Under the Spotlight: Inflammation
How your diet and lifestyle contribute to inflammation is a hot topic in biomedicine today because of their impact on your body and mind.
What is inflammation?
Inflammation is the body's natural response to injury or infection.
Following a cut, immune cells release certain chemicals that trigger inflammation to clear out damaged cells and eliminate pathogens (fight infection) and regenerate new tissue.
Inflammation is characterized by redness, swelling, warmth, pain, and sometimes fever. It takes just a few seconds for the body to mount an immune response and kick in the inflammatory process. It then shuts off within 72 to 96 hours.
“Inflammation is a natural process that all organisms — animals, plants, even single-celled organisms — undergo in order to address threats and danger. The initial inflammatory response is lightning quick.”
Schematic representation of inflammatory processes and associated symptoms
What is the purpose of inflammation?
Inflammation is a protective response involving host cells, blood vessels, immune cells and certain proteins with the aim to:
1. Eliminate the cause of injury and microbes that may have entered the body
2. Remove dead cells and tissue
3. Initiate the process of healing/repair and “switch off” the inflammation responses.
It is important to note that inflammation, if unresolved, can become chronic, systemic or low-grade (think slow burner — fire is ongoing but symptoms may be unnoticeable). This is in part due to cytokines (see illustration above), signalling proteins with the main function of controlling inflammation. They have a specific effect on the interactions and communications between cells and allow your immune system to mount a defence in the presence of pathogens or other substances that can make you sick. As seen in the illustration, some cytokines have pro-inflammatory activity. They are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions (e.g., IL-1, IL-6, and TNF-α) and pain.
Too many cytokines can lead to excess inflammation and conditions like autoimmune diseases. For example, interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-α are produced in excess in rheumatoid arthritis, where they're involved in inflammation and tissue destruction.[1]
A quick note on cytokines
There are many different types of cytokines, which serve a number of functions in the body, such as:
Stimulating the production of blood cells
Supporting the development, maintenance, and repair of tissues
Regulating the immune system
Driving inflammation through interferons, interleukins, and tumour necrosis factor-alpha (TNF-α)[2]
Cytokines are identified based on either the type of cell that secretes them or the mode of action, including:
Lymphokines — made by lymphocytes, they attract immune cells such as macrophages
Monokines — made by monocytes, they attract neutrophils
Chemokines are associated with chemotactic actions (attract and direct the migration of certain immune cells, such as neutrophils, to the site of inflammation)
Interleukins — made by one leukocyte but act on other leukocytes, allowing communication between cells. Specific interleukins can have a major impact on cell-cell communication.
So, inflammation is a good thing?
Absolutely.
Inflammation is essential to our survival. Without it the body would not be able to fight infections.
Inflammation becomes a problem when it develops into chronic inflammation and the body is not able to it shut down, as is the case in low-grade inflammation.
“Instead of inflammatory cytokines targeting the injured tissue, they start reacting on the surrounding tissue. When this happens, they have an effect on the normal cellular structure, which in turn, can result in chronic disease.”
What causes inflammation to become excessive and chronic?
There are several factors that can contribute to excessive and chronic inflammation. Poor dietary habits, stress, lack of exercise, smoking, exposure to pollution, and chronic infections are some of the common culprits. These factors can trigger the production of inflammatory cells and chemicals in the body, leading to long-term damage to tissues and organs.
In some cases, genetic factors may also play a role in increasing the risk of inflammatory disorders.
While acute inflammation is necessary for the healing and repair processes and to fight infections, chronic inflammation, systemic or low-grade, can be harmful to the body. Long-term inflammation has been linked to various health conditions such as arthritis, heart disease, diabetes, autoimmune conditions and cancer.
Can what I eat affect inflammation?
When we typically talk of inflammation, we usually refer to “acute” inflammation. As previously mentioned, chronic inflammation often leads to ill health since cytokines can cause damage to the body's tissue.
