Polyphenols represent a complex group of phytochemicals that provide one of the main methods that plants use to fight to defend themselves from microbial invasion. They are also nutrients that can activate gene transcription factors thereby changing gene expression.
Polyphenols cannot be synthesized by the human body and therefore must be provided by the diet. In this sense, they can be considered to be essential nutrients by nature of their gene activation properties in human cells and their ability of maintain a healthy gut microbiota.
There are approximately 8,000 known polyphenols, and probably twice that number that have not been structurally analyzed. Little was known about the biological activities of polyphenols before 1995 (1). It is now known that they are powerful activators of human genes involved in the synthesis of anti-oxidant enzymes, modulation of anti-inflammatory pathways, and activation of anti-aging genes as well as critical factors to maintaining a healthy gut microbiota.
There is a great deal of epidemiological data that increased dietary intake of foods components rich in polyphenols (vegetables, fruits, and whole grains) are associated with lower rates of chronic disease and mortality (2,3). Further, increased levels of polyphenols in the urine (indicating absorption) are strongly associated with reduced mortality and frailty in elderly populations (4,5).
Mechanisms of polyphenols on health
The complexity of health benefits of polyphenols must be understood into two distinct areas. These are (a) their effect on human cells and (b) their effect on the gut microbiota.
The most intriguing mechanism of polyphenol actions on human cells is their ability to activate key genes, in particular those involved in the production of anti-oxidant enzymes, reduction of inflammatory responses, and activating genes associated with a reduced rate of aging.
Although polyphenols do have anti-oxidant actions per se, they have a far greater impact in the activation of anti-oxidative genes such as Nrf2 (6-8). Once these genes are activated, they generate increased expression of anti-oxidative enzymes such as glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase. Unlike typical dietary anti-oxidants, these anti-oxidative enzymes can reduce thousand times more free radicals. The reduction of the excess free radicals and their associated decrease of oxidative stress are generally associated with decreased mortality (9).
The anti-inflammatory actions of polyphenols are associated with their stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG). PPARG controls lipid uptake and fat cell synthesis. Increased expression of this gene transcription factor also inhibits the activation of nuclear factor kappaB (NF-κB), which is the master switch for turning on the innate inflammatory response (10).
Finally polyphenols activate the anti-aging gene (SIRT-1) that expresses increased AMP kinase , which controls general metabolism and initiates autophagy (11-13)
The activation of all of these human genes depends on the levels of polyphenols in the blood. Since polyphenols generally have a poor bioavailability (2-20%), to activate these genes usually requires consuming large amounts of polyphenols in the diet (14).
The role of polyphenols in gut health is even more complex. Unlike the human body where oxygen is required for life, the colon which is home of the gut microbiota is devoid of oxygen. Polyphenols can that absence of oxygen by acting as classical anti-oxidants as they can reach the colon without being absorbed in the small intestine (15,16). It is only when the environment in the colon is totally oxygen-free that many pathogens have a difficult time establishing themselves.
The second important purpose for polyphenols in the gut is their ability to be a primary defense against pathological microbial invaders as they do for plants. Polyphenols enhance the production of those unique strains of bacteria (such as Akkermansia muciniphila) in the gut microbiota that appear to act as a master switch for controlling the gut microbiota especially for the improvement of the integrity of the mucus barrier and tight junctions of the mucosal cells to prevent penetration of bacterial fragments such a lipopolysaccharide (LPS) into the blood (17-19). As the levels of LPS increase in the blood, they can interact with toll-like receptors (TLR) to generate low-level chronic inflammation that leads to metabolic endotoxemia with a corresponding increase in obesity and diabetes (20).
Whereas the poor availability of polyphenols is rate-limiting on their actions on the activation of gene transcription factors in human cells, their inability to be absorbed by the small intestine allows a directed delivery to the colon and the microbiota in that region for maximum impact.
Within the colon, a great deal of metabolic modification of polyphenols can take place, however much of details of that metabolism remain unknown. It is estimated that 40% of the metabolites in the blood come from the metabolism of polyphenols. Because the lifetime of these polyphenol metabolites is relatively short often measured with a half-live of few hours, a constant dietary supply of polyphenols is required to maintain optimal levels in the gut and their metabolites in the blood.
