Through the last few decades, science has unraveled some (but certainly not all) of the science behind inflammation. Some level of inflammation is a vital part of human physiology, but too much or chronic inflammation has been linked to many health ailments, especially things like heart disease, arthritis, cancer, autoimmune disorders, etc. The link to chronic illness has set off a search for compounds, novel and naturally-occurring, to limit the destructive nature of inflammation. Extra virgin olive oil and olive-derived polyphenols have been identified by an abundance of clinical research as compounds that may exert anti-inflammatory effects in the body.

As a key component of the Mediterranean diet, extra virgin olive oil is believed to be one of the major reasons for the efficacy of the Mediterranean diet at preventing chronic illness, in part because of its impact on levels of inflammation in the body[i], [ii]. Research ranging from epidemiologic studies using food frequency questionnaires to RCT’s have linked EVOO consumption to improvements in markers of inflammation in the body. Though some of the initial thought was that the monounsaturated fat was behind the anti-inflammatory nature of EVOO, further research has elucidated that the phenolic content of EVOO appears to be more important than just the type of fat supplied by this ancient superfood.

Some of the main phenols found in EVOO can also be found in the leaves and fruit of the olive tree, and each at varying levels depending on the ripeness, weather, varietal of tree, and other factors. The most studied polyphenols include: oleuropein, oleocanthal, oleacein, hydroxytyrosol and tyrosol. Each of these have been linked to some level of anti-inflammatory effect in their own right[iii], [iv], [v].

 

 

 

 

Oleuropein

Oleuropein appears to be one of the most promising polyphenols in terms of impact on inflammation, with its anti-inflammatory effect being touted as the reason for its protective effect on many chronic health conditions[vi]. Much of the work done thus far on oleuropein and inflammation has been done in-vitro and in vivo, but these studies have shown oleuropein to be beneficial for positive modulations in markers of inflammation like IL-1β[vii], NF-κB[viii], annexin A1[ix], COX-2 and IL-17[x]. Human clinical research that specifically measured markers of inflammation showed that oleuropein did not have an impact on Il-8, TNF-α, and us-CRP, but that it did have an impact on IL-6, which can be a pro- or anti-inflammatory cytokine depending on other factors in the body[xi]. In a randomized, double blind, placebo controlled crossover trial including pre-hypertensive males, supplementation with olive leaf extract standardized to oleuropein and hydroxytyrosol resulted in a statistically significant reduction in IL-8, but not other markers of inflammation (including CRP, IL-6, IL-10, IL-1β or TNF-α). It should be noted that this study only measured inflammatory markers in a subset of the study population and the authors noted that greater statistical power (i.e. a larger sample size) is likely needed to detect statistical significance in markers with as much individual variation as inflammatory cytokines[xii]. Ex vivo research in human chondrocytes have also showed that oleuropein may be useful to limit expression of IL-1β and NF-κB[xiii].

 

Oleocanthal

Oleocanthal is a phenol that is found primarily in extra virgin olive oil, as the process of creating EVOO creates the oleocanthal molecule. It has an incredible amount of promise as an anti-inflammatory ingredient. In-vitro experiments have shown that oleocanthal actually inhibits both COX-1 and COX-2 (Cyclooxygenase 1 and 2) which are enzymes involved in making inflammatory prostaglandins[xiv]. The COX-2 enzyme is upstream of many inflammatory conditions, so inhibition of COX-2 makes oleocanthal a very strong candidate for ealth promoting benefits.

 

Oleacein

Like the other phenols derived from olives, oleacein is exhibits potential as an anti-inflammatory agent in in-vitro research, both by reduction in the release of inflammatory compounds as well as increasing expression of receptors needed to allow macrophages to reduce inflammation[xv]. It also shows promise as an anti-inflammatory agent because it reduces inflammatory cytokines like IL-8 (Interleukin-8)[xvi]. Similar to other compounds, human research needs to be conducted to better understand the role of oleacein in reduction of inflammation and inflammatory processes in the body.

 

Hydroxytyrosol

Hydroxytyrosol is one of the metabolites of oleuropein, so the 2 phenols are commonly found together. Like oleuropein, hydroxytyrosol has antioxidant effects as well as anti-inflammatory activity. In-vitro and in-vivo research has shown it to reduce inflammatory agents like iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2), TNF-α (tumor necrosis factor-α) and IL-1β (Interleukin-1β)[xvii],[xviii], [xix]. Human clinical research has also shown benefits with low doses of hydroxytyrosol (15mg/day) showed promising results for modulation of expression of genes related to inflammatory processes,[xx] but another human clinical showed that olive mill waste water enriched with hydroxytyrosol did not have an impact on any markers of inflammation[xxi]. Animal studies have shown hydroxytyrosol to exert beneficial effects on markers of liver health, including the inflammatory progression of non-alcoholic fatty liver disease to steatohepatitis[xxii].  A similar rat study also showed that hydroxytyrosol actually helps to recover the activity of Δ-5 and -6 desaturase enzymes, which are responsible for chain elongation in the creation of biosynthesis of fatty acids that are anti-inflammatory in nature including: eicosapentaenoic acid (EPA), docasahexaneoic acid (DHA) and arachidonic acid (ARA)[xxiii].