The “acute” inflammatory process is resolved by an active intrinsic mechanism regulated by mediators (e.g., lipoxins, resolvins, maresins, and protectins) derived from omega-6 and omega-3 fatty acids, collectively termed specialised pro-resolving mediators (SPMs). SPMs promote the end-stage of inflammation by counter-regulating pro-inflammatory signals and mediators (such as the recruitment of immune cells) and activate macrophage-assisted phagocytosis and efferocytosis (the removal of dead cells), which leads to the clearance of inflammatory exudate and restoration of cellular homeostasis
Acute inflammation may persist due to the ongoing presence of non-degradable pathogens or foreign substances (e.g., gluten, chemicals, smoking, etc.), persistent injury (e.g., ulcer), or autoimmune reactions, In chronic inflammation, the process is not resolved and continues until there is damage to the tissue as observed in rheumatoid arthritis, to use as an example. The problem with chronic inflammation is that inflammation coexists with tissue damage and attempted repair with scaring.
A diet with an excessive intake of omega-6 fatty acids and low in omega-3 fatty acids has been shown to dysregulate inflammatory processes because omega-6 fatty acids can reduce the activity of SPMs.
Chronic inflammation can result from the following:
Failure to eliminate the agent causing acute inflammation (e.g., infectious organisms, fungi or parasites) that can resist host defences and remain in the tissue for an extended period.
Exposure to a low level of a particular irritant or foreign material that cannot be eliminated by enzymatic breakdown or phagocytosis in the body (e.g., chronic exposure to certain chemicals).
An autoimmune disorder in which the immune system mistakes the normal component of the body as foreign and, as a result, attacks healthy tissue (e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), thyroiditis).
A defect in the cells responsible for mediating inflammation, which leads to persistent or recurrent inflammation, such as auto-inflammatory disorders (causing intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling. However, autoinflammatory diseases are a separate class from autoimmune diseases. The key difference is that autoinflammatory diseases are caused by a malfunction of the innate immune system and autoimmune diseases occur due to malfunction of the adaptive immune system).[3]
Recurrent episodes of acute inflammation. It is important to note that, in some cases, chronic inflammation is an independent response and not a sequel to acute inflammation, as is the case of tuberculosis and rheumatoid arthritis.
Inflammatory and biochemical inducers causing oxidative stress (increased production of free radical molecules) and mitochondrial dysfunction, advanced glycation end products (AGEs), uric acid crystals, oxidised lipoproteins (bad cholesterol), homocysteine (a marker of inflammation signalling methylation problems), and many others.[4]
What are the symptoms of chronic inflammation?
Some of the common signs and symptoms that develop during chronic inflammation are listed below.
Body pain, muscle and joint pain
Chronic fatigue and insomnia
Depression, anxiety and mood disorders
Gastrointestinal complications like constipation, diarrhea, and acid reflux
Weight gain or weight loss
Frequent infections.[4]
Chronic inflammatory diseases are the most significant cause of death in the world with more than 73% of all deaths being attributable to inflammation-related (non-communicable) diseases such as ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease (NAFLD) and autoimmune and neurodegenerative conditions.[5]
The prevalence of diseases associated with chronic inflammation is anticipated to increase persistently for the next 30 years. In 2000, in the United States only, nearly 125 million Americans were living with chronic conditions and 61 million (21%) had more than one.
Which food should I avoid?
If we understand that at the simplest level, dietary factors control intercellular messaging, then when we consume ultra-processed, refined and high-calorie food products, high in trans fats and omega-6 fatty acids, and high in sugar, these may stop the signalling system from operating properly. These types of food products also cause spikes in blood glucose levels that can trigger the release of pro-inflammatory molecules and stress hormones (due to the negative output created by large levels of insulin). It may be suitable to avoid those food products if you suffer from a chronic inflammatory disorder.
What is an anti-inflammatory diet?
Think of the classic Mediterranean Diet, which is often recognised as the standard of a healthy diet because it contains a lot of vegetables, whole grains, fish and unsaturated fats such as cold-pressed extra virgin olive oil, and a small amount of meat and dairy products.
In recent years, some experts have recommended plant-based and vegan diets because they are designed around plants; however, in today’s society, few are true vegans eating only plants. Most people following a vegan or plant-based diet mostly consume ultra-processed (chemical-laden) meat replacement products and refined grains, and very few unprocessed plants (e.g., raw or minimally-cooked vegetables).
