Although they do not have minimum intake requirements such as vitamins, minerals, and other dietary components, it is now clear that the consumption of polyphenols contributes to the maintenance of health and the prevention of disease. This motivated me to begin reading for and then writing this series of articles. Now, as I write this introduction having done all my reading and writing, I’m not only even more convinced by their role in health and disease prevention but also have a much greater awareness of how exactly they do this, and also which ones do it best. Having this knowledge will now allow me to make better food choices that will lead to better long-term health — and after reading this, the same will be true for you!
It’s just not me that’s taken an interest in polyphenols. Take a look at the number of publications that have been made on the topic in the PubMed database over the last 34 years. Granted, an upward trend like this can be observed for many topics due to an increase in research in general, however, it still provides a nice indication of topics of interest in science. My guess is that in the coming years as we move beyond simply looking at calories and macros and start to understand other components of food and the food matrix as a whole (Aguilera, 2019), we will acquire even more knowledge on polyphenols and their interaction with health, enlightening us even further on how we can use these compounds to our advantage.
Let’s have a look at what some of these publications have to say. Here in Part 1, we will open with a description of what polyphenols are and the divisions within them, and then look at their interaction with health and some mechanisms of action. In Part 2, we look at one interaction in particular that polyphenols have with the body — namely, the microbiota. Many of the health effects of polyphenols are now thought to be related to their interaction with the microbiota, and since the microbiota is a trendy and fascinating topic in nutrition research at the moment, I thought that diving deeper into this would be valuable. Finally, we finish in Part 3 with practical applications (i.e., how you can use your newly acquired knowledge to lead to tangible health outcomes); we discuss other points of interest on polyphenols; and finally, potential adverse effects to be aware of. I hope you enjoy the series and learn plenty!
What Are Polyphenols?
Polyphenols represent a group of compounds of plant origin that are mostly involved in the growth of the plant and the defence of the plant. Their role in defence includes antibacterial and antifungal activities, UV protection, chelation of toxic compounds or elements, and antioxidant functions (Lavefve et al., 2020). Aside from providing context, these functions are worth mentioning since they’re involved in the interaction with health that polyphenols demonstrate. There are over 8000 members in the family of polyphenols, with many subdivisions that exist which are categorized based on their structure (Pandey & Rizvi, 2009).
The first division splits them into two groups: flavonoids, which contain flavanones, flavones, dihydroflavonols, flavonols, flavanols, anthocyanidins, isoflavones, and proanthocyanidins; and non-flavonoids, which contains phenolic acids, stilbenes, and lignans (Van Hul & Cani, 2019). Within these subdivisions are individual polyphenol compounds which means that things can get quite complicated if you’re trying to keep track of names. Fortunately, you probably don’t have to — just know that if you see these names later in the article series, they represent different divisions of polyphenols that are devised based on their stricture. Knowing the intricacies won’t be much help to you unless you want to research them!
In line with their abundance and complexity, polyphenols are found in a wide variety of plant-based foods. Some contain only few types; some contain many different types; some contain large quantities of one type and less of others, whereas others contain a somewhat equal distribution of various polyphenols (Lavefve et al., 2020). Some polyphenols are ubiquitous, found in virtually all plants (for example, quercetin), whereas others occur specifically, fouund in only a select few plants and their food products (Pandey & Rizvi, 2009). Some you’ll have heard of — caffeine, for example — but most will be foreign to you (forgivable in a family of 8000). Below, Fraga et al. provide an incomprehensive overview some polyphenol subdivisions, specific examples within them, and foods they occur in.
