Anti-inflammatory Activity of Extra Virgin Olive Oil Polyphenols: Which Role in the Prevention and Treatment of Immune-Mediated Inflammatory Diseases?


Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 18 , Issue 1 , 2018

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Anti-inflammatory Activity of Extra Virgin Olive Oil Polyphenols: Which Role in the Prevention and Treatment of Immune-Mediated Inflammatory Diseases?

Carmela Santangelo, Rosaria Varì, Beatrice Scazzocchio, Patrizia De Sanctis, Claudio Giovannini, Massimo D’Archivio and Roberta Masella*

Istituto Superiore di Sanità, Center for Gender-specific Medicine, Viale Regina Elena 299; 00161Rome, Italy

Abstract: Background and Objective: Altered inflammatory response characterizes chronic immune-mediated inflammatory diseases (IMID) such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis. Accumulating evidence indicates that regular consumption of extra virgin olive oil (EVOO), the main source of fat in the Mediterranean diet, is associated with a reduced risk of developing chronic degenerative disorders such as cardiovascular diseases, type 2 diabetes and cancer. The beneficial effects on health of EVOO have been attributed, besides to the monounsaturated fats content, to the presence of phenolic compounds that have antioxidant, anti-inflammatory and immunomodulatory properties. The purpose of this review is to provide an overview of the effects of EVOO polyphenols on IMID highlighting the potential mechanisms of action.

Methods: Scientific papers were found by searching in PubMed up to May 2017 using the following key words: rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis also in combination with EVOO, phenolic compounds, oleuropein, oleocantal, hydroxytyrosol,tyrosol and oleochantal.

Results: In vitro and in vivo studies indicate that EVOO and its polyphenols can improve diseases symptoms in IMID, by acting both at local and systemic levels and by modulating several molecular pathways. Nevertheless, there are not sufficient data to achieve specific nutritional guidelines.

Conclusion: Further research is needed to evaluate the real contribution of EVOO and its phenolic compounds in modulating the IMID-associated inflammatory perturbations, in order to develop appropriate nutritional recommendations.

Keywords: Anti-inflammatory, antioxidant, extra virgin olive oil, immune-mediated inflammatory diseases, phenolic compounds, EVOO polyphenols.

Article Information

Identifiers and Pagination:

Year: 2018
Volume: 18
Issue: 1
First Page: 36
Last Page: 50
Publisher Id: EMIDDT-18-1-36
DOI: 10.2174/1871530317666171114114321

Article History:

Received Date: July 07, 2017
Revised Date: July 20, 2017
Accepted Date: October 30, 2017

* Address correspondence to this author at the Istituto Superiore di Sanità, Centre for Gender-specific Medicine, Viale Regina Elena 299, 00161 Rome, Italy; Tel: +390649902544; E-mail:


Immune-mediated inflammatory diseases (IMID) affect approximately 5-8% of well-developed industrialized countries and result in increased morbidity and mortality showing differences between sex/gender with greater and worsen effects in women [1, 2]. IMID comprise more than 100 different clinical diseases characterized by exaggerated and altered immune responses, and include inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis [2]. Different IMID affect specific organs such as the gastrointestinal tract in IBD, the synovium in RA, the central nervous system in MS, and the skin in psoriasis. In addition, systemic inflammation and comorbidities (including other IMID) contribute to the burden of the disease [3 - 5]. IMID are heterogeneous disorders resulting from a complex interplay among genetic, epigenetic and environmental factors including diet and obesity [6 - 9]. It is well known that nutrition can help either to preserve good health or, on the contrary, to increase the risk of developing chronic degenerative diseases. Diet influences all of the aspects of human biology by connecting nutrient metabolism, gut microbiota and immune system. The individual response to dietary changes depends on the genetic background, the sex, the immunological context, and the microbial gut communities of the host [10, 11]. Adipose tissue expansion participates to the onset of the obesity-associated low-grade inflammation by secreting a wide variety of soluble inflammatory mediators named adipokines. Adipokines, such as leptin, adiponectin, resistin, visfatin [12], together with immune cell infiltration and activation, contribute to the altered immune regulation found in IMID. Moreover, obesity favors the expansion and activation of the pro-inflammatory T-helper (Th)-17 cells, the hallmark of IMID, [13], thus creating a pro-inflammatory environment that increases the risk of IMID.

The Mediterranean dietary pattern (MD), recognized as Immaterial Human Heritage by the United Nations Education, Scientific & Cultural Organization (UNESCO) [14], is considered as the model of healthy diet [15]. MD helps to preserve human health [16], protects against major chronic degenerative diseases such as cardiovascular diseases (CVD) and cancer, decreases the overall mortality [16], improves metabolic control in type 2 diabetes (T2D) patients [17, 18], prevents alterations in gut microbiota composition (dysbiosis) and the subsequent inflammation [19], reduces obesity rate [20], and exerts long-term anti inflammatory effects [21].

High intake of vegetal food (e.g., vegetables, fruit, cereals, nuts and legumes, extra virgin olive oil), moderate intakes of fish, poultry meat and dairy products, characterize MD [22]. EVOO is considered to be one of the main responsible for the health benefits of MD [23]. Indeed, it exerts potent antioxidant, anti-inflammatory and immunomodulatory activities most likely due to the content of phenolic compounds [24 - 26]. The demonstration that EVOO phenolic compounds after the ingestion are absorbed, metabolized and distributed by the blood stream throughout the body, also crossing the blood brain barrier [27], makes these compounds potential useful agents in modulating local and systemic inflammatory environment in IMID.

The purpose of this review is to give a picture of how EVOO polyphenols can modulate the pathophysiological mechanisms involved in IMID in order to advance in the comprehension of the beneficial effects of EVOO on human health. All of the data discussed were found by searching PubMed articles in English published up to May 2017.