The theory based on the Mediterranean diet or plant-based diet is simple: when we consume plants, we ingest particular components that have certain properties in our bodies. Plus, plants are typically considered nutrient-dense, rich in antioxidants, and low in calories.
“The deeper the colour of a plant, whether it’s black, blue or green, the more anti-inflammatory a food tends to be.”
Various non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce pain and inflammation by blocking the metabolism of arachidonic acid by cyclooxygenase enzyme, thereby reducing the production of prostaglandin.[6]
Yet, this type of drug is found to have a long list of side effects while many plants with anti-inflammatory properties do not.[7] This is why it is important to consume a true plant-based diet, rich in raw or minimally-cooked vegetables. It is important to note that some of the anti-inflammatory compounds and certain antioxidants are destroyed by heat.
The anti-inflammatory activity of plants is directly related to the concentration of the phenolic compounds (polyphenols) and other constituents they contain such as alkaloids, saponins, phytosterols, tannins, and flavonoids. Many of these compounds are often pigments and/or are generally involved in defence against ultraviolet radiation or aggression by pathogens.
Main plant compounds with anti-inflammatory activity:
Polyphenols are a large group of naturally-occurring chemicals found in plants. There are more than 8,000 different types of polyphenols identified so far. Some polyphenols that have gained popularity are epigallocatechin gallate (EGCG) in green tea and resveratrol in grapes and wine. Most polyphenols work as antioxidants (help combat free radical damage, also known as oxidative stress) in the body and are more generally found in fruits, vegetables, cereals, legumes, chocolate, oils, and spices. Click here for a list of polyphenols-rich foods, some of the richest are blueberries (hydroxycinnamic acids, peonidin), blackberries (cyanidin), aubergines (ferulic acid, anthocyanins), curly kale (quercetin), black grape (delphinidin), beans (catechin), green tea (epicatechin), miso (genistein), and coffee (sinapic acid).
Alkaloids are found primarily in plants and are especially common in certain families of flowering plants to protect them from predators and regulate their growth. Alkaloids can be found in leaves, bark, and roots. They have a bitter taste and high level of toxicity (to protect from pathogens and herbivores).[8] Caffeine belongs to the family of alkaloids. Berberine belongs to the isoquinoline class of alkaloids with a bitter taste and yellow colour, having medicinal use in Ayurvedic and Chinese medicines for about 3000 years.[9] Piperine is another, and so are nicotine (found in tobacco plants) and morphine (found in Papaver somniferum (opium poppy).
Saponins are bitter-tasting usually toxic plant chemicals that have a foamy quality. They are widely distributed but found particularly in soapwort, soapbark trees and legume plants (including soybeans). It is important to note dietary cholesterol interferes with the absorption of saponins by forming insoluble complexes.[10] Saponins can be gastrointestinal irritants and can also lead to oesophagal reflux in sensitive or overweight individuals. They are highly toxic when given intravenously[11], yet they are the subject of research as adjuvants in certain vaccines.[12]
Phytosterols also known as plant sterols or stanols esters, are a family of bioactive compounds related to cholesterol that serve as structural components of the membranes of plants. Their affinity with cholesterol is very interesting because studies have shown that they can reduce LDL (the so-called bad cholesterol) and total cholesterol in the blood once consumed, but has no effect on HDL (the so-called “good” cholesterol). Most guidelines on the treatment of dyslipidemia and/or prevention of cardiovascular disease recommend the intake of phytosterols in the amount of approximately 2 g/day with the goal of reducing LDL-cholesterol by approximately 10%, in association with lifestyle changes.[13,14] Food rich in phytosterols includes nuts and seeds, and their oils, vegetable oil, legumes, and many fruits and vegetables, including berries. Therefore, edible fat and oil are among the most important natural sources of phytosterols in human diets. The highest content is found in wheat germ oil (4,240 mg/100 g) and rice bran oil (972-1,034 mg /100 g). In general, β-sitosterol is the most abundant phytosterol (50-70% of phytosterols investigated) followed by campesterol, stigmasterol, brassicasterol, and ∆5-avenasterol. The refining methods of vegetable/seed oils generate a loss of up to 70% loss in phytosterols.[15,16] Therefore, it is necessary to only consume unfiltered cold-pressed, extra virgin oils (avoid steam and solvent-extracted industrial oils, which are pro-inflammatory)
Plant tannins are water-soluble polyphenols that are widely found in all parts of plants, including the bark of trees, leaves, stems, fruits, seeds and roots. They protect plants from being infected by bacteria or fungi and deter predators. They are currently studied for various applications in farming since they can effectively improve the quality of meat and milk, and enhance the oxidative stability of the product (when added to feed). Most tannins display anti-inflammatory functions. It is speculated that the anti-inflammatory properties of tannins may be caused by regulating cytokine expression and reducing the production of inflammatory substances. A study on grape seed procyanidin extract demonstrated that it can reduce obesity-induced inflammation by mediating the expression of cytokines.[17] In addition, tannins can form a gastroprotective barrier to improve gastritis symptoms based on their antioxidant activity.[18] Animal studies have shown that some plant tannins have anti-diarrhoea effects.[19] It is important to note that tannins belong to the group of antinutrients as they have the ability to form complexes with carbohydrates, proteins (molecular size and pH-dependent), polysaccharides, and enzymes involved in protein and carbohydrate digestion.
