Introduction

Comorbidities may predispose individuals to high-risk infective diseases such as SARs-CoV-2, with more severe complications, making interventions more complicated ¹. An important comorbidity prone to infectious diseases, particularly to SARs-CoV-2 infection and to COVID-19, is obesity, an alarming pandemic ³ that predisposes them to comorbidities, such as diabetes mellitus, hypertension or metabolic syndrome and that adds a higher risk for poor outcomes and mortality in case of impact with novel viruses ^1,4. Recent studies suggest that omega-3 PUFAs may interact at different stages of SARS-CoV-2 infection, particularly in contrasting the viral entry and replica-tion phases, where persistent viral infection may be responsible for the sustained in-flammatory state of long COVID.

There is growing evidence for the beneficial effects of omega-3 PUFAs and their metabolites, namely specialized pro-resolving mediators (SPMs), including ameliora-tion of uncontrolled inflammatory responses, reduction of oxidative stress and mitiga-tion of coagulopathy. Therefore, the nutritional status of omega-3 is crucial for the overall immune response, tissue inflammation and repair, which may be beneficial for the condition of long COVID.

Protective and supportive therapies may be helpful to improve COVID-19 pa-tients’ prognosis. In this respect, the beneficial effect of n-3 polyunsaturated fatty ac-ids, (n-3 PUFA or omega-3) includes the reduction of uncontrolled phlogistic reactions, oxidative stress and coagulopathies as well. In the light of their favorable safety pro-file, it is rational to consider n-3 PUFAs as a potential preventive strategy or adjuvant therapy in order to improve COVID-19 patients’ outcomes.

The role of inflammation and obesity as a comorbid condition

A persistent pathological inflammatory process is generated during some comor-bidities, such as diabetes mellitus, hypertension, metabolic syndrome and obesity: in particular, adipose tissue constitutes an autonomous endocrine organ, releasing large amounts of “adipokines” ⁵, bioactive peptides with a central role in vascular homeo-stasis, regulation of appetite, glucose and lipid metabolism, and immunity. Adipokines can target different organs and influence phlogosis responses and can exert pro-inflammatory or anti-inflammatory actions ⁶. Leptin is the leading adipokine; it promotes the displacement of local macrophages in the white adipose tissue (WAT) determining a shift toward a pro-inflammatory profile and decreases regulatory T-cells, also inducing Th17 polarization ^7,8. Hyperleptinemia is a typical obesity marker ⁹, with leptin resistance upsetting the endothelial signals, contributing to a pro-inflammatory microenvironment, and predisposing to cardiac and vascular com-plications ¹⁰. Adiponectin, which is the antagonist adipokine with an-ti-inflammatory activity, is inversely linked to the amount of adipose tissue in obese subjects ¹¹: a low adiponectin level is correlated to higher inflammatory mediators (particularly CRP and IL-6) levels and to several obesity-related metabolic diseases ^12-15. Adipocyte hypertrophy is correlated to unbalanced intracellular signaling: the c-Jun NH2-terminal kinase (JNK) and the nuclear factor-kB (NF-kB) pathways are ac-tivated; enlarged omental adipocytes are hyper-responsive to TNF-α, determining ad-ipokines over-excretion ^16,17. Also, oxidative stress and hypoxia (due to hypoperfu-sion of the expanding adipose tissue) contribute to the obese pro-inflammatory micro-environment ^18,19 by decreasing the mRNA levels of adiponectin, while increasing the levels of both pro-inflammatory genes (TGF, TNF-α, PAI-1, IL-1, IL-