In addition to the complexity in which they occur in nature, levels of polyphenols are also influenced by factors such as storage conditions, processing, and preparation. To these ends, however, it’s not always as straightforward as giving sweeping recommendations (e.g., “store at 4°C for max polyphenolness”). This is basically due to the diversity within them, meaning the effects should be investigated on an individual basis. For example, oxidation reactions due to storage can affect the quality of the food in question, leading to changes in taste or smell. In some cases, such as black tea, this is desirable, whereas in others it is undesirable, such as with fruits and vegetables (Pandey & Rizvi, 2009). Processing techniques such as dehulling of seeds can greatly reduce polyphenol content, which again can be either desirable, by reducing antinutritive effects that some polyphenols possess (discussed further in Part 3, “Adverse Effects”), or undesirable, by worsening the health profile. To make things even more complicated, the same post-harvest treatment (storage, cooking, etc.) can have divergent effects on polyphenols within the same food. For example, cooking tomatoes reduces their quercetin content (Pandey & Rizvi, 2009) but increases lycopene content (Story et al., 2010). Since both of these polyphenols have beneficial health effects, it would be reasonable to try and optimize both; however, this is obviously not possible (though the solution I recommend to this is elaborated in Part 3, “Practical Applications”).
This can make things seem overwhelming, but that need not be so. If you know either the polyphenol you wish to prioritize within each food or the health affects you wish to acquire with their consumption, then this can guide your decision-making on post-harvest treatment accordingly. Alternatively, if you’re not being so specific, you could consider getting a rough idea on what would be best generally based on the polyphenols a food contains or rotate between different post-harvest methods to account for divergent treatment effects.
The processing of polyphenols is also complex but looks something like this. A small amount are capable of being absorbed through the stomach (Pandey & Rizvi, 2009), though the fate of most is further along the digestive tract. At the small intestine, certain low-molecular weight polyphenols are absorbed into enterocytes or the portal circulation. Those not absorbed at the small intestine go to the large intestine where they have three fates: absorption by colonocytes or into portal circulation; utilization by the microbiota (after which the modified metabolites may be absorbed); or excretion via the faeces. This effect on the microbiota has become obviously relevant to the health over the last decade and is discussed in detail in Part 2. In the liver, polyphenols in their native form or their metabolites are modified by phase I and phase II reactions, after which they then enter systemic circulation followed by tissue penetration, where they exert effects (Cardona et al., 2013; Pandey & Rizvi, 2009). The figure of Cardona et al. below shows this schematically.
It is reverberated in the litearature that bioavailability of polyphenols is low; this is true but leaves out part of the picture. “Low bioavailability” is sometimes just a function of the modifications polyphenols undergo following ingestion (Pandey & Rizvi, 2009). Thus, looking for their native form in the system following consumption might leave you empty handed and with the conclusion that bioavailability is low. This does not mean, however, that their metabolites are without bioactive properties. As you may have guessed by now, there exists also large variety between absorption rates, modifications, and biological effects between polyphenols. Some are absorbed earlier in the gastrointestinal tract, others later; others not at all, and others only after modification by the microbiota, at which point they will differ from their native structure. One study demonstrated this variation using ileostomy patients. Whilst ~85% of anthocyanins were recovered in ileostomy bags following blueberry consumption, only a maximum of 33% (and sometimes much less) of polyphenols of apple juice were recovered, showing that apple juice polyphenols are largely absorbed prior to the large intestine in the gastrointestinal timeline (Kahle et al., 2006).
These — modification from the native state and variation in absorption — are some of the reasons why getting an idea on the epidemiology of polyphenol intake is challenging. Another is that, unlike with macronutrients and vitamins, databases that list polyphenol content of various foods are incomprehensive, which means estimations for polyphenol content of foods are not always available (Del Bo et al., 2019). Despite this, some values do exist on estimates for differences in daily intakes between regions, countries, age groups, and other defining characteristics (see: Del Bo et al., 2019).
Polyphenols in Relation to Health
In the mid-90s reports describing the relationship between polyphenols and health started becoming abundant, with articles ascribing anti-carcinogenic (Stavric, 1994; Yang et al., 1997), anti-thrombotic (Bertelli et al., 1996), anti-viral (Nakayama et al., 1993), cardiovascular disease (CVD) protective (Brouillard et al., 1997), and general health properties to polyphenols. These lines of research, amongst others, have now been investigated more thoroughly.