2.1. EVOO Polyphenols

The growing interest on the relationship between EVOO and human health is demonstrated by the increasing number of published studies aimed at dissecting EVOO mechanisms of action [24, 25, 28 - 32]. EVOO, besides high level of monounsaturated fatty acids, especially oleic acid [33, 34], contains a minor fraction mainly constituted of a complex mixture of polyphenols that is responsible for EVOO oxidative stability and sensorial attributes [35, 36]. These compounds are well known to exert antioxidant, anti-inflammatory, insulin-sensitizing, cardioprotective, anti-atherogenic, neuroprotective, immunomodulatory and anticancer activities [37 - 46].

The most represented phenolic molecules in EVOO are secoiridoids, such as oleuropein, ligstroside, and oleocanthal, and their derivatives phenolic alcohols, such as hydroxytyrosol (HT) and tyrosol, accounting for ~90% of the total phenols. The remaining 10% of the mixture is mainly constituted by flavonoids and lignans [37, 47]. It is worth to note that a remarkable amount of polyphenols has been found in different olive-derived matrices (i.e., paste, pomace, aqueous extract) [48] that contain flavonoids as luteolin-7-glucoside and rutin, [49, 50]. Olive leaves contains HT, luteolin-7-glucoside, apigenin-7-glucoside [51, 52], and a relevant amount of oleuropein (1-14%), much more than olive oil (0.005% - 0.12%) [53].

Phenolic concentration in EVOO (range 50-800 mg/kg) depends on several variables, namely, olive cultivar, ripening stage of fruit, environmental factors (altitude, cultivation practices, and amount of irrigation), extraction conditions (heating, added water, extraction systems used to separate oil from olive pastes) and storage conditions, due to spontaneous oxidation, and suspended particle deposition [54 - 56]. EVOO intake for Mediterranean populations is reported to be 30–50 g/day, with ingested olive oil phenols in the range of 4-9 mg/day [57].

However, the contribution of these compounds to human health is the result of several factors including the concentration and composition, the extent of absorption and metabolism, and the bioavailability in target tissues of EVOO phenolics [38, 58 - 60]. In addition, further variables need to be taken into consideration when investigating the health benefits of such components in humans. In particular, they should be considered sex/gender-driven responses to EVOO intake [61], and gut microbiota variation that, besides to greatly vary between individuals, may, in turn, be modified by phenolics [19, 62]. Finally, the synergistic effects among EVOO phenolics and those ones contained in other food should be taken in account.

Nevertheless, the useful effects of polyphenols in olive oil has been recognized by the American Food and Drugs Administration [63] and by the European Food Safety Authority. This latter recommends a daily consumption of 5 mg of HT and its derivatives (20 g EVOO daily = two tablespoons) to prevent the onset of CVD and inflammation, and to counteract oxidative stress caused by free radicals [64].

2.2. Immuno-inflammatory Network in IMID

Altered inflammatory and autoimmune responses, principally mediated by T lymphocytes and involving antigen presenting cells [(APCs): dendritic cells, monocyte/macro- phages, B cells], are the hallmarks of IMID [65]. The balance between pro- and anti-inflammatory mechanisms is critical for immune homeostasis. Antigens, cytokines and costimulatory molecules drive differentiation of naïve CD4+T cell into specific lineages including Th1 [interferon (IFN)-γ, interleukin (IL)-2], Th2 (IL-4, IL-5, IL-6, IL-10), Th17 (IL-17, IL-21, IL-22), and regulatory T cells (Treg); IL-10, IL-35, transforming growth factor (TGF)-β that coordinate tissue inflammation. APCs secrete a number of cytokines, including IL-12, IL-23, IL-27, IL-35, that participate in IMID expression. Actually, the pro-inflammatory cytokines IL-12 and IL-23 promote Th1 and Th17 activation. IL-27 appears to possess both pro-inflammatory (Th1 promotion) and anti-inflammatory activity (Th17 inhibition), and IL-35, secreted by Treg as well, suppresses Th-17 differentiation and function [66]. The imbalance in Th1/Th2 as well as in Treg/Th-17 contribute to the pathogenesis and progression of IMID.

The cytokine environment influences the activation of naïve T cells. TGF-β is required for both Th-17 and Treg differentiation. On the other hand, the balance between IL-6/inflammatory cytokines and TGF-β will decide the direction of differentiation towards Th-17 or Treg lineages, respectively [67]. The modifications above described associate also with changes in the i) expression of pro-inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, ii) altered activation of kinase cascade including the mitogen-activated protein kinase/extracellular-signal-regulated kinases (MAPKs/ERKs), c-Jun N-terminal kinases (JNK), and iii) dysregulations of the nuclear transcription factor kappa B (NF-κB), the Janus kinase/signal transducer and activator of transcription (JAK/STAT), and the nuclear factor E2-related factor 2 (Nrf2), that amplify the altered immune response in IMID [68, 69].

These pathways are illustrated in Fig. (1).

Fig. (1). Schematic representation of the potential action of EVOO polyphenols on immune mediate inflammatory diseases. Dysregulation of T cells lineages and APC functions, dysfunction of adipose tissue, and alteration in gut microbiota composition constitute the trait that join SLE, RA, MS, IBD and psoriasis. EVOO and its phenolic compounds positively influence the expression of pro- and anti-inflammatory mediators involved in the immune-mediated processes in IMID by modulating specific signaling molecules such as JAK/ STATs, ERK/MAPKs, JNK and AKT pathways, and by activating or inhibiting related transcription factors, including Nrf2, NFκB, STATs, TFs. Abbreviations: APCs: antigen presenting cells; COX-2: cyclooxygenase-2; EVOO: extra virgin olive oil; GPx: glutathione peroxidase; GR: glutathione reductase; GST: glutathione S-transferase; GSH: glutathione; IBD: inflammatory bowel disease; IL-10:, interleukin-10; IMID: immune mediated inflammatory diseases; iNOS: nitric oxide synthase; JAK STAT: c-Jun N-terminal kinases/signal transducer and activator of transcription; MMPs: metalloproteinases; MS: multiple sclerosis; Nrf2: nuclear factor E2-related factor 2; NF-κB nuclear transcription factor kappa B; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; TF: transcription factors; TGF-β: transforming growth factor β.

