Study: Potential usefulness of Mediterranean diet polyphenols against COVID‑19‑induced inflammation: a review of the current knowledge. Image Credit: Antonina Vlasova /

Mediterranean diet polyphenols may modulate COVID-19 inflammation

The Mediterranean diet (MD), which people in the Mediterranean region generally follow, has been hailed for its rich anti-obesity and anti-inflammatory content. However, the onset of the coronavirus disease 2019 (COVID-19) pandemic, which has since claimed more than 6.6 million lives, has led researchers to focus on the potential benefits of this diet in preventing serious illness. and deaths related to COVID-19.

A new Journal of Physiology and Biochemistry The study examines the available evidence for the beneficial role of polyphenolic plant compounds in MD in the prevention and treatment of COVID-19.

Study: Potential utility of Mediterranean diet polyphenols against COVID‑19-induced inflammation: a review of current knowledge. Image Credit: Antonina Vlasova /


The MD includes few processed foods, small portions of meat, a moderate amount of olive oil, and red wine with meals. Apart from this, little fat is consumed in this diet, apart from that provided by fish and shellfish, the amounts of which vary between individuals and communities. In contrast, fiber intake in DM is high and is mainly provided by vegetables, legumes, fruits and whole grains.

Taken together, these ingredients provide abundant antioxidants and have been linked to a reduced risk of many chronic diseases, including cardiovascular disease and metabolic syndrome. Since the presence of these health conditions is considered a high risk factor for severe COVID-19, this diet may be associated with protection against COVID-19.

Like other viral infections, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen responsible for COVID-19 triggers the release of reactive oxygen species (ROS) that produce inflammation, l Overactive inflammation can become systemic, reducing the likelihood of survival.

Oxidative stress depletes antioxidant defenses and predisposes the individual to infections. Moreover, such a situation can alter the way viral antigens are presented to the immune system and even alter the distribution and abundance of the angiotensin-converting enzyme receptor 2 (ACE2) that SARS-CoV- 2 uses to enter host cells.

Obesity is also linked to an increased risk of severe COVID-19, possibly due to higher expression of ACE2 in fat cells. In addition, their engagement by SARS-CoV-2 could disrupt the metabolism of apelin, a fatty hormone.

Levels of other cell cycle factors like the nucleotide-binding domain, the inflammasome containing the pyrin domain of the leucine-rich protein (NLR) family (NLRP3), and toll-like receptors (TLRs) change also in severe cases of COVID-19.

When SARS-CoV-2 binds to ACE2, its metabolic role remains partly unfulfilled, causing vascular factors like angiotensin II to accumulate instead of being broken down like normal to vasoactive peptides, which could trigger the release of inflammatory cytokines. These findings were reported in patients with COVID-19 who developed lung damage and support the contribution of severe inflammation to adverse COVID-19 outcomes.

Thus, the double benefit of DM, in terms of a balanced diet and the supply of antioxidant, anti-inflammatory and immunomodulatory compounds, must be evaluated. Furthermore, additional mechanisms of action to attenuate COVID-19 may also be involved, such as inhibition of SARS-CoV-2 binding to its chaperone protein, glucose-regulated protein 78 (GRP78).

The importance of such diet-modified risk reduction is evident when one considers the fact that most Western diets cause chronic systemic inflammation and oxidative stress, in addition to a suppressed immune response.

These factors also increase the risk of more severe COVID-19 outcomes correlated with high amounts of simple carbohydrates, saturated fats and low fiber. For example, a recent experiment in hamsters showed that continuous ingestion of large amounts of sugar increased the severity of SARS-CoV-2 infection.

Some human studies have also shown that COVID-19 cases and deaths are reduced in a cohort after DM. Current research reviews published evidence to determine the potentially beneficial role of polyphenols in MD, including hydroxytyrosol, resveratrol, quercetin, catechin, and naringenin.

What does the study show?

Olive oil, especially extra virgin oil, contains many bioactives and nutrients that have activity against cardiovascular disease, diabetes and certain cancers. Among these is hydroxytyrosol, which has been shown to support the protection of blood lipids against oxidative stress and to induce anti-inflammatory and antiviral effects.

Hydroxytyrosol suppresses matrix metalloproteinase-9 (MMP-9) and cyclo-oxygenase (COX) enzymes. MMP-9, released from neutrophils, is considered a potential biomarker of acute lung injury in COVID-19. Additionally, MMP-9 breaks down the alveolar-capillary wall during lung inflammation, allowing inflammatory cells to migrate into the lungs and cause damage.

