and curcumin synergistically suppressed the proliferation of colorectal cancer cells (Iwuchukwu et al., 2011). Beta-carotene increases the bioavailability of lycopene in human plasma (Zanfini et al., 2010), and quercetin-3-glucoside reduces the absorption of anthocyanins (Walton et al., 2006). Lycopene combined with astaxanthin enhanced the inhibition of liposome oxidation (Phan et al., 2018).
However, the mixture of certain phytochemicals may reduce the biological effects if they are combined in inappropriate ratios (Hidalgo et al., 2010; Jiang et al., 2015) or they are not in the proper spatial orientation.
Potential synergy is indicated in binary mixtures of fat-soluble carotenoids: lycopene-beta-carotene, lycopene-lutein and b-carotene-lutein, or the combination of a-tocopherol and lycopene showed stronger free-radical scavenging activity than the sum of individual compounds (Phan et al., 2018).
The combination of some hydrophilic (water-loving/soluble) with lipophilic (fat-loving/soluble) may also be highly synergistic. For example, tomato and carrots (lipophilic) with eggplant and purple potatoes had a higher percentage of free radical scavenging activity. Conversely purple cauliflower combined with tomato had a reduced synergy. (Phan et al., 2018)
These basic science studies can give way to some biological plausibility and mechanistic insight for what we see in double blind, placebo controlled randomized controlled trials (the gold standard) and large epidemiological studies (to pinpoint potential associations that we can further test).
Host related factors: this can be subdivided into intestinal and systemic factors. The bioavailability and subsequent biological effects of the phytochemicals in foods is dependent on individual gut microbiome, intestinal integrity, genetics, etc. (D’Archivio et al., 2010)
Randomized Controlled Trials
An eight-week study by Sanchez et al showed that a food supplement in powder form of citrus flavonoids (combination of grapefruit, orange and olive extracts) versus a placebo had a significant reduction in CVD risk assessed by flow-mediated vasodilation as a measurement of endothelial function. The intervention group (n=51) also had a substantial reduction of 9 mg/dL on average on oxidized LDL cholesterol compared to no change in the placebo (n=45) group. Flavonoids can protect against oxidized LDL cholesterol, which is some of the mechanistic speculation as to why there might be brain benefits – they are perhaps acting through pathways preventing cell death that would be caused by oxidized LDL-C. As I alluded to before, there is strong overlap between the brain and the heart. Protection against oxidized LDL-C is a very important aspect of pathogenesis of atherosclerosis within the vasculature. Interleukin-6 (IL-6), a marker of inflammation which is associated with myocardial farction risk, was reduced by ~40% in the intervention group. While there was no significant effect on TNF-a or CRP, there was a significant reduction in IL-6, which could be a more clinically relevant, robust inflammatory biomarker as it relates to CVD risk. (Sanchez et al., 2020).
A study by Della Pepa and colleagues had three groups: high intake of long chain omega 3 fatty acids (EPA and DHA), a high polyphenol intake group, and a group consuming high polyphenols and high omega 3s concurrently. The high polyphenol group had a stronger effect on reducing post-prandial triglycerides and VLDL than the omega-3 group. It’s interesting that the polyphenol group outperformed the omega-3 group because one of the most stand-out features of omega-3s is their ability to lower triglycerides. Further, oxidative stress (using isoprostanes) was significantly reduced from baseline in the polyphenol group and no effect was observed in the omega-3 group (Della Pepa et al., 2020).
Odai et al investigated the effects of grape seed proanthocyanidin extract on blood pressure and vascular endothelial function in adults (aged 40-64) with prehypertension. The subjects were randomized to receive tablets containing either low-dose (200 mg/day) or high-dose (400 mg/day) grape seed extract or placebo, for 12 weeks. Systolic and diastolic blood pressures (SBP and DBP, respectively), brachial flow-mediated dilation, and other cardiovascular parameters were measured before and after 4, 8, and 12 weeks of treatment. The mean SBP in the high-dose group significantly decreased by 13 mmHg after 12 weeks, although flow-mediated dilation did not change (Odai et al., 2019).
Bondonno and colleagues investigated the independent and additive effects of flavonoid-rich apples and nitrate-rich spinach on nitric oxide status, endothelial function, and blood pressure in a crossover study with 30 “healthy” men and women. Compared to control, all treatments resulted in higher flow-mediated dilatation and lower systolic blood pressure, with the highest impact being in the flavonoid-rich apple group, spinach second, and combination of spinach had less of an effect than each in isolation. There were no differences in oxidative stress from baseline, but that could’ve just been because the population did not have higher baseline levels of oxidative stress (Bondonno et al., 2012).