Over the last years, restoring the correct immune homeostasis by targeting specific cytokines and their downstream signaling molecules has gained attention as therapeutic approach in the management of these inflammatory disorders [70 - 72]. However, the absence of benefits and the presence of adverse effects observed in some patients, along with the absence of information on long-term effects [72, 73], indicate that the inhibitory strategies need further evaluation and that new non-pharmacological approaches have to be taken into consideration.

2.3. EVOO Polyphenol Interactions

The capability of EVOO polyphenols to exert several biological activities and to modulate many signaling pathways [24, 39], has made them worthy of consideration as useful agents in the management of IMID (Table 1).

Table 1. Effects of EVOO and its compounds on immune-mediated inflammatory diseases.

Compounds Experimental Model Outcomes References
Rheumatoid Arthritis
Human studies
EVOO (topic application 1gr, 3 times/day) for 4 weeks
EVOO (topical application 10gr) for 12 sessions
Fish oil / EVOO (3gr/9,6ml) for 24 weeks
Osteoarthritis female patients
Phonophoresis on kleen pain female athletes
RA patients
↓ Pain intensity, disease improvement
↓ Pain, improves physical functions
↓ Joint pain intensity, ameliorates clinical and laboratory parameters of disease, ↓ rheumatoid factor
Animal studies
Bilayer film containing HT 7,8 mg/cm2 (topical application 16h daily for 16 days)
Olive oil rich in HT (10mg/Kg) for 10 days
EVOO-PE (100 or 200mg/Kg) for 12 days
HT-Acetate (0.05% diet) or EVOO rich in polyphenols (600ppm) pretreatment for 6 weeks

HT (5mg/Kg/day) for 12 days
Oleuropein aglycone (40µg/Kg) for 10 days
Adjuvant-induced arthritis in rat
Carrageenan treated-mice
CIA mice
CIA mice

CIA rats
CIA mice
↓ Inflammatory symptoms and synovitis, ↓ IL-6 serum levels
Restores IL-10 depletion in paws
↓ Join edema; ↓ IL-1, IL-6, TNFα, PGE2, COX-2 and the phosphorylation of JNK, p38MAPK, STAT3, NFκB in knee joint section
Delays arthritis onset; ↓ arthritis severity and plasma MMP-3 levels; ↓ TNFα, IL-1β, IFNγ, IL-6, IL-17, COX-2, PGE-1 and phosphorylation of STAT3, JNK, p38, ERK, NFκB in hind paws homogenates; ↑ Nrf2, HO1
↓ Severity of RA; ↓ COX-2 and iNOS expression in knee joints and serum TNFα levels
↓ Joints inflammation; ↓ COX-2, iNOS expression and leucocytes infiltration; ↓ TNFα, IL-1β and IL-6 plasma levels
[80, 115]
In vitro studies
Oleuropein (pretreatment 1-200µM for 24h)
Oleocanthal (pretreatment 15µM for 12h)
Human synovial sarcoma cell line (SW982), IL1β-induced
ATDC5, murine LPS-treated chondrocytes
MAPK, NFκB, IL-6, TNFα, MMP-1, MMP-3,
COX-2 and phosphorylation of JNK, p38, ERK; ↑ Nrf2, HO-1
↓ IL-6, MIP-1α mRNA and protein expression
Inflammatory Bowel Disease
Human studies
EVOO (500mg/Kg phenolics, 25ml/day)
for 3 weeks
EVOO and thyme (1:1) (500mg/Kg phenolics, 25ml/day) for 3 weeks
Hypercholesterolemic patients
Hypercholesterolemic patients
↓ Mucosal immunity, IgA-coated bacteria
↓ oxLDL
Animal studies
Oleuropein (500mg/Kg/day) for 8 weeks
Oleuropein (100mg/Kg/day) for 9 weeks

Diet rich in fish oil + EVOO for
8 weeks before colitis induction
EVOO (100g/kg of diet) and EVOO+HT (40mg/kg diet) for 30 days before colitis induction
DSS-induced colitis mice
DSS-induced colitis mice

DSS-induced colitis rats
DSS-induced colitis mice
↓ Inflammatory symptoms; ↓ cell infiltration, IL-6,
IL-1β, COX-2, iNOS expression and phosphorylation of p38MAPK in colon tissue; ↓ IL-10
Ameliorates colitis; ↓ IL-6, IFNγ, TNFα, IL-17,
↓ COX-2, and STAT3, NFκB, Akt activation and percentage of CD4 Rorγt in colon tissue
COX-2, IL-1β, TNFα, IL-6, IL-8, iNOS expression in colon tissue
Ameliorates damage, ↑ IL-10, ↓ COX-2, iNOS and p38MAPK in colon tissue