MMP-9 may also be involved in the cytokine storm characteristic of severe and deadly COVID-19. Similarly, the surge of inflammatory cytokines could result from the induction of COX-2, along with p38 mitogen-activated protein kinase (p38MAPK), to cause lung inflammation and alveolar damage. Animal models have shown that hydroxytyrosol effectively inhibits the release of the inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), both of which are elevated in severe COVID-19.

MMP-9 also increases the antioxidant capacity of cells at the level of gene expression, where it acts on the erythroid nuclear factor 2 (Nrf2)-related factor 2 (Nrf2) pathway that protects against acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Together, MMP-9s could be an important therapeutic target in the treatment of COVID-19.

Similarly, resveratrol, which is found in grapes, red wine, berries and nuts, all of which are abundant in MD, has been shown to inhibit a range of human respiratory viruses both in vitro and live through various mechanisms.

For example, resveratrol can trigger Nrf2, boost cellular antioxidant defenses, or regulate immune defenses against SARS-CoV-2. Additionally, resveratrol supplementation has been shown to prevent oxidative stress damage, enhance endoplasmic reticulum stress markers like eukaryotic initiation factor 2 (eIF2α), and inhibit superoxide production by a family of enzymes called NADPH oxidases.

The result is a reduction in ROS levels and the activation of other pathways that make nitric oxide (NO) available to the cell. This could cause vasodilation and inhibit platelet aggregation, thus explaining the positive vasoactive properties of resveratrol that make it useful in mitigating COVID-19, especially in patients with hypertension or atherosclerosis.

This compound also protects the endothelium by preventing clot formation while inhibiting MAPK and other inflammation pathways triggered by COVID-19. In humans, resveratrol appears useful in preventing severe inflammation during COVID-19 through its ability to act on different signaling pathways.

The current study also discusses the promise of flavonoids, compounds found in most MD foods that can scavenge toxic free radicals. Flavonoids also activate the Nrf2 pathway, reduce bromodomain-containing protein 4 (BRD4), and reduce the production of inflammatory cytokines to modulate inflammation. These properties have been elucidated by in vitro studies; therefore, further preclinical research is warranted.

One type of flavonoid is quercetin, which has been reported to possibly prevent acute kidney injury in COVID-19. Quercetin not only stimulates antioxidant activity, but reduces the formation of lipid peroxide and prevents the activation of toxic macrophages. Moreover, this compound can also prevent the degradation of Nrf2, thereby enhancing the expression of antioxidant elements.

Previous human studies have demonstrated the safety of quercetin and its association with reduced COVID-19 cases, hospitalizations and intensive care unit (ICU) admissions, in addition to accelerated recovery of symptomatic patients. Laboratory tests also showed lower levels of inflammation in treated subjects.

Epigallocatechin-3-gallate (EGCG) is another popular antioxidant found in green tea extract, nuts, and beans. To this end, EGCG acts via the JAK/STAT pathway to reduce type III interferon (IFN III) activation, which is associated with enhanced immune antiviral responses and cytokine storm.

Other modes of action of EGCG include preventing the entry of a transcription factor called nuclear factor κB (NF-κB) into the nucleus to up-regulate inflammatory cytokines like IL-6 and TNF-α.


The current review discusses evidence on various potentially effective polyphenols in MD, with biological activities that could help prevent or mitigate COVID-19. These act as powerful antioxidants by increasing Nrf2 activity, reducing ROS production and enhancing free radical scavenging.

These compounds also attenuate cytokine storm by inhibiting inflammatory pathways such as MMP-9 and COX-2, as well as the JAK/STAT3 pathway. Finally, the reduction of ROS causes the shutdown of the pro-inflammatory NF-κB pathway.

These molecules induce positive effects on several alterations induced by this disease, in conditions other than SARS-COV-2 infection, such as oxidative stress, inflammation and thrombosis.”

Further research is needed to elucidate the efficacy of these compounds in the treatment of COVID-19 before recommendations can be made.

Journal reference:

  • Milton-Laskibar, I., Trepiana, J., Macarulla, MT, et al. (2022). Potential utility of Mediterranean diet polyphenols against COVID‑19-induced inflammation: a review of current knowledge. Journal of Physiology and Biochemistry. doi: 10.1007/s13105-022-00926-0a.

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