Flavonoids also belong to the class of polyphenols and are very abundant (6,000 different structures have been found) in plants, fruits, and seeds, responsible for colour, fragrance, and flavour. In plants, flavonoids perform many functions like regulating cell growth, attracting pollinators and insects, and protecting against biotic and abiotic stresses.[20] For instance, plant flavonoids can operate as signal molecules, UV filters, and reactive oxygen species (ROS) scavengers (antioxidant properties). These compounds have been extensively researched for their bioactive properties, such as anti-inflammatory, anticancer, anti-ageing, cardio-protective, neuroprotective, immunomodulatory, antidiabetic, antibacterial, antiparasitic, and antiviral properties.[21,22,23] Based on the structure of the flavonoids, they can be classified into six major classes, flavan-3-ols, flavones, flavanols (The most prevalent flavonol is quercetin), flavanones, isoflavones (important estrogenic activity), and anthocyanins (pigments, pink to blue).[24] Many of these are used by the cosmetics, food and pharmaceutical industries.[20] For a complete list of flavonoids and plant sources, click here.
Can omega-3-rich foods be included in an anti-inflammatory diet?
Absolutely.
Favour cold-water small fatty fish that are exceptionally high in omega-3 fatty acids, as long as wild and not farmed, including sockeye salmon, Atlantic mackerel, sardines, herrings, anchovies and river trout. If you prefer to supplement with supplements from trusted sources, it works too.
According to a meta-analysis of studies involving a total of 4,601 participants, researchers concluded that omega-3 supplementation had a significant lowering effect on levels of inflammation markers in the body.
Can anyone follow an anti-inflammatory diet?
A typical answer would be “it depends.”
Pretty much anyone can benefit from following an anti-inflammatory diet; however, it is not a one-size-fits-all approach. Many people have developed hypersensitivities to certain foods and inherited intolerances to others (most food intolerances are transgenerational) and, therefore, one food may be in theory anti-inflammatory but be pro-inflammatory for some people.
“Some people are sensitive to nightshade vegetables, which include bell peppers, tomatoes and aubergines. So, even though these foods can be anti-inflammatory for certain people who have an allergy. For example, they will experience a pro-inflammatory response”
You do not necessarily need a food intolerance test to uncover foods that may be a problem. Feeling discomfort, bloating and or digestive issue when eating certain foods are good indications that those foods are not “good” for you.
A recent study, published in the American Journal of Clinical Nutrition, suggests that some people are more prone to excessive inflammatory responses after eating certain foods. The research, in which more than 1000 participants consumed the same meals at the same intervals, fund that those with more body ft and a greater body mass index (BMI) were more likely to have an uptick in inflammation after eating. Levels were also higher in men than women, older people than younger, and postmenopausal than premenopausal women.
Gut inflammation can also lead to malnutrition and further immune dysfunction (including autoimmunity), creating a vicious circle until the body is left unable to combat tissue damage and organ/system difficulties (e.g., IBD/IBS have been associated with colon cancer, autoimmune thyroiditis has been linked to gluten intolerance).