In vitro studies
HT + oleic acid
(preincubation 200µM+200µM for 5h)
EVOO-PE (pretreatment 400-500mg/kg/phenolics for 1h)
Oleuropein (3mM for 20h)
tBHT-treated Caco2
LPS-treated Caco2
LPS-stimulated colonic mucosa from ulcerative colitis patients
Restores GSH depletion, ↓ IL-8 synthesis
↓ IL-8 mRNA expression and secretion by modulating NFκB and p38MAPK
↓ COX-2 and IL-17 expression and secretion and leucocyte infiltration
Multiple sclerosis
Animal studies
Olive oil polyphenols
HT (pretreatment 10-50 mg/kg/day)
for 2 weeks
Animal models
Animal models
Prenatal stress-model in rat
Neuroprotective effects by modulating NGF and BDNF
Neuroprotection by regulating Nfr2,GSH-related enzymes, Akt, JNK and ERK1/2
Improves cognitive function in offspring; restores BDNF expression, mitochondrial copy number,
SOD-2 and HO-1 expression by activating Nfr2,
FOX-1 and FOX-3 in hippocampus
In vitro studies
Tyrosol (100µM),
and oleic acid (100µM)
pretreatment for 24h
Human glioblastoma cell line
U-87MG treated with TNFα
↓ COX-2 expression and PGE2 secretion; ↓ ERK, NFκB, JNK activation [161]
Systemic Lupus Erythematosus
Animal studies
EVOO rich in phenolics
(600ppm) for 6 months
Pristine-induced SLE
in mice
↓ Serum MMP-3; ameliorates renal damage and ↓ PGE2 expression; ↑ Nrf2 and HO-1; modulates JAK/STAT, MAPK and NFκB pathways; IL-6, IL-10, IL-17, TNFα in LPS-stimulated splenocytes [69]
In vitro studies
EVOO-PE (1-10µg/ml) for 24h
PBMC PHA-stimulated
from SLE patients
↓ T cell activation, ↓ IFNγ, TNFα, IL-6, IL-10
secretion by modulating NFκB and ERK activation
Human studies
Diet rich in EVOO
Herbal preparation containing high % of olive oil, (local application twice-daily) for 12 weeks
Psoriatic vs health subjects
Patients with skin psoriasis
Inverse association of disease severity and CPR levels with EVOO consumption
Strong improvement of psoriasis signs
Animal studies
(topic application 0,1-4,4 mM) for 5 days
IMQ-induced psoriasis
in mice
Regulates hyper proliferative processes; improves skin damage by ↓ STAT3 activation [201]
In vitro studies
(20µM for 24h)
Human keratinocytes
treated with IL-22
↓ Hyper proliferation and PGE2 expression; blocks nuclear translocation of activated STAT3 [201]

↓ decreases; ↑ increases;

Abbreviations: BDNF: brain-derived neurotrophic factor; CIA: collagen-induced arthritis; COX-2: cyclooxygenase-2; CPR: c-reactive protein; DSS: dextran sulfate sodium; EVOO: extra virgin olive oil; GSH: glutathione; HT: hydroxytyrosol; IMQ: imiquimod: iNOS: nitric oxide synthase; JNK: Jun N-terminal kinases; LPS: lipopolysaccharides; MIP-1α: macrophage inflammatory protein 1 alpha; MMPs: metalloproteinases; NF-κB: nuclear transcription factor kappa B; NGF: nerve growth factor; Nrf2: nuclear factor E2-related factor 2; OH-1: heme oxygenase; ox-LDL: oxidized low-density lipoprotein; PBMC: peripheral blood mononuclear cell; PE: phenolic extract; PGE2: Prostaglandin E2; PHA: phytohemagglutinin; STAT-3: signal transducer and activator of transcription-3; tBTH; t-butyl hydroperoxide.

In this regard, several in vivo studies have shown that EVOO and its polyphenols influence the expression of pro- and anti-inflammatory mediators as well as their downstream molecules in different tissues providing additional evidence of their nutrigenomic effects.

Specifically, EVOO ingestion has been shown to decrease the levels of inflammatory markers such as IL-6 [74], visfatin [18], tumor necrosis factor (TNF)-α, IL-1β, COX-2 [75] in plasma, IFN-γ in plasma and in the epididymal adipose tissue [76], TNF-α, IL-6, and IL-17, in splenocytes [69], and IL-1, IL-3, IL-8, COX-2 in peripheral blood mononuclear cells (PBMCs) [77, 78]. The beneficial effects of EVOO intake also consist in improving the anti-inflammatory and antioxidant defenses by increasing the expression of the anti-inflammatory cytokines such as IL-10 [75], the activity of the antioxidant enzyme glutathione peroxidase (GPx) [79], and by upregulating the antioxidant transcription factor Nrf2 [80].

Similar results have been observed with dietary supplementation of single EVOO polyphenol such as oleuropein and its derivative HT [39, 81 - 83], tyrosol [84], and oleocanthal [85]. In particular, the intake of oleuropein, commercially available as food supplement in Mediterranean countries [82, 86], reduces the expression of TNF-α, IL-1β, COX-2, iNOS [87], and matrix metalloproteinase (MMP)-2, MMP-9, MMP-13 expression [88]. HT supplementation decreases TNF-α, IL-6 and COX-2 [89], and increases IL-10 levels [90]. Tyrosol diminishes TNF-α, IL-6 and IL-1β secretion [84] whereas oleocanthal attenuates IL-1β levels [91].

Increasing number of in vitro studies have been clarifying the molecular mechanisms of EVOO to influence the immune-inflammatory response. Most of the cross-interacting signaling pathways activated in IMID appear to be modulate by EVOO polyphenols [77, 92]. The reduced expression of pro-inflammatory mediators induced by EVOO polyphenols might be related to the inhibition of NF-κB and p38MAPK [50, 84, 93], JNK [94], ERK1/2 [95], STAT3 and MAPKs [69]. On the other hand, the ability of HT, tyrosol, oleuropein, and other EVOO polyphenols to preserve the endogenous defense systems by increasing the intracellular GSH content, the antioxidant/ detoxify enzymes GPx, glutathione reductase, glutathione S-transferase, and γ-glutamylcysteine synthetase, might depend on the activation of Akt, ERK, and Nrf2 induced by EVOO polyphenols [45, 92, 96 - 98].