Cardiovascular disease (CVD) is one of the most notable benefactors of polyphenols, which is convenient since CVD is responsible for more deaths worldwide than anything else (WHO, 2020). Those with higher polyphenol intakes have lower CVD risk, both in terms of events and all-cause mortality (Del Bo et al., 2019; Durazzo et al., 2019). Likewise, hypertension, an important risk factor for CVD, is also beneficially affected by polyphenol intake. For example, grape polyphenols and anthocyanins reduce systolic blood pressure; epicatechin (found in cocoa, tea, and fruits) improves systolic and diastolic blood pressure; and a high-polyphenol diet (based on the intake of fruits, vegetables, berries, and dark chocolate) improves microvascular function in hypertensives (Fraga et al., 2019).
Metabolic syndrome (MetS), type 2 diabetes (T2D), and hypertriglyceridemia all benefit from polyphenol intake. Durazzo et al. describe an inverse relationship between polyphenol intake and T2D onset (Durazzo et al., 2019). Green tea flavan-3-ols reduce fasting glucose and anthocyanins reduce both fasting glucose and HbA1c (a marker of blood-sugar level over a 2–3 month period) (Durazzo et al., 2019). Resveratrol is also protective against some of the pathological consequences of diabetes, such as diabetic nephropathy (Pandey & Rizvi, 2009). For MetS, again Durazzo found an inverse association with polyphenol intake (Durazzo et al., 2019). A meta-analysis of randomized controlled trials (RCTs) showed significant improvements of flavan-3-ols derived from cocoa on cardiometabolic markers (Lin et al., 2016). Body mass index has also been shown to be favourably modified by anthocyanins (Fraga et al., 2019).
A broad range of polyphenols have anti-carcinogenic activity through various mechanisms and at various stages of cancer development. Some stand-out examples are curcumin (one of my favourite health-promoting compounds), black-tea derived polyphenols, and resveratrol (Pandey & Rizvi, 2009). It should be kept in mind, though, that work thus far has been mostly in vitro and there is a need for human RCTs (Durazzo et al., 2019). Anti-viral effects, such as reducing influenza infectiousness and preventing HIV virus entry into host cells are also described in tea polyphenols (Nakayama et al., 1993; Pandey & Rizvi, 2009). In fact, the black tea polyphenol theaflavin inhibits Severe Acute Respiratory Syndrome (SARS) coronavirus, so may also have (minor) utility in the current, never-ending COVID-19 pandemic (I’m speculating).
Polyphenols also demonstrate neuroprotective and cognitive-enhancing effects, and are protective of lung function and beneficial for asthma (Fraga et al., 2019; Pandey & Rizvi, 2009). All-cause mortality is sometimes used as a crude measure to gauge the impact of dietary components. Here, too, observational research has identified a beneficial association with polyphenol intake (Fraga et al., 2019), though there can also be other explanations for this (e.g., engagement in other health-promoting activities of those who consume more polyphenols). Regardless, at this point, it is fairly reasonable to conclude that polyphenols have a net positive effect on health and that one could expect, broadly speaking, improvements in health with increased intakes.
Mechanisms of Action
The mechanism of action by which polyphenols lead to beneficial health outcomes depends on the health effect in question. Polyphenols also have diverse actions on health and therefore also distinct mechanisms, which can make this a complicated topic at times. However, the 2009 review by Pandey and Rizvi provides a great overview of proposed or proven mechanisms of actions of various polyphenols on the health outcomes.
