Anthocyanins: What do we know until now?
Abstract
Diets enriched in plant-based foods are associated with the maintenance of a good well-being and with the prevention of many non-communicable diseases. The health effects of fruits and vegetables consumption are mainly due to the presence of micronutrients, including vitamins and minerals, and polyphenols, plant secondary metabolites. One of the most important classes of phenolic compounds are anthocyanins, that confer the typical purple-red color to many foods, such as berries, peaches, plums, red onions, purple corn, eggplants, as well as purple carrots, sweet potatoes and red cabbages, among others. This commentary aims to briefly highlight the progress made by science in the last years, focusing on some unexpected aspects related with anthocyanins, such as their bioavailability, their health effects and their relationship with gut microbiota.
Cancer, cardiovascular diseases, obesity, diabetes, cognitive impairment and respiratory pathologies are the major leading cause of disability and death in the world, affecting both developed and developing countries [1]. Many risk factors are linked with the onset of these non-communicable diseases (NCDs): some of these, including aging, gender and genetics, are not modifiable, while others, such as lifestyle-related factors, exert a prominent role in NCDs development, especially at individual level; among these factors, nutrition is one of the most important [2–4]. Indeed, dietary choices, based for example on high levels of refined grains, saturated fats, processed meats, salt and sugar but lacking in vegetables and fruits, increase the risk to develop cancer, diabetes and cardiovascular diseases, by increasing inflammation, oxidative stress, hypercholesterolemia and hypertension, among others [5]. In the view to address unhealthy dietary patterns, in the last years the World Health Organization (WHO) has promoted some initiatives for reducing behavioral risk factors, recommending, for example, balancing the daily energy intake, limiting the intake of trans- and saturated fats, augmenting the consumption of vegetables and fruits and reducing those of sugar and salt. Some common diets follow the recommendations promoted by WHO, such as for example the Mediterranean diet [6], the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet [7], or the Dietary Approaches to Stop Hypertension (DASH) [8]. One peculiarity shared by these diets is the large daily consumption of fresh vegetables and fruits, that, besides micronutrients such as minerals and vitamins, contain a wide quantity and variety of phytochemicals, including polyphenols, which confer most of the health benefits correlated with the intake of plant-based foods [9, 10]. One of the most common group of polyphenols are anthocyanins, pigments that provide red, pink, blue and purple color to several vegetables, fruits and flowers [11]. The most important dietary sources of anthocyanins are berries, like blueberries, strawberries, grapes, blackberries, blackcurrants, bilberries, pomegranates, chokeberries, cherries, but also black beans, peaches, plums, red radishes, red onions, purple corn, eggplants, purple carrots, purple sweet potatoes and red cabbages. The concentration of anthocyanins in plants depend on many factors, including the species and the cultivars, as well as the environmental aspects, including light and temperature, ranging from 0.205 mg/100 g in currants to 2468 mg/100 g in chokeberries, as recently reviewed [11]. Other current underestimated sources of anthocyanins are tropical and subtropical fruits, such as, for example, Brazilian jussara palm tree (Euterpe edulis) and Açai (Euterpe oleracea Mart.) fruits, Australian Davidson’s plum (Davidsonia pruriens), Asian butterfly pea flower (Clitoria ternatea), and Indian mangosteens (Garcinia indica), where the concentration of anthocyanins may reach up to 691 mg/100 g [11].
Regarding the chemical structure, anthocyanins are formed by an anthocyanidin backbone (aglycone), namely cyanidin, pelargonidin, malvidin, delphinidin, petunidin and peonidin, linked to a range of mono-, di-, and trisaccharides (often glucose, galactose, rutinose and arabinose), which can be acetylated to aliphatic and aromatic acids, resulting in numerous anthocyanin structures [11].
Considering the wide diffusion of anthocyanins in common dietary plan-based foods, in the last 30 years many efforts have been done by the scientific community to evaluate their health effects, as evidenced by the increasing number of papers published on PubMed every year (Fig. 1); 14.7% of these studies have been performed on culture cells, 50.0 % on animals, and 32.3 % on humans.