Unfortunately, very few studies have investigated the capability of EVOO polyphenols in modulating Th17 and IL-17 that have a key role in IMID.


Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by local and systemic inflammation that lead to join damage, and destruction of bone and cartilage with progressive loss of function [99]. RA is a multistep and complex process that leads to immune-inflammation by involving innate and adaptive immune cells as well as resident cells including osteoclasts, fibroblast-like synoviocytes and chondrocytes. In addition, autoantibodies are produced such as rheumatoid factor and anti-citrullinated peptide antibodies [100]. Altered balance among different T cells types and dysregulated expression of cytokines they produce [101 - 104], as well as alterations in gastrointestinal microbiota [105] have been found in RA subjects. The resulting inflammatory environment, most likely due to the activation of inflammatory signal transduction pathways, contributes to RA progression [106]. Most of the above mentioned players represent therapeutic targets for biological inhibitors that have been developed to ameliorate the prognosis of RA [101]. In addition, the increased risk of developing gender-specific comorbidities, such as CVD [4] and diabetes in men [107], and depression, osteoporosis and hypothyroidism in women [107, 108], has to be taken into account in planning therapeutic approaches in RA patients.

Moreover, a positive association between obesity and increased risk of developing RA has been reported. In this regard, men with abdominal obesity are at greater risk compared with women [109]. As oxidative stress participates in the join destruction [110], a diet (Table 1) rich in dietary polyphenols [111], may represent a useful tool for counteracting oxidative stress and inflammation in RA patients [112, 113].

Rosillo and colleagues have deeply investigated the effects of EVOO phenolic compounds in RA. In collagen-induced RA mice (male DBA-1/J) they found that dietary EVOO [80], EVOO-polyphenol extract (100-200 mg/kg, for 12 days) [114], and HT-acetate (0.05% diet for 6 weeks) [115] ingestion reduce joint edema and cartilage destruction. These effects are associated with reduced expression of inflammatory cytokines such as TNF-α, IL-1β, IL-17, and the related transduction signaling molecules JNK/STAT, MAPK and NF-κB, along with increased expression of the transcription factor Nrf2. Further studies have also observed that administration of HT-enriched EVOO (5 mg/kg/day, for 12 days) improves articular function, and, at the same time, downregulates COX-2 and iNOS expression in the knee joints [116]. Furthermore, the ingestion of olive oil rich in HT (10 mg/kg, for 10 days), extracted from olive pomace, increases IL-10 expression in the paws [90] in RA animal models.

Similarly, oleuropein aglycone (40µg/kg, for 10 days) ameliorates arthritis symptoms and reduces TNF-α, IL-1β, and IL-6 plasma levels and leukocyte infiltration in the affected joints, in collagen-induced RA mice [117]. In vitro studies have shown that oleuropein (1-200 µM for 24h) decreases IL-6, TNF-α, MMP-1, MMP-3 and COX-2 overexpression in human synovial sarcoma cell line [118], whereas (-)-oleocanthal (15 µM for 12h) inhibits macrophage inflammatory protein-1α, and IL-6 expression in ATDC5 chondrocytes [119].

Interestingly, Bohlooli and colleagues have observed that EVOO has beneficial effects on RA also following topical application (EVOO 1 gr, 3 times/day; 4 weeks) [120]. In a double blinded clinical trial they have observed that short-term phonophoresis with EVOO (10 gr; 12 sessions) reduces pain and improves physical function faster than piroxicam gel, in female athletes' anterior knees. These findings indicate that anti-inflammatory compounds contained in EVOO can be responsible for these beneficial effects [121]. More specifically, it has been developed a bilayer film containing high amount of HT (7,8 mg/cm2) that, by topical application in a RA rat model (16 h daily for 16 days), improves inflammatory symptoms, including the decrease in serum IL-6 levels [122].

However, EVOO acts in synergistic manner along with other components of MD. In this regard, in patients with RA a daily combination of fish oil (3 gr), rich in omega 3 fatty acids, and EVOO (9,6 ml), for 24 weeks, appears to be more effective in ameliorating symptoms compared to that of fish oil alone [123]. In addition, a diet supplemented with EVOO reduces inflammation and preserves articulation and the entire join, with a greater effect achieved in combination with physical activity [124].

In the end, all of the data collected show the broad range of activities of EVOO that can be useful in developing therapeutic approaches to prevent and reduce RA symptoms.


The inflammatory bowel diseases (IBD), e.g., ulcerative colitis and Crohn's disease, are chronic relapsing disorders of unknown etiology that affect the intestinal tract, resulting from dysregulated interplay among host genetics, immune system and gut microbiota [125]. A number of factors appear to be responsible for both local and systemic inflammation involved in the origin and progression of IBD. These factors include increased levels of inflammatory cytokines (e.g., IL-6, IL-8, IL-1β, IL-17, TNF-α, IL-12 family), and increased local infiltration of innate and adaptive immune cells that lead to an inappropriate immune response [68, 126, 127]. Targeting specific inflammatory cytokine pathways represents a promising and on-going approach to manage IBD, even though several side effects as well as short clinical remission and disease-relapse need to be taken into account [128, 129].

The association between diet and IBD has been suggested (Table 1). Dietary polyphenols appear to positively modulate local and systemic inflammation in IBD, as well as oxidative stress, by regulating transcription signaling pathways, such as NF-κB, JAK-STATs, MAPK-ERK, and Nrf2 [68] Specifically, polyphenols contained in fruit, vegetables and EVOO appear to possess protective and therapeutic effect in IBD management [130]. Furthermore, dietary habits deeply influence the composition of gut microbiota which plays many roles including the regulation of the host’s metabolism [131].