Regardless of the potential of polyphenols for gene activation and improved gut health, their levels in foods are very low. As an example, the levels of polyphenols in vegetables are usually about 0.1% of their weight and only slightly higher (0.2% by weight) in fruits. Thus it requires a consistent consumption of adequate levels of fruits and vegetables to maintain adequate intakes of polyphenols for optimal health.
However, plants sources can be processed to yield polyphenol extracts that contain up to 40% polyphenols by weight. Such extracts make it possible to consume adequate levels of polyphenols to generate consistent therapeutic benefits.
The extraction methodology for polyphenol extracts starts with dehydration of the food source to give a dry powder. This dehydration step usually doubles the polyphenol concentration. The dried powder can be further extracted by alcohol to increase the polyphenol content. This is because polyphenols have higher solubility in alcohol compared to other plant components. This explains the use of wine as a classical way to ingest higher levels of polyphenols. However, the alcoholic extracts can be even further purified by chromatography to generate refined polyphenol extracts approaching 40-50% polyphenols by dry weight.
Purified polyphenol extracts allow for human clinical studies to demonstrate their therapeutic efficacy.
To date, three groups of polyphenols have shown to have therapeutic benefits under clinically controlled experiments. These polyphenols include cocoa flavanols (21,22), anthocyanin from berries (23,24), and finally a subclass of anthocyanins known as delphindins (25,26).
Cocoa flavanols in high concentration (a minimum of 450 mg per day) have demonstrated benefits in vascular flow and improving cognitive function as well as the size of the hippocampus. Anthocyanin extracts from blueberries have demonstrated improvements in cognitive function and reduction in oxidized LDL cholesterol, and delphindins extracts from the maqui berry have benefits in reducing glycemic responses and reducing oxidative stress and oxidized LDL cholesterol.
However, these clinical benefits come from the entry of the polyphenols into the blood. In this respect, the delphinidins from the maqui berry are interesting in that this class of polyphenols is known to be absorbed intact compared to other polyphenol extracts (27). Improved bioavailability is important as demonstrated in epidemiological studies in which the levels of the polyphenols in the urine (indicative that the polyphenols had to be absorbed) are best related to reduced mortality and frailty (4,5).
What are adequate intake levels for polyphenol extracts?
The answer depends on what genes you are trying to activate. A general suggestion might be the following:
|Nrf2||Reduce oxidative stress||500 mg per day|
|PPAR||Reduce inflammation||1000 mg per day|
|SIRT-1||Reduce rate of aging||1500 mg per day|
To reach those levels will generally require the use of extracts. However, at those therapeutic levels, significant relevant clinical change is observed. In essence, this becomes gene therapy in the kitchen.
Polyphenols have a remarkable range of physiological actions in both human cells and in the gut microbiota. Because of these unique actions, the dietary polyphenols have a unique role to play in the treatment of chronic diseases associated with increase inflammation. The key to this potential goal is the consumption of adequate levels of polyphenols to activate these unique metabolic mechanisms. The use of polyphenol extracts makes that potential goal more likely.
