Polyphenols in Mediterranean diet may modulate COVID-19 inflammation

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The Mediterranean diet (MD), which residents of the Mediterranean region typically follow, has been praised for its rich anti-obesity and anti-inflammatory content. However, the onset of the coronavirus disease 2019 (COVID-19) pandemic, which has since claimed over 6.6 million lives, led researchers to focus on the potential benefit of this diet in preventing severe illness and death related to COVID-19.

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

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

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


The MD includes little processed food, small portions of meat, moderate olive oil, and some red wine at mealtimes. Apart from this, little fat is consumed as part of this diet, other than that which is provided by fish and shellfish, of which the amounts vary between individuals and communities. On the other hand, fiber consumption in the MD is high and is primarily provided by vegetables, legumes, fruits, and whole-grain cereals.

Taken together, these ingredients supply abundant antioxidants and have been associated with a reduced risk for many chronic health conditions, 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 could 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, hyperactive inflammation may become systemic, thus reducing the likelihood of survival.

Oxidative stress exhausts antioxidant defenses and predisposes the individual to infection. Moreover, such a situation may change how viral antigens are presented to the immune system and even alter the distribution and abundance of the angiotensin-converting enzyme 2 (ACE2) receptor SARS-CoV-2 uses to gain entry into host cells.

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

The levels of other cell cycle factors like nucleotide-binding domain, leucine-rich containing (NLR) protein family pyrin domain-containing 3 (NLRP3) inflammasome, and toll-like receptors (TLRs) also change in severe COVID-19.

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

Thus, the dual benefit of the MD, in terms of balanced nutrition and its supply of antioxidant, anti-inflammatory, and immunomodulatory compounds, should be evaluated. Furthermore, additional mechanisms of action in mitigating COVID-19 may also be involved, such as the inhibition of SARS-CoV-2 binding to its chaperone protein, tissue-binding glucose-regulated protein 78 (GRP78).

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

These factors also increase the risk of more severe COVID-19 outcomes correlated with high amounts of simple carbohydrates, saturated fat, and low fiber content. For example, one recent hamster experiment showed that continuous ingestion of large quantities 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 following the MD. The current research examines published evidence to determine the potentially beneficial role of polyphenols in the MD, including hydroxytyrosol, resveratrol, quercetin, catechin, and naringenin.

What does the study show?

Olive oil, especially extra virgin oil, contains numerous bioactives and nutrients that have activity against cardiovascular disease, diabetes, and some cancers. Among these is hydroxytyrosol, which has been shown to support the protection of blood lipids from oxidative stress and elicit 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 damage in COVID-19. Furthermore, MMP-9 breaks down the alveolar-capillary wall during lung inflammation, thus allowing inflammatory cells to migrate into the lungs and cause damage.

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

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

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

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

The outcome is a reduction in ROS levels and activation of other pathways that make nitric oxide (NO) available to the cell. This could cause vasodilation and inhibit platelet aggregation, thus accounting for the positive vasoactive properties of resveratrol that make it useful in COVID-19 attenuation, 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 helpful 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 capture toxic free radicals. Flavonoids also activate the Nrf2 pathway, reduce bromodomain-containing protein 4 (BRD4), and reduce inflammatory cytokine production to modulate inflammation. These properties have been elucidated through in vitro studies; therefore, further preclinical research is warranted.

One type of flavonoid is quercetin, which has been reported to prevent acute kidney injury in COVID-19 possibly. Quercetin not only boosts antioxidant activity but reduces lipid peroxide formation and prevents the activation of toxic macrophages. Furthermore, this compound may also prevent the breakdown of Nrf2, thus 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 have also shown lower levels of inflammation in treated subjects.

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

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


The current review discusses evidence on various potentially effective polyphenols in the MD, with biological activities that might help prevent or alleviate COVID-19. These act as powerful antioxidants by increasing Nrf2 activity, reducing ROS production, and enhancing free radicals' removal.

These compounds also mitigate the cytokine storm by muting inflammatory pathways such as MMP-9 and COX-2, as well as the JAK/STAT3 pathway. Finally, the reduction in ROS causes the pro-inflammatory NF-κB pathway to shut down.

These molecules induce positive effects on several alterations induced by this disease, under 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 treating COVID-19 before any recommendations can be made.

Journal reference:
  • Milton-Laskibar, I., Trepiana, J., Macarulla, M. T., et al. (2022). Potential usefulness of Mediterranean diet polyphenols against COVID‑19‑induced inflammation: a review of the current knowledge. Journal of Physiology and Biochemistrydoi:10.1007/s13105-022-00926-0a.
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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