Adherence to MD favors a healthy intestinal microbiota and prevents bowel alterations [19, 132]. EVOO polyphenols actively participate to MD effects by influencing gut microbial population and host metabolism [25, 62]. In this regard, it has been observed that the ingestion of high polyphenol content-EVOO (500 mg/kg of phenolic compounds/kg, 25 ml/day for 3 weeks) increases the proportion of intestinal IgA-coated bacteria [133]. Another study carried out in hypercholesterolemic subjects consuming a mixture of phenol-rich olive oil and thyme polyphenols (500 mg/kg phenolics, 25 ml/day for 3 weeks), showed the increase in bifidobacteria in association with higher levels of polyphenol metabolites showing antioxidant activity. These findings also highlight that the presence of thyme polyphenols enhances the immune stimulatory action of EVOO phenolic compounds [26].

Synergistic effects of different EVOO polyphenols have been observed both in in vivo and in vitro studies. In a dextran sodium sulfate colitis rat model, diet enriched with EVOO (100 g/kg of diet) improves clinical and histological symptoms, increases IL-10 levels and reduces COX-2, iNOS and p38 MAPK activities. Worth of note, EVOO enriched with HT (40 mg/kg of diet) amplified the above described effects [134]. Moreover, in the same rat colitis model, the combined treatment with EVOO, oleic acid and omega 3 fatty acids attenuates colon tissue damages characterized by increased levels of TNF-α, IL-1β, IL-6, IL-8, COX-2, iNOS. Finally, a combination of omega 3 fatty acids and HT (200 µM: 200 µM for 5h), restores GSH depletion and reduces IL-8 overexpression in t-butyl hydroperoxide-treated Caco2 cells [135]. A similar anti-inflammatory environment can also be favored by oleuropein (500 mg/kg/day for 8 weeks) in a colitis mouse model. This treatment is capable to ameliorate inflammatory symptoms, to increase plasma levels of IL-10 and to reduce CD4+RORγt+ T cells, and IL-17A and IFN-γ [136] levels in colonic tissue. These effects occur, most likely, through the reduced activation of NF-κB, phosphatidylinositol-3-kinase (P3IK)/Akt, and STAT3 after 9-week supplementation with 100 mg/kg/day oleuropein [137]. Oleuropein (3 mM for 20h) attenuates inflammatory damages also in human ulcerative colitis by reducing COX-2 and IL-17 expression, in lipopolysaccharide (LPS)-stimulated colonic biopsies [138]. These results strengthen the potential protective role of this phenol in modulating the intestinal immune response.

A deeper investigation has shown that EVOO phenolic extract (PE) (phenolic content 400-500 mg/kg) inhibits the LPS-induced IL-8 secretion and expression, by modulating NF-κB signaling and p38 MAPK pathway in Caco-2 cells, indicating that polyphenols may act at both transcriptional and posttranscriptional levels [139].

However, increasing evidence indicates that the susceptibility to intestinal inflammatory diseases is established in the early life. According to the Barker’s theory of “fetal origin of adult disease” [140] the perinatal nutritional environment, through changes in intestinal microbiota and epigenetic modifications in the offspring, influences the development of the gastrointestinal tract as well as the susceptibility to diseases later in life [141].


Multiple sclerosis (MS) is a chronic T-cell mediated autoimmune disease of the central nervous system characterized by myelin destruction and neuron damages. It is an inflammatory disease caused by the interaction between genetic and environmental risk factors with relapsing-remitting or progressive course [142]. The complex heterogeneity of this disorder rends the current therapeutic approaches not effective in providing long term effects.

Several players are involved in MS pathogenesis including glial cells, neurons, B cells and different T cell lineages (Th1, Th2, Th17 and Treg) whose dysregulated functions (i.e., altered cytokines levels) contribute to disease symptoms. Th17 cells appear to have a significant role in MS since they cross the blood-brain barrier initiating inflammatory cascades in the central nervous system that lead to neuroaxonal damage [143, 144]. Beside the heterogeneity of the disease, comorbidities including depression, hypertension, hyperlipidemia, and chronic lung disease [145] represent a great concern in the therapeutic management of the MS [146]. It should be also considered that the current therapeutic approaches, including immunomodulators, immunosuppressants, and biologics, do not produce satisfactory results in terms of long-term preventing relapses and disabilities [147]. Moreover, accumulating evidence indicates that obesity, characterized by a chronic, low-grade inflammation, represents a relevant risk factor for MS [5]. Indeed, dysregulated adipocytokine secretion characterizing obesity, such as elevated plasma levels of leptin, visfatin, resistin, chemerin and low level of adiponectin, have been found in patients with MS [148]. Moreover, changes in the intestinal microbiota, that is involved in the systemic immunity, have been observed in MS subjects with respect to healthy subjects, and most likely contribute to the neuro-inflammatory processes [149]. Nutrition seems to participate either in exacerbation or amelioration of MS symptoms [150, 151], also by influencing intestinal microbiota [150]. A link between brain and gut does exist, and between gut and MS as well [152]. Although no specific nutritional recommendations are established so far for MS, healthy dietary habits may contribute to the well-being of MS subjects [153]. Adherence to MD (Table 1) associates with reduced onset of MS. In particular, fruit and vegetables consumption is inversely associated with MS risk, as observed in a hospital-based case-control study in Teheran, thus suggesting the positive effects of MD in MS prevention and treatment [154]. Similarly, an Italian pilot study showed that a calorie-restricted, semi-vegetarian diet based on MD principles, results in the improvement of the chronic inflammatory status that characterizes MS patients. Specifically, this dietary regimen determined both an increase in omega 3/omega 6 fatty acids ratio and a reduction in MMP-9 active levels in serum of MS subjects [155]. Dietary polyphenols exert neuroprotective functions by modulating immune response and several inflammatory and metabolic signaling pathways including peroxisome proliferator-activated receptors, Nrf2, STATs, and MAPK [156]. In addition, they can affect the expression of numerous genes encoding pro-survival proteins, including antioxidant enzymes, neurotrophic, and anti-apoptotic factors [157, 158]. Finally, polyphenols are able to enhance neuronal survival by acting on ERK, and PI3K/Akt pathways [159]. EVOO polyphenols, beside the well-known anti-inflammatory and antioxidant activities, can act as neurotrophin modulators by regulating levels and activities of the signaling neurotrophins [e.g., nerve growth factor and brain derived neurotrophic factor (BDNF)] that are impaired in neurodegenerative diseases [28]. In this regard, it has been observed that HT administration (10 and 50 mg/kg/day for 2 weeks) during pregnancy ameliorates cognitive function and neurogenesis, in rats exposed to restraint stress. Specifically, in offspring’s hippocampus, HT increases the expression of Nrf2 and Nrf2 target gene heme oxygenase 1 (HO-1), as well as the mitochondrial content and neuronal markers as BDNF [160].