Should I consider anything else alongside a change in diet?
Other lifestyle factors can play a pivotal role in ramping up inflammatory responses — cigarette and e-cigarette smoking, excessive alcohol intake, over-exposure to certain pollutants/toxicants (indoor and outdoor pollution, chemicals presents in household products, cosmetics and foods), over-exercising, and chronic stress.
I’ve heard that chronic inflammation can affect my mental health, is it true?
Indeed, it is true.
It is a growing subject in research today. Some studies have already highlighted a link between food, inflammation and depression. In a study, published in the BMJ, researchers found patients with major depressive disorders to have increased numbers of cytokines, suggesting a correlation between high levels of inflammation and depression.
While research is pretty inconclusive and lacking when it comes to what food offers the best protection for mental health, we already know that nutrient-dense foods, foods that are naturally rich in antioxidants, might be beneficial when it comes to how diet influences mental health disorders.
Foods that irritate you, make you feel fatigued and somehow not like yourself (e.g., brain fog, irritability, lack of judgement) are those that would typically negatively impact your mental well-being.
“Diets with a high glycaemic index and load, containing high amounts ot refined carbohydrates and sugars, may have a detrimental effect on psychological well-being. ”
Research shows an association between high dietary glycaemic index and the incidence of mental health problems. Clinical studies have also shown potential causal effects of refined carbohydrates on mood — a high glycaemic index can lead to an increase in depressive symptoms in healthy individuals.
Let’s hope that this field of research focuses on diet rather than a magic pill, which could lead to targeted — even personalised — interventions to improve mood, anxiety and other symptoms through nutritional approaches.
Sleep, Mental Health and Inflammation
When it comes to cognitive dysfunction, such as brain fog, poor memory and concentration, sleep and stress are often the culprits. Powerful stressors also include inflammation and low-grade gut inflammation.
Sleep deprivation is associated with increased levels of inflammatory markers, such as cytokines, interleukin-6, and C-reactive protein. These markers are also elevated in people with cardiovascular disease, high blood pressure, and diabetes. This suggests that sleep deprivation may play a role in increasing the risk of developing any of these chronic conditions.
There are several possible mechanisms by which sleep deprivation may contribute to inflammation. One of the theories focuses on blood vessels. During sleep, blood pressure drops and blood vessels relax. When sleep is restricted, blood pressure does not reduce as it should, which may trigger cells in the blood vessel walls to activate inflammation. Sleep deprivation may also alter the body's stress response system, leading to increased inflammation. In both cases, blood sugar dysregulation is also a major problem because elevated blood sugar levels are extremely toxic to the blood vessels (inflammatory) and also fuel the release of stress hormones (making sleeping more difficult).
Another mechanism by which sleep deprivation may contribute to inflammation involves the brain's glymphatic system. The glymphatic system is a cerebrospinal fluid (CSF) pathway system that circulates through the brain and removes waste products, including beta-amyloid protein. Beta-amyloid is a protein that can form plaques and is associated with Alzheimer's disease. When sleep is restricted, the glymphatic system is less effective at removing beta-amyloid, heavy metals and other toxic materials (including metabolic waste), which can lead to accumulation and brain inflammation.
The effects of sleep deprivation on inflammation are cumulative. Even a single night of sleep loss can lead to increased levels of inflammatory markers. However, the more frequently sleep is restricted, the greater the risk of developing chronic inflammatory conditions, because the more difficult it is for the body to shut off inflammatory responses as it should.