A cross-over RCT investigated the impact of coffee (which is rich in polyphenols such as chlorogenic acid) in males, with a particular focus on chlorogenic acid on vascular function (measured by flow-mediated vasodilation) and whether chlorogenic acids are involved in potential effects. The groups differed in chlorogenic acid content but were matched for caffeine content. Results of this study showed qualitatively different outcomes based on where consumption was on the J shaped curve. There was an acute response to flow-mediated dilation which was greater with high chlorogenic acid intervention and that was observed both at 1 hour and 5 hours post coffee consumption. The magnitude at 5 hours was greater in relation to the high chlorogenic intervention than it was at 1 hour post intervention. Anywhere between 5, 6 or 7 hours it where you see peak bioavailability of the metabolites which tends to correspond with the maximal response of an outcome you might get. We see similar patterns with cerebrovascular blood flow studies using anthocyanin intervention, where the increase in cognition corresponds to the peak of anthocyanin bioavailability from metabolite production (Mills et al., 2017).
Takeaway
The converging lines of evidence (RCTs, epidemiological studies, and biological plausibility from the mechanisms that have been elucidated) all tend to corroborate each other when we evaluate the role that phytochemicals have on healthspan. We see various health effects across a spectrum of ages, populations and health status of participants that lends support to the mechanistic insights that have been unveiled in basic science research.
There is some dispute that because phytochemicals are non-nutritive and not essential per se, that they are superfluous. Just because something is not essential for survival (i.e., fiber) in the way that essential fatty acids, vitamins or minerals are, does not mean they don’t have important health benefits. While you won’t develop an acute disorder from a catechin deficiency like you would scurvy (from Vitamin C deficiency) or rickets (from Vitamin D deficiency), that does not mean there won’t be negative consequences if we do not consume these phytonutrients.
So how can we get them in our diet? You have probably heard the saying “eat the rainbow” before. That’s because the different phytochemicals are reflected in the different color pigments in food (i.e., anthocyanins in purple/blue hues like purple cabbage and blueberries). A simple way to think about this is to look for a lot of color (skittles and fruit loops don’t count) in different plant foods, but there are also phytonutrients in some animal foods (like astaxanthin in wild salmon). Herbs, spices, coffee, cacao/cocoa, and tea leaves all tend to be rich sources of a variety of different phytochemicals. Getting a diverse array of these different phytonutrients is really the key. A lot of phytochemicals are imbedded in the fiber of foods (note: there are many different varieties of fiber that elicit different biological effects and feed different species of microbiota), so keep that in mind when you decide to embark on a juice cleanse (although there can certainly be value in that depending on the context). Consuming carotenoids and fat-soluble nutrients (such as Vitamins A, D, E and K) with fat also increases their absorption.
What we can also take away here is that, it’s not as simple as just consuming isolated compounds haphazardly. We have seen this with antioxidant supplements that, when rigorously evaluated in controlled trials in humans and animals, antioxidants such as vitamins C, E and A, have failed to not only prevent or ameliorate disease, but appeared to be detrimental. That could be for different reasons (i.e., inhibiting our own endogenous antioxidant defense systems which are more powerful than direct antioxidants). We know that there are many factors that influence how phytochemicals exert their effects on us, including the food matrix they are embedded in and interact with, the configuration and co-consumption with other compounds, etc. So we should keep all of this in mind. Many plant compounds, herbs and other foods have been historically used for their purported medicinal properties. Now we have emerging scientific rationale to support leveraging “food as medicine,” or at least understand that our diet has a more profound impact on our well-being and functionality than was once appreciated.
References:
Bacanli, M., Dilsiz, S. A., Başaran, N., & Başaran, A. A. (2019). Effects of phytochemicals against diabetes. Advances in food and nutrition research, 89, 209–238. https://doi.org/10.1016/bs.afnr.2019.02.006
Bellik, Y., Boukraâ, L., Alzahrani, H. A., Bakhotmah, B. A., Abdellah, F., Hammoudi, S. M., & Iguer-Ouada, M. (2012). Molecular mechanism underlying anti-inflammatory and anti-allergic activities of phytochemicals: an update. Molecules (Basel, Switzerland), 18(1), 322–353.