HT, tyrosol, and oleuropein might contribute to MD neuroprotective effects through the activation of the antioxidant Nrf2 pathway, that promotes the expression of phase II enzymes preserving GSH levels, and by reverting the dysregulation of signaling pathways such as ERK-MAPK/RSK2, PI3K/Akt1, NF-κB and JAK2/STAT3, as it has been observed in several in vitro studies [29, 158, 161].


Systemic lupus erythematosus is a complex autoimmune disease, predominant in females, with an extremely diversified symptomatology and multi-organ involvement [72, 162]. In the etiopathogenesis of SLE genetic, epigenetic and environmental factors, including nutrition and infection, concur [163]. Altered B cells functions, imbalance of T cell subsets, dysregulation of cytokines as well as of various signaling pathways such as JAK/STATs and NF-κB appear to be involved in the heterogeneous clinical manifestations of SLE [72, 164, 165]. Also gut microbiota modifications contribute to altered Th17 response in SLE [166]. Several comorbidities associate with SLE including CVD, T2D and increased cancer risk [167], as well as a greater possibility to develop other IMID such as IBD [168] and endometriosis [169].

The unknown etiology of SLE makes hard to develop therapeutic strategies aimed at fighting this multifaceted disorder [72]. However, recently biological drugs have gained more attention than conventional drugs in the SLE treatment [170]. Targeting specific cytokines (e.g., IL-6, IL-17, IL-23, and IFN-γ) and downstream regulatory molecules (JAK/STAT pathways), reducing circulating B cells and autoantibody titers [72, 170, 171] as well as modulating IL-27 [172] and IL-35 [173] appear to be interesting therapeutic routes to hinder SLE.

Several studies have shown that nutritional deficiency and/or malnutrition impair immune functions and influence autoimmune diseases [174]. An adequate nutrition in SLE patients is fundamental for both counteracting disease symptoms and reducing the risk of developing comorbidities [175]. In fact, dietary nutrients appear to modify the clinical course of disease in female patients [176]. In this activity the interaction between intestinal microbiota and host seems to have a pivotal role through cellular and molecular mechanisms that are not well known yet [177].

EVOO, in virtue of the anti-inflammatory and antioxidative effects, could alleviate SLE symptoms (Table 1). To this end, Aparicio-Soto and colleagues have evaluated the effects of EVOO [69] and its phenolic extract (PE) [178] on a mouse model of SLE, and on PBMCs from inactive SLE patients, respectively.

Specifically, in a pristane-induced SLE model in mice, 6-month EVOO diet (600 ppm) ameliorates renal damage. Indeed, EVOO reduces serum level of MMP-3, downregulates HO-1 expression via Nrf2 activation, and reduces NF-κB, STAT3 and MAPK activation in kidney. In addition, in the same mouse model, dietary EVOO reduces TNF-α, IL-6, IL-10 and IL-17 levels in LPS-stimulated splenocytes [69].

Results obtained with PBMC provide further evidence on the immunomodulatory role of EVOO polyphenols in humans. Authors demonstrated that PBMCs stimulated with phytohemaglutinin and incubated for 24 h with PE (1-10µM), show a decreased activation of T cells, reduced secretion of IFN-γ, TNF-α, IL-6 and IL-10 together with a reduced activation of NF-κB and ERK. Worth of note, the observation that PE reduces IL-10 in SLE patients and increased IL-10 levels in healthy subjects highlights the potent ability of phenolic compounds to regulate IL-10 deregulation [178]. Interestingly, the daily administration of 12 green olive tablets for 30 days is able to significantly reduce oxidative stress and IL-6 levels in healthy subjects [179] indicating that green olive tablets ingestion could counteract cytokine dysregulation, including IL-6 upregulation, whose levels have been found higher in SLE patients several years before autoantibodies comparison [180].


Psoriasis is a chronic inflammatory immune-mediated skin disease. Genetic and environmental factors contribute to its pathogenesis, and, among the latter, nutrition appears to have a major role [181]. In the pathogenesis and progression of psoriasis participate Th cells, APCs, and natural killer cells that, by altered secretion of immune regulatory cytokines, are responsible for the systemic and local inflammation responsible for the altered proliferation and differentiation of keratinocytes [182, 183]. Th17 cells play a crucial role in psoriasis; the expression and production of IL-17, is increased in psoriatic skin lesions [184] and in the peripheral circulation [185]. Gut dysbiosis found in patients with psoriasis [186] participates to the enhanced Th17 response [187]. Moreover, reduced levels of IL-27 and its receptor IL-27R have been found in psoriatic lesions with concomitant reduced plasma IL-27 and IL-10 expressions [182]. Of note, treatment with IL-27 significantly reduced psoriatic lesions and serum IL-17 levels, in a imiquimod (IMQ)-induced psoriasis mouse model [182], indicating the importance of the correct balance between pro- and anti-inflammatory molecules in counteracting IMID and psoriasis as well.