 

Tyrosol

Tyrosol is another phenol found in olives, and though its antioxidant activity is not that strong, it is effective because it has a high degree of intracellular accumulation[xxiv]. It has been shown to inhibit inflammation in a manner that may be beneficial against hypertension, atherosclerosis, coronary heart disease, chronic heart failure, insulin resistance and obesity[xxv]. In streptozotocin-induced diabetic rats, hydroxytyrosol inhibited inflammation in the liver and pancreas[xxvi]. Other than bioavailability work, study of tyrosol in humans is somewhat limited, but animal and in-vitro work seem promising[xxvii].

 

 

References:

[i] Schwingshackl, L.; Christoph, M.; Hoffmann, G. Effects of Olive Oil on Markers of Inflammation and Endothelial Function-A Systematic Review and Meta-Analysis. Nutrients 2015, 7, 7651–7675.

 

[ii] Casas, R.; Sacanella, E.; Urpí-Sardà, M.; Chiva-Blanch, G.; Ros, E.; Martínez-González, M.A.; Covas, M.I.; Salas-Salvadó, J.; Fiol, M.; Arós, F.; et al. The effects of the mediterranean diet on biomarkers of vascular wall inflammation and plaque vulnerability in subjects with high risk for cardiovascular disease. A randomized trial. PLoS ONE 2014, 9, e100084.

 

[iii] Rigacci, S; Stafani, M. Nutraceutical Properties of Olive Oil Polyphenols. An Itinerary from Cultured Cells through Animal Models to Humans. Int. J. Mol. Sci. 2016, 17, 843.

 

[iv] Cicerale, S.; Lucas, L.; Keast, R. Antimicrobial, antioxidant and anti-inflammatory phenolic activites in extra virgin olive oil. Curr. Opin. Biotech. 2012, 23, 129-135.

 

[v] Fabiani, R. Anti-cancer properties of olive oil secoiridoid phenols: A systematic review of in vivo studies. Food Funct. 2016, 7, 4145-4159.

 

[vi] Hassen, I.; Casabianca, H.; Hosni, K. Biological activities of the natural antioxidant oleuropein: Exceeding the expectation – A mini-review. J. Funct. Food 2015,  18, 926-940.

 

[vii] Miles, E.A.; Zoubouli, P.; Calder, P.C. Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures. Nutrition 2005, 21, 389-394.

 

[viii] Dell’Agli, M.; Fagnani, R,; Galli, G.V.; Maschi, O.; Gilardi, F.; Bellosta, S.; Crestani, M.; Bosisio, E.; De Febiani, E.; Caruso, D. Olive Oil Phenols Modulate the Expression of Metalloproteinase0 in THP-1 Cells by Acting on Nuclear Factor-κB Signalling. J. Agric. Food Chem. 2010, 58, 2246-2252.

 

[ix] Giner, E.; Recio, M.; Rios, J.; Giner, R. Oleuropein Protects agains Dextran Sodium Sulfate-Induced Chronic Colitis in Mice. J. Nat. Prod. 2013, 76, 1113-1120.

 

[x] Larussa, T.; Oliverio, M.; Suraci, E.; Greco, M.; Placida, R.; Gervasi, S.; Marasco, R.; Imeneo, M.; Paolino, D.; Tucci, L.; et al. Oleuropein Decreases Cyclooxygenase-2 and Ilterleukin-17 Expression and Attenuates Inflammatory Damage in Colonic Samples from Ulcerative Colitis Patients. Nutrients 2017, 9, 391

 

[xi] De Bock, M.; Derraik, JGB.; Brennan, C.M.; Biggs, J.B.; Morgan, P.E.; Hodginson, S.C.; Hoffman, P.L.; Cutfield, W.S. Olive (olea europaea L.) Leaf Polyphenols Improve Insulin Sensitivity in Middle-Aged Overweight Men: A Randomized, Placebo-Contorlled, Crossover Trial. PLoS One. 2013.  8, 57622.

 

[xii] Lockyer, S; Rowland, I; Spencer, J.P.E; Yaqoob, P.; Stonehouse, W. Impact of a phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: A randomized controlled Trial. Eur. J. Nutr. 2017, 56, 1421-1432.

 

[xiii] Feng, Z.; Li., X.; Lin, J.; Zheng, W.; Hu, Z.; Xuan, J.; Ni, W.; Pan, X. Oleuropein inhibits the IL-1B induced expression of inflammatory mediators by suppressing the activation of NF-kB and MAPKs in human osteoarthritis chondrocytes. Food Funct. 2017, 8, 3737-3744.