Fig. 1
Number of papers published on PubMed from 1996 and focused on anthocyanins and health effects.
Current summary evidence from meta-analyses suggests a potential association between higher anthocyanin intake and reduced CVD risk [12] and mortality [13], lower risk of hypertension [14] and type-2 diabetes [15], as well as reduction of certain cancers [16]. Moreover, later summary evidence from observational and intervention studies shows a potential preventive effect of anthocyanin intake for cognitive disorders [17].
In this context, the progress made recently by science and technology shed the light on many unexpected aspects related with anthocyanins. For example, today we know that anthocyanin bioavailability is not so low as thought in the past (less than 1–2%), when only the parental anthocyanidin glycosides and few phase II metabolites were detected and quantified: thanks to the metabolomic approach, indeed, a series of new metabolites derived from phase I or II biotransformation, enzymatic and chemical reactions, as well as from gut microbiota degradation, have been described [18–20]. Some studies showed that anthocyanins are present as hundreds of derivates of phase II conjugates, both in circulation and in tissues, for a prolonged period [21–23]. For example, after cranberry juice consumption, the maximum concentration of parental anthocyanins was at least 1000-fold lower than that of the anthocyanin glucoronide metabolites in plasma and 30-fold lower than that of their phase II glucoronide metabolites in urine [24, 25]; similar results were found also after strawberry consumption [26].
Besides bioavailability, another advance made by science regards the type of activities exerted by anthocyanins. A growing body of recent studies suggests in fact that anthocyanins and their biometabolites may prevent several common chronic diseases through complex mechanisms of action [11, 27–34]. For example, regarding cardiovascular diseases, the effects of anthocyanins and derived compounds seem to be related to their capacity of attenuating endothelial inflammation and oxidative stress, improving lipid profile and modifying vascular glycocalyx, while in metabolic disorders, like diabetes and obesity, anthocyanins consumption has shown to decrease blood glucose and glycated hemoglobin levels, inflammation and oxidative stress, ameliorate insulin secretion and resistance, reduce body mass index and total fats, increase lipolysis [11]; similarly, in cancer anthocyanins are associated with an inhibition of apoptosis, cell growth and differentiation, inflammatory responses and oxidative stress [11]. All these effects are ascribed not only to the mere antioxidant capacity (i.e., the ability of compounds to neutralize and sequester radicals) of anthocyanins as thought in the past, but especially to their ability in modulating different molecular pathways, including, for example, those correlated with cytoprotection and inflammation (i.e., nuclear factor erythroid 2-related factor 2, nuclear factor kappa-light-chain-enhancer of activated B cells, eNOS), metabolism (i.e., phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma pathways) [35], proliferation and apoptosis (i.e., AMPK, MAPKs, and PI3K/AKT/mTOR pathways) [10, 36–38] as well as angiogenesis [39].
Finally, another recent aspect is the anthocyanin effects on gut microbiota. A positive correlation between the intake of anthocyanins and the composition of gut microbiota has been indeed discovered [40]. The effects of anthocyanins on intestinal microbiota include, for example, the increase in the overall microbial quantity and diversity (in terms of both Phylum and Genus changes), together with the increased production of specific microbial substances, such as acetate, propionate, butyrate and short chain fatty acid [34, 35]. Through affecting the ratio between harmful and beneficial bacteria taxes, anthocyanins could be very beneficial in those pathological conditions where a lack of microbiome diversity has been highlighted, including cardiovascular diseases and neurological disorders [11, 41, 43, 44].
In conclusion, even if many steps forward have been made in recent years, several aspects remain to be understood, such as for example the dose/response effects, the ability of anthocyanins to cross cellular membranes or their interactions with biological molecules or other food components; in addition, other factors to take into consideration should regard the different technological processes used to isolate anthocyanins from foods or to increase their stability in commercial fortified products.
Funding
The work received no funding.