For example, certain cardiovascular protective effects are ascribed to their antioxidant and anti-inflammatory potential, anti-platelet activity, their high-density lipoprotein (HDL; “good cholesterol”) boosting effect, and their ability to improve endothelial function (Pandey & Rizvi, 2009). Quercetin disrupts atherosclerotic plaques, modulates chemicals that alter endothelial properties (e.g., nitric oxide (NO) products and endothelin-1), and reduces systolic and diastolic blood pressure (Fraga et al., 2019; Pandey & Rizvi, 2009). Resveratrol alters cytokine release and inflammatory status; has strong anti-oxidant effects; modulates NO release; and prevents platelet aggregation (Fraga et al., 2019; Pandey & Rizvi, 2009). Finally, catechins derived from tea interfere with smooth muscle cell invasion and proliferation of the arterial wall, a step in the sequence of events that lead to atherosclerosis (Pandey & Rizvi, 2009).
In cancer, the antioxidant and anti-inflammatory functions of polyphenols are important. Additionally, however, polyphenols modulate the P450 system to prevent the progression of pro-carcinogens to carcinogens. Phase II enzymes are also induced by polyphenols, which is interesting since it may suggest that polyphenols are seen by the body as a toxic threat, causing an upregulation of protection systems that lead to beneficial effects (Pandey & Rizvi, 2009). This is similar to the concept of hormesis, which explains the beneficial effects seen after things like heat and cold exposure, and possibly exercise. Thus, this has been appropriately named “xenohormesis” (hormesis induced by a xenobiotic) in places (Anhê et al., 2016). Other mechanisms include estrogenic/antiestrogenic activity, antiproliferation, induction of cell cycle arrest or apoptosis, and immune system regulation. Black tea polyphenols are particularly impressive in terms of anti-cancer effects, though resveratrol and curcumin also stand out. Additionally, black raspberries modulated tumour-suppressor genes in cancer patients favourably (Lavefve et al., 2020).
Anti-diabetic effects of polyphenols are various. For example, inhibition of glucose transporters in the small intestine delays the absorption of glucose, blunting postprandial hyperglycaemia. Modulation of sirtuin-1 activity by polyphenols, such as resveratrol, improves whole-body glucose sensitivity (Pandey & Rizvi, 2009). Some flavonoids have been seen to enhance insulin secretin, promote β-cell proliferation and decrease their apoptosis, and reduce insulin resistance in various tissues (Fraga et al., 2019).
Many of the anti-aging and neuroprotective effects of polyphenols are ascribed to their antioxidant properties. Anthocyanins inhibit lipid peroxidation and the inflammatory COX enzymes, and catechins chelate iron, which is helpful in Parkinson’s (Pandey & Rizvi, 2009). Resveratrol has been consistently shown to extend lifespan in various models likely due to its antioxidant properties (Pandey & Rizvi, 2009), though modulation of sirtuins is also described (Fraga et al., 2019). Quercetin, too, may have anti-aging properties, which is good news due to its ubiquity in the plant kingdom.
You may have noticed a theme across the last few paragraphs — the antioxidative properties of polyphenols. Traditionally, this is what the health effects of polyphenols were largely ascribed to. There can be no doubt about the antioxidant capacity of polyphenols. Polyphenols accept free electrons and chelate pro-oxidants such as iron. After consumption of polyphenol-rich food stuffs, the antioxidative capacity of the plasma is enhanced and markers of DNA damage in cells of the plasma are decreased (Pandey & Rizvi, 2009). However, there is another mechanism by which polyphenols can impact health that has gained much attention over the last decade or so: their effect on the microbiota.
It may seem like the microbiome is all anyone talks about at the moment (well, at least in my circles…) but there is good reason for this. The way the bacteria in our gut interact with our health is becoming clearer with more research, and it is now obvious that microbiota is involved in the progression of diseases that you’d be forgiven for thinking have no relationship to gut health whatsoever. The topic is made even more exciting because of the fact that we seem to understand relatively little about what is going on. That is, we know there are relationships and roles to be discovered, but we don’t know the specifics. This means there’s plenty to be discovered and, potentially, diseases to be cured.
Next, in Part 2, we’ll shift our focus to the interaction between polyphenols and the microbiota, and what this means for your health.
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