Psoriasis management represent a great concern because the results obtained with current therapeutic treatments, i.e., conventional systemic therapies and biological agents targeting IL-17, IL-23, TNF-α, and JAK, are not particularly satisfying [188, 189]. In addition, patients are at increased risk of developing comorbidities including other IMID such as psoriatic arthritis [186], SLE [190], IBD [191], and metabolic disorders such as obesity, T2D, hypertension, and metabolic syndrome [192].

Increased fat accumulation increases the risk of developing psoriasis whereas weight loss improves psoriasis severity [193]. In addition, elevated levels of the adipokines visfatin, leptin and TNF-α in the serum of psoriatic subjects associate with disease severity [194]. Finally, a good adherence to MD (Table 1), that associates with low risk of obesity and metabolic and inflammatory diseases [195, 196], might ameliorate psoriasis symptoms and progression.

Further evidence of these effects was provided by a recent cross-sectional case-control observational study that highlighted an inverse association between psoriasis severity and the degree of adherence to MD [197]. Specifically, the authors observed that a high consumption of EVOO associates with lower C-reactive protein levels in the control group compared with psoriatic patients [197]. Although there are no national and international nutritional guidelines for psoriatic patients [198], promoting the adoption of a healthy dietary pattern that improves nutrition-related risk factors can be helpful in the management of this disorder [181].

Topical medications aimed at counteracting local inflammation and keratinocytes hyper- proliferation are part of the psoriasis therapies. It has been observed that the daily application on skin lesions for 12 weeks of a cream containing plant based extracts, including olive oil and black cumin oil, strongly improves psoriatic signs. The anti-inflammatory and reactive oxygen species scavenging activities of all the components of the cream can explain the beneficial effects [199].

Luteolin-7-glucoside (LUT-7G), a flavonoid present in olives and their derivatives such as paste, pomace and wastewater, appears to have a promising role [200]. Specifically, topical application of LUT-7G (0,1-4,4 mM for 5 days) modifies cell cycle regulation towards keratinocyte differentiation, in IMQ-induced psoriasis mouse model. Moreover, investigation on the molecular mechanisms has shown that LUT-7G (20 µM for 24h) counteracts the pro-inflammatory and proliferative effect of IL-22 and IL-6 by blocking the nuclear translocation of activated STAT3 in human keratinocytes [201].


Dietary components, such as EVOO that represents a fundamental component of MD, are major regulators of the complex network of mechanisms responsible for body homeostasis maintenance. Disturbance of nutrient metabolism, genetic and epigenetics factors, and immune system dysregulation, observed in IMID seem to be counteracted, to some extent, by EVOO and its polyphenols.

Even though both in vivo and in vitro studies have shown that EVOO, by acting at local and systemic levels, ameliorates disease symptoms in IMID, there are not sufficient data to achieve specific nutritional guidelines.

Because it is widely accepted that EVOO and its components have health promoting properties, appropriate clinical and epidemiological studies are necessary to evaluate the real contribution of this nutrients on IMID management. To achieve this objective some activities are required: i) measurement and quantification of biomarkers of EVOO ingestion that may provide tools to validate the association between EVOO intake and disease outcome; ii) identification of specific “dysbiotic signature” for each disease that will give a better knowledge of the interaction between immune system and microbiota to develop strategies aimed at restoring “eubiosis” status; iii) further investigations on the effects of EVOO on T cells lineage imbalance that is a trait of the immune mediated diseases.

Integration with “omics” approaches, also taking in account gender-related differences, may provide additional understanding on how EVOO and its components can influence regulatory processes, in order to translate this information into nutritional recommendation for IMID.


APCs = Antigen presenting cells
BDNF = Brain-derived neurotrophic factor
COX-2 = Cyclooxygenase-2
CVD = Cardiovascular disease
ERK = Extracellular-signal-regulated kinase
EVOO = Extra virgin olive oil
GPx = Glutathione peroxidase
GSH = Glutathione
HO-1 = Heme oxygenase-1
HT = Hydroxytyrosol
IBD = Inflammatory bowel disease
IFN-γ = Interferon γ
IL = Interleukin
IMID = Immune mediated inflammatory diseases
IMQ = Imiquimod
iNOS = Inducible nitric oxide synthase
JAK = c-Jun N-terminal kinases
JNK = Jun N-terminal kinases
LPS = Lipopolysaccharides
LUT-7G = Luteolin-7-glucoside
MAPK = Mitogen-activated protein kinases
MD = Mediterranean diet
MMPs = Metalloproteinases
MS = Multiple sclerosis
NF-κB = Nuclear transcription factor kappa B
Nrf2 = Nuclear factor E2-related factor 2
PBMCs = Peripheral blood mononuclear cells
PE = Phenolic extract
P3IK/Akt = Phosphatidylinositol-3 kinase
RA = Rheumatoid arthritis
SLE = Systemic lupus erythematosus
STAT = Signal transducer and activator of transcription
T2D = Type 2 diabetes
TGF-β = Tumor growth factor β
Th = T helper
TNF-α = Tumor necrosis factor α


Not applicable.


The authors declare no conflict of interest, financial or otherwise.


This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

C. S., R. M., contributed to the idea and development of research and wrote the first draft of the paper. R. V., B. S., P. DS., C. G., M. DA., contribute literature review and data collection. All authors reviewed multiple drafts of the paper and approved the final manuscript.


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