- Scalbert A, Johnson IT, and Saltmarsh M. “Polyphenols: antioxidants and beyond.” Am J Clin Nutr 81: 215S–217S (2005)
- Bao Y, Han J, Hu FB, Giovannucci EL, Stampfer MJ, Willett WC, and Fuchs SC. “Association of nut consumption with total and cause-specific mortality.” N Engl J Med 369: 2001–2011 (2013)
- Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH and EB. “High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women.” Circulation 127: 188–196 (2013)
- Zamora-Ros R, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, Andres-Lacueva C. “High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults.” J Nutr 143: 1445–1450 (2013)
- Urpi-Sarda M, Andres-Lacueva C, Rabassa M, Ruggiero C, Zamora-Ros R, Bandinelli S, Ferrucci L, and Cherubini A. “The Relationship Between Urinary Total Polyphenols and the Frailty Phenotype in a Community-Dwelling Older Population: The InCHIANTI Study.” J Gerontol A Biol Sci Med Sci 70:1141-1147 (2015)
- Erlank H, Elmann A, Kohen R, and Kanner J. “Polyphenols activate Nrf2 in astrocytes via H2O2, semiquinones, and quinones.” Free Radic Biol Med 51: 2319–27 (2011)
- Scapagnini G, Vasto S, Abraham NG, Caruso C, Zella D, and Fabio G. “Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders.” Mol Neurobiol 44: 192–201 (2011)
- Hybertson BM, Gao B, Bose SK, and McCord JM. “Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation.” Mol Aspects Med 32: 234–246 (2011)
- Schottker B, Saum KU, Jansen EH, Boffetta P, Trichopoulou A, Holleczek B, Dieffenbach AK, and Brenner H. “Oxidative stress markers and all-cause mortality at older age: a population-based cohort study.” J Gerontol A Biol Sci Med Sci 70:518-24 (2015)
- Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, and Kong AN. “Activation of Nrf2-antioxidant signaling attenuates NF-kappaB-inflammatory response and elicits apoptosis.” Biochem Pharmacol 76: 1485–1489 (2008)
- Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, and Rahman I. “Regulation of SIRT1 in cellular functions: role of polyphenols.” Arch Biochem Biophys 501: 79–90 (2010)
- Ayissi VB, Ebrahimi A, and Schluesenner H. “Epigenetic effects of natural polyphenols: A focus on SIRT1-mediated mechanisms.” Mol Nutr Food Res 58: 22–32 (2014)
- Hwang JT, Kwon DY, and Yoon SH. “AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols.” N Biotechnol 26: 17–22 (2009)
- Landete JM. “Updated knowledge about polyphenols: functions, bioavailability, metabolism, and health.” Crit Rev Food Sci Nutr 52: 936–948 (2012)
- Ozdal T, Sela DA, Xiao J, Boyacioglu D, Chen F, and Capanoglu E. “The Reciprocal Interactions between Polyphenols and Gut Microbiota and Effects on Bioaccessibility.” Nutrients 8:2-36 (2016)
- Cardona F, Andres-Lacueva C, Tulipani S, Tinahones FJ, and Queipo-Ortuno MI. “Benefits of polyphenols on gut microbiota and implications in human health.” J Nutr Biochem 24: 1415–1422 (2013)
- Anhe FF, Pilon G, Roy D, Desjardins Y, Levy E, and Marette A. “Triggering Akkermansia with dietary polyphenols: A new weapon to combat the metabolic syndrome?” Gut Microbes 7:146-153 (2016)
- Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, Gomis R, Claret M, and Cani PD. “Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice.” Sci Rep 13:16643 (2015)
- Roopchand DE, Carmody RN, Kuhn P, Moskal K, Rojas-Silva P, Turnbaugh PJ, and Raskin I. “Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome.” Diabetes 64:2847-2858 (2015)
- Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, and Burcelin R. “Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.” Diabetes 57:1470-1881(2008)
- Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, and Small SA. “Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.” Nat Neurosci 17:11798-1803 (2014)
- Davison K, Coates AM, Buckley JD, and Howe PR. “Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects.” Int J Obesity 32:1289-1296 (2008)
- Basu A, Du M, Leyva MJ, Sanchez K, Betts NM, Wu M, Aston CE, and Lyons TJ. “Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome.” J Nutr 140: 1582–1587 (2010)
- Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, and Joseph JA. “Blueberry supplementation improves memory in older adults.” J Agric Food Chem 58:3996–4000 (2010)
- Hidalgo J, Flores C, Hidalgo MA, Perez M, Yanez A, Quinones L, Caceres DD, and Burgos RA. “Delphinol standardized maqui berry extract reduces postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition.” Panminerva Med 56:1-7 (2014)
- Davinelli S, Bertoglio JC, Zarrelli A, Pina R, and Scapagnini G. “A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract (Delphinol®) on oxidative stress biomarkers.” J Am Coll Nutr 34 Suppl 1:28-33 (2015)
- Matsumoto H, Inaba H, Kishi M, Tominaga S, Hirayama M, and Tsuda T. “Orally administered delphinidin 3-rutinoside and cyanidin 3-rutinoside are directly absorbed in rates and humans and appear in the blood as the intact forms.” J Agric Food Chem 49:1546-1551 (2001)