Conflict of interest
Maurizio Battino (Editor-in-Chief), Francesca Giampieri (Associate Editor), Josè Luis Quiles, Tamara Yuliett Forbes-Hernandez and Bruno Mezzetti (Editorial Board members) disclose their roles in the journal. However, none of them have been involved in or accessed any of the peer-review steps.
References
[1] | Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020;World Health Organ:Geneva, Switzerland, 2013. |
[2] | Tamimi RM , Spiegelman D , Smith-Warner SA , Wang M , Pazaris M , Willett WC , Eliassen AH , Hunter DJ Population attributable risk of modifiable and nonmodifiable breast cancer risk factors in postmenopausal breast cancer, American Journal of Epidemiology (2016) :184: :884–93. |
[3] | Yu E , Rimm E , Qi L , Rexrode K , Albert CM , Sun Q , Willett WC , Hu FB , Manson JE Diet, lifestyle, biomarkers, genetic factors, and risk of cardiovascular disease in the Nurses’ Health Studies, American Journal of Public Health (2016) :106: :1616–23. |
[4] | Kolb H , Martin S Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes, BMC Medicine (2017) :15: :131. |
[5] | Koene RJ , Prizment AE , Blaes A , Konety SH Shared risk factors in cardiovascular disease and cancer, Circulation (2016) :133: :1104–14. |
[6] | Bach-Faig A , Berry EM , Lairon D , Reguant J , Trichopoulou A , Dernini S , Medina FX , Battino M , Belahsen R , Miranda G , et al. Mediterranean diet pyramid today, Science and cultural updates. Public Health Nutrition (2011) :14: :2274–84. |
[7] | Marcason W What are the components to the MIND diet? Journal of the Academy of Nutrition and Dietetics (2015) :115: :1744. |
[8] | Appel LJ , Moore TJ , Obarzanek E , Vollmer WM , Svetkey LP , Sacks FM , Bray GA , Vogt TM , Cutler JA , Windhauser MM , Lin PH , Karanja N A clinical trial of the effects of dietary patterns on blood pressure, DASH Collaborative Research GrouNew England Journal of Medicine (1997) :336: (16):1117–24. |
[9] | Probst YC , Guan VX , Kent K Dietary phytochemical intake from foods and health outcomes: A systematic review protocol and preliminary scoping, BMJ Open (2017) :7: :e013337. |
[10] | Grosso G Effects of Polyphenol-Rich Foods on Human Health, Nutrients (2018) :10: (8):1089. |
[11] | Panchal SK , John OD , Mathai ML , Brown L b Anthocyanins in Chronic Diseases: The Power of Purple, Nutrients (2022) :14: (10):2161. |
[12] | Micek A , Godos J , Del Rio D , Galvano F , Grosso G Dietary Flavonoids and Cardiovascular Disease: A Comprehensive Dose-Response Meta-Analysis, Molecular Nutrition & Food Research (2021) :65: (6):e2001019. |
[13] | Grosso G , Micek A , Godos J , Pajak A , Sciacca S , Galvano F , Giovannucci EL Dietary Flavonoid and Lignan Intake and Mortality in Prospective Cohort Studies: Systematic Review and Dose-Response Meta-Analysis, American Journal of Epidemiology (2017) :185: (12):1304–16. |
[14] | Godos J , Vitale M , Micek A , Ray S , Martini D , Del Rio D , Riccardi G , Galvano F , Grosso G Dietary Polyphenol Intake, Blood Pressure, and Hypertension: A Systematic Review and Meta-Analysis of Observational Studies, Antioxidants (2019) :8: (6):152. |
[15] | Rienks J , Barbaresko J , Oluwagbemigun K , Schmid M , Nöthlings U Polyphenol exposure and risk of type 2 diabetes: dose-response meta-analyses and systematic review of prospective cohort studies, The American Journal of Clinical Nutrition (2018) :108: (1):49–61. |