Bondonno, C. P., Yang, X., Croft, K. D., Considine, M. J., Ward, N. C., Rich, L., Puddey, I. B., Swinny, E., Mubarak, A., & Hodgson, J. M. (2012). Flavonoid-rich apples and nitrate-rich spinach augment nitric oxide status and improve endothelial function in healthy men and women: a randomized controlled trial. Free radical biology & medicine, 52(1), 95–102. https://doi.org/10.1016/j.freeradbiomed.2011.09.028
D’Archivio, M., Filesi, C., Varì, R., Scazzocchio, B., & Masella, R. (2010). Bioavailability of the polyphenols: status and controversies. International journal of molecular sciences, 11(4), 1321–1342. https://doi.org/10.3390/ijms11041321
Della Pepa, G., Vetrani, C., Vitale, M., Bozzetto, L., Costabile, G., Cipriano, P., Mangione, A., Patti, L., Riccardi, G., Rivellese, A. A., & Annuzzi, G. (2020). Effects of a diet naturally rich in polyphenols on lipid composition of postprandial lipoproteins in high cardiometabolic risk individuals: an ancillary analysis of a randomized controlled trial. European journal of clinical nutrition, 74(1), 183–192. https://doi.org/10.1038/s41430-019-0459-0
Hidalgo, M., Sanchez-Moreno, C. and De Pascual-Teresa, S. (2010). Flavonoid–flavonoid interaction and its effect on their antioxidant activity. Food Chemistry, 121: 691–696.
Iwuchukwu, O. F., Tallarida, R. J., & Nagar, S. (2011). Resveratrol in combination with other dietary polyphenols concomitantly enhances antiproliferation and UGT1A1 induction in Caco-2 cells. Life sciences, 88(23-24), 1047–1054. https://doi.org/10.1016/j.lfs.2011.03.016
Jiang, H. W., Li, H. Y., Yu, C. W., Yang, T. T., Hu, J. N., Liu, R. and Deng, Z. Y. (2015). The Evaluation of Antioxidant Interactions among 4 Common Vegetables using Isobolographic Analysis. Journal of Food Science, 80:C1162–C1169.
Luca, S. V., Macovei, I., Bujor, A., Miron, A., Skalicka-Woźniak, K., Aprotosoaie, A. C., & Trifan, A. (2020). Bioactivity of dietary polyphenols: The role of metabolites. Critical reviews in food science and nutrition, 60(4), 626–659. https://doi.org/10.1080/10408398.2018.1546669
Mills, C. E., Flury, A., Marmet, C., Poquet, L., Rimoldi, S. F., Sartori, C., Rexhaj, E., Brenner, R., Allemann, Y., Zimmermann, D., Gibson, G. R., Mottram, D. S., Oruna-Concha, M. J., Actis-Goretta, L., & Spencer, J. (2017). Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: Two randomized, controlled, crossover intervention trials. Clinical nutrition (Edinburgh, Scotland), 36(6), 1520–1529. https://doi.org/10.1016/j.clnu.2016.11.013
Odai, T., Terauchi, M., Kato, K., Hirose, A., & Miyasaka, N. (2019). Effects of Grape Seed Proanthocyanidin Extract on Vascular Endothelial Function in Participants with Prehypertension: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients, 11(12), 2844. https://doi.org/10.3390/nu11122844
Phan, M., Paterson, J., Bucknall, M., & Arcot, J. (2018). Interactions between phytochemicals from fruits and vegetables: Effects on bioactivities and bioavailability. Critical reviews in food science and nutrition, 58(8), 1310–1329.
Rathaur, P., & S R, J. K. (2019). Metabolism and Pharmacokinetics of Phytochemicals in the Human Body. Current drug metabolism, 20(14), 1085–1102. https://doi.org/10.2174/1389200221666200103090757
Sánchez Macarro, M., Martínez Rodríguez, J. P., Bernal Morell, E., Pérez-Piñero, S., Victoria-Montesinos, D., García-Muñoz, A. M., Cánovas García, F., Castillo Sánchez, J., & López-Román, F. J. (2020). Effect of a Combination of Citrus Flavones and Flavanones and Olive Polyphenols for the Reduction of Cardiovascular Disease Risk: An Exploratory Randomized, Double-Blind, Placebo-Controlled Study in Healthy Subjects. Nutrients, 12(5), 1475. https://doi.org/10.3390/nu12051475
Selby-Pham, S., Miller, R. B., Howell, K., Dunshea, F., & Bennett, L. E. (2017). Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine. Scientific reports, 7(1), 1931. https://doi.org/10.1038/s41598-017-01888-w
Walton, M. C., McGhie, T. K., Reynolds, G. W., & Hendriks, W. H. (2006). The flavonol quercetin-3-glucoside inhibits cyanidin-3-glucoside absorption in vitro. Journal of agricultural and food chemistry, 54(13), 4913–4920. https://doi.org/10.1021/jf0607922
Zanfini, A., Corbini, G., La Rosa, C., & Dreassi, E. (2010). Antioxidant activity of tomato lipophilic extracts and interactions between carotenoids and α-tocopherol in synthetic mixtures. Lebensmittel-Wissenschaft + [i.e. und] Technologie, 43, 67-72. doi: 10.1016/j.lwt.2009.06.011