 

[xiv] Beauchamp, G.K.; Keast, R.S.J.; Morel, D.; Lin, J.; Pika, J.; Han, Q.; Lee, C.H.; Smith, A.B.; Breslin, P.A.S. Ibuprofen=like activity in extra-virgin olive oil: Phytochemistry. Nature 2005, 437, 45-46

 

[xv] Filipek, A.; Czerwinska, M.E.; Kiss, A.K.; Wrzosek, M.; Naruszeqica, M. Oleacein enhances anti-inflammatory activity of human macrophages by increasing CD163 receptor expression. Phytomedicine 2015,  22, 1255-1261

 

[xvi] Naruszewicz, M.; Czerwinska, M.E.; Kiss, A.K. Oleacein. Translation from Mediterranean Diete to Potential Antiatherosclerotic Drug. Curr. Pharm. Des. 2015 21, 1205-1212

[xvii] Parkinson, L.; Cicerale, S. The Health Benefitting Mechanisms of Virgin Olive Oil Phenolic Compounds. Molecules. 2016, 21, 1734

 

[xviii] Scoditti, E.; Nestola, A.; Massaro, M.; Calabriso, N.; Storelli, C.; De Caterina, R.; Carluccio, M.A. Hydroxytyrosol suppresses MMP-9 and COX-2 actiity and expression in activated human monocytes via PKCα and PKCβ1 inhibition. Atherosclerosis 2014, 232, 17-24

 

[xix] Bigagli, E.; Cinci, L.; Paccosi, S.; Parenti, A.; D’Ambrosio, M.; Luceri, C. Nutritionally relevant concentrations of resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocites and monoctes and the production of pro-inflammtory mediators in LPS-stimulated RAW 264.7 macrophages. Int. Immunopharmacol. 2017, 43, 147-155.

 

[xx] Colica, C., Di Renzo, L., Trombetta, D., Smeriglio, A., Bernardini, S., Cioccoloni, G., . . . De Lorenzo, A. (2017). Antioxidant Effects of a Hydroxytyrosol-Based Pharmaceutical Formulation on Body Composition, Metabolic State, and Gene Expression: A Randomized Double-Blinded, Placebo-Controlled Crossover Trial. Oxid Med Cell Longev, 2017, 2473495.

 

[xxi] Crespo, M. C., Tomé-Carneiro, J., Burgos-Ramos, E., Kohen, V. L., Espinosa, M. I., Herranz, J., & Visioli, F. One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes. Pharmacological research, 2015, 95, 132-137.

 

[xxii] Pirozzi, C.; Lama, A.; Simeoli, R.; Paciello, O.; Pagano, T.B.; Mollica, M.P.; Di Guida, F.; Russo, R.; Magliocca, S.; Canani, R.B.; et al. Hydroxytyrosol prevents metabolic impairment reducing hepatic inflammation and restoring duodenal integrity in a rat model of NAFLD. J. Nutr. Biochem. 2016, 30, 108-115.

 

[xxiii] Lemonakis, N.; Poudyal, H.; Halabalaki M.; Brown, L.; Tsarbopoulos, A.; Skaltsounis, A.; Gicas, E. The LC-MS-based metabolomics of hydroxytyrosol administration in rats reveals amelioration of the metabolic syndrome. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2017, 1041, 45-59.

 

[xxiv] Di Benedetto, R.; Van, R.; Scazzocchio, B.; Filesi, C.; Santangelo, C.; Giovannini, C.; Matarrese, P.; D’ Archivio, M.; Masella, R. Tyrosol, the major extra virgin olive oil compound, restored intracellular antioxidant defences in spite of its weak antioxidative effectiveness. Nutr. Metab. Cardiovasc.Dis. 2007, 17, 535-545.

 

[xxv] Chang, C.Y.; Huang, I.T.; Shih, H. J.; Chang, Y.Y.; Kao, M.C.; Shih, P.C.; Huang, C. J.; Cluster of differentiation 14 and toll-like receptor 4 are involved in th anti-inflammatory effects of tyrosol. J. Funct. Food 2019, 53, 93-104.

 

[xxvi] Chandramohan, R.; Pari, L. Anti-inflammatory effects of tyrosol in streptozotocin-induced diabetic Wistar rats. J. Funct. Food 2016, 27, 17-28

[xxvii] Di Benedetto, R.; Van, R.; Scazzocchio, B.; Filesi, C.; Santangelo, C.; Giovannini, C.; Matarrese, P.; D’ Archivio, M.; Masella, R. Tyrosol, the major extra virgin olive oil compound, restored intracellular antioxidant defences in spite of its weak antioxidative effectiveness. Nutr. Metab. Cardiovasc.Dis. 2007, 17, 535-545.

 

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