[16] | Grosso G , Godos J , Lamuela-Raventos R , Ray S , Micek A , Pajak A , Sciacca S , D’Orazio N , Del Rio D , Galvano F A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations, Molecular Nutrition & Food Research (2017) :61: (4):10.1002/mnfr.201600930. |
[17] | Caruso G , Torrisi SA , Mogavero MP , Currenti W , Castellano S , Godos J , Ferri R , Galvano F , Leggio GM , Grosso G , Caraci F Polyphenols and neuroprotection: Therapeutic implications for cognitive decline, Pharmacology & Therapeutics (2022) :232: :108013. |
[18] | Lila MA , Burton-Freeman B , Grace M , Kalt W Unraveling Anthocyanin Bioavailability for Human Health, Annual Review of Food Science and Technology (2016) :7: :375–93. |
[19] | Czank C , Cassidy A , Zhang Q , Morrison DJ , Preston T , Kroon PA , Botting NP , Kay CD Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a (13)C-tracer study, The American Journal of Clinical Nutrition (2013) :97: (5):995–1003. |
[20] | Alvarez-Suarez JM , Cuadrado C , Ballesteros Redondo I , Giampieri F , González-Paramás AM , Santos-Buelga C Novel approaches in anthocyanin research - Plant fortification and bioavailability issues, Trends in Food Science & Technology (2021) :117: :92–105. |
[21] | Kalt W , Liu Y , McDonald JE , Vinqvist-Tymchuk MR , Fillmore SA Anthocyanin metabolites are abundant and persistent in human urine, Journal of Agricultural and Food Chemistry (2014) :62: (18):3926–34. |
[22] | Kalt W , McDonald JE , Liu Y , Fillmore SA Flavonoid metabolites in human urine during blueberry anthocyanin intake, Journal of Agricultural and Food Chemistry (2017) :65: :1582–91. |
[23] | Kalt W , McDonald JE , Vinqvist-Tymchuk MR , Liu Y , Fillmore SAE Human anthocyanin bioavailability: effect of intake duration and dosing, Food & Function (2017) :8: (12):4563–69. |
[24] | Cassidy A , Minihane AM The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids, American Journal of Clinical Nutrition (2017) :105: (1):10–22. |
[25] | McKay DL , Chen CY , Zampariello CA , Blumberg JB Flavonoids and phenolic acids from cranberry juice are bioavailable and bioactive in healthy older adults, Food Chemistry (2015) :168: :233–40. |
[26] | Mullen W , Edwards CA , Serafini M , Crozier A Bioavailability of pelargonidin-3-O-glucoside and its metabolites in humans following the ingestion of strawberries with and without cream, Journal of Agricultural and Food Chemistry (2008) :56: (3):713–9. |
[27] | Micek A , Owczarek M , Jurek J , Guerrera I , Torrisi SA , Grosso G , Alshatwi Ali A , Godos J Anthocyanin-rich fruits and mental health outcomes in an Italian cohort, Journal of Berry Research (2022) :12: (4):551–64. |
[28] | Navarro-Hortal MD , Romero-Márquez JM , Jiménez-Trigo V , Xiao J , Giampieri F , Forbes-Hernández TY , Grosso G , Battino M , Sánchez-González C , Quiles JL Molecular bases for the use of functional foods in the management of healthy aging: Berries, curcumin, virgin olive oil and honey; three realities and a promise. Critical Reviews in Food Science and Nutrition. 2022;1-20. |
[29] | Mu T , Guan Y , Chen T , Wang S , Li M , Chang AK , Yang Z , Bi X Black raspberry anthocyanins protect BV2 microglia from LPS-induced inflammation through down-regulating NOX2/TXNIP/NLRP3 signaling, Journal of Berry Research (2021) :11: (2):333–47. |
[30] | Navarro-Hortal MD , Romero-Márquez JM , Esteban-Muñoz A , Sánchez-González C , Rivas-García L , Llopis J , Cianciosi D , Giampieri F , Sumalla-Cano S , Battino M , Quiles JL Strawberry (Fragaria×ananassa cv, Romina) methanolic extract attenuates Alzheimer’s beta amyloid production and oxidative stress by SKN-1/NRF and DAF-16/FOXO mediated mechanisms in C. elegans. Food Chemistry (2022) :372: :131272. |
[31] | Iqbal AZ , Javaid N , Hameeda M Synergic interactions between berry polyphenols and gut microbiota in cardiovascular diseases, Mediterranean Journal of Nutrition and Metabolism (2022) :15: (4):555–73. |
[32] | Grosso G , Godos J , Currenti W , Micek A , Falzone L , Libra M , Giampieri F , Forbes-Hernández TY , Quiles JL , Battino M , La Vignera S , Galvano F The Effect of Dietary Polyphenols on Vascular Health and Hypertension: Current Evidence and Mechanisms of Action, Nutrients (2022) :14: (3):545. |
[33] | Gasparrini M , Forbes-Hernández TY , Canciosi D , Quiles JL , Mezzetti B , Xiao J , Giampieri F , Battino M The efficacy of berries against lipopolysaccharide-induced inflammation: A review, Trends in Food science and Technology (2021) :117: :74–91. |
[34] | Battino M , Giampieri F , Cianciosi D , Ansary J , Chen X , Zhang D , Gil E , Forbes-Hernández T The roles of strawberry and honey phytochemicals on human health: A possible clue on the molecular mechanisms involved in the prevention of oxidative stress and inflammation, Phytomedicine (2021) :86: :153170. |
[35] | Burton-Freeman B , Brzeziński M , Park E , Sandhu A , Xiao D , Edirisinghe I A Selective Role of Dietary Anthocyanins and Flavan-3-ols in Reducing the Risk of Type 2 Diabetes Mellitus: A Review of Recent Evidence, Nutrients (2019) :11: (4):841. |
[36] | Ho ML , Chen PN , Chu SC , Kuo DY , Kuo WH , Chen JY , Hsieh YS Peonidin 3-glucoside inhibits lung cancer metastasis by downregulation of proteinases activities and MAPK pathway, Nutrition and Cancer (2010) :62: (4):505–56. |
[37] | Afaq F , Malik A , Syed D , Maes D , Matsui MS , Mukhtar H Pomegranate fruit extract modulates UV-B-mediated phosphorylation of mitogen-activated protein kinases and activation of nuclear factor kappa B in normal human epidermal keratinocytes paragraph sign, Photochemistry and Photobiology (2005) :81: (1):38–45. |
[38] | Shin DY , Lee WS , Lu JN , Kang MH , Ryu CH , Kim GY , Kang HS , Shin SC , Choi YH Induction of apoptosis in human colon cancer HCT-116 cells by anthocyanins through suppression of Akt and activation of p38-MAPK, International Journal of Oncology (2009) :35: (6):1499–504. |
[39] | Tsakiroglou P , Weber J , Ashworth S , Del Bo’ C , Klimis-Zacas D Angiogenesis is Differentially Modulated by Anthocyanin and Phenolic Acid Extracts from Wild Blueberry (V, angustifolium) Through PI3K Pathway. Journal of Medicinal Food (2021) :24: (3):226–35. |
[40] | Hair R , Sakaki JR , Chun OK Anthocyanins, Microbiome and Health Benefits in Aging, Molecules (2021) :26: (3):537. |
[41] | Pan P , Lam V , Salzman N , Huang YW , Yu J , Zhang J , Wang LS Black Raspberries and Their Anthocyanin and Fiber Fractions Alter the Composition and Diversity of Gut Microbiota in F-344 Rats, Nutrition and Cancer (2017) :69: :943–51. |
[42] | Lee S , Keirsey KI , Kirkland R , Grunewald ZI , Fischer JG , de La Serre CB Blueberry supplementation influences the gut microbiota, inflammation, and insulin resistance in high-fat-diet-fed rats, Journal of Nutrition (2018) :148: :209–19. |
[43] | Wang Z , Zhao Y Gut microbiota derived metabolites in cardiovascular health and disease, Protein & Cell (2018) :9: :416–31. |
[44] | Krga I , Milenkovic D Anthocyanins: From sources and bioavailability to cardiovascular-health benefits and molecular mechanisms of action, Journal of Agricultural and Food Chemistry (2019) :67: :1771–83. |