References
1. Tisoncik, JR. et al. (2012). Into the eye of the cytokine storm. Microbiology and Molecular Biology Reviews. 76(1), pp. 16–32. doi:10.1128/MMBR.05015-11
2. Ferreira, VL. et al. (2018). Cytokines and Interferons: Types and Functions. Autoantibodies and Cytokines. doi:10.5772/intechopen.74550
3. Zen, M. et al. (2013). Clinical guidelines and definitions of autoinflammatory diseases: Contrasts and comparisons with autoimmunity - A comprehensive review". Clinical Reviews in Allergy & Immunology. 45 (2), pp. 227–235. doi:10.1007/s12016-013-8355-1
4. Pahwa, R. Goyal, A. Jialal, I. (2022). Chronic Inflammation. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493173
5. GBD 2017 Causes of Death Collaborators. (2018). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 392(10159), pp. 1736–1788. doi:10.1016/S0140-6736(18)32203-7
6. Sanchez, O. (2021). The truth about fats. In: Energise - 30 Days to Vitality. London: Nutrunity Publishing. pp. 91-122. (diagram with the mode of action of NSAIDs can be found on page 102)
7. Oguntibeju, OO. (2018). Medicinal plants with anti-inflammatory activities from selected countries and regions of Africa. Journal of Inflammation Research. 11, pp. 307-317. doi:10.2147/JIR.S167789
8. Hussain, G. et al. (2018). Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. International Journal of Biological Sciences. 14(3), pp.341-357. doi:10.7150/ijbs.23247
9. Cai, Z. Wang, C. Yang, W. (2016). Role of berberine in Alzheimer's disease. Neuropsychiatric Disease and Treatment. 12, pp. 2509-2520.
10. Liener, IE. (2003). Detoxification. In: Trugo, L. Finglas, PM. (Ed). Encyclopedia of Food Sciences and Nutrition. 2nd ed. San Diego: Elsevier Science Ltd. pp. 4587-4593.
11. Bartnik, M. Facey, PC. (2017). Glycosides. In: McCreath, SB. Delgoda, R. Pharmacognosy — Fundamentals, Applications and Strategies. London: Academic Press. pp.101-161.
12. Gautam, M. et al. (2017). Vaccines and immunodrugs discovery. In: Patwardhan, B. Chaguturu, R. Innovative Approaches in Drug Discovery Ethnopharmacology, Systems Biology and Holistic Targeting. London: Academic Press. pp.315-341.
13. Cabral CE, Klein MRST. (2017). Phytosterols in the treatment of hypercholesterolemia and prevention of cardiovascular diseases. Arquivos Brasileiros de Cardiologia. 109(5), pp. 475-482. doi:10.5935/abc.20170158
14. Katan, MB. et al. (2003). Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clinic Proceedings. 78, pp. 965–978. doi:10.1016/S0025-6196(11)63144-3
15. Kochhar, SP. (1983). Influence of processing on sterols of edible vegetable oils. Progress in Lipid Research. 22(3), pp. 161-188.
16. Bai, G. Ma, C. Chen, X. (2021). Phytosterols in edible oil: Distribution, analysis and variation during processing. Grain & Oil Science and Technology. 4(1), pp. 33-44.
17. Pallarès, V. et al. (2013). Effects of grape seed procyanidin extract over low-grade chronic inflammation of obese Zucker fa/fa rats. Food Research International. 53, pp. 319–24. doi:10.1016/j.foodres.2013.05.006
18. Demarque, DP. et al. (2018). The role of tannins as antiulcer agents: A fluorescence-imaging based study. Revista Brasileira de Farmacognosia [Brazilian Journal of Pharmacognosy]. 28(4). doi:10.1016/j.bjp.2018.03.011
19. Bonelli, F. et al. (2018). Oral administration of chestnut tannins to reduce the duration of neonatal calf diarrhea. BMC Veterinary Research. 14, 227. doi:10.1186/s12917-018-1549-2
20. Dias, MC. Pinto, DCGA. Silva, AMS. (2021). Plant flavonoids: Chemical characteristics and biological activity. Molecules. 26(17), 5377. doi:10.3390/molecules26175377
21. Saini N., Gahlawat S.K., Lather V. (2017). Flavonoids: A nutraceutical and its role as anti-inflammatory and anticancer agent. In: Gahlawat S, Salar R. Siwach P. et al: Plant Biotechnology: Recent Advancements and Developments. Springer; Singapore.
22. Jucá, MM. et al. (2020). Flavonoids: Biological activities and therapeutic potential. Natural Product Research. 5, pp. 692–705. doi: 0.1080/14786419.2018.1493588
23. Fraga, CG. et al. (2019). The effects of polyphenols and other bioactives on human health. Food & Function. 10, pp. 514–528. doi:10.1039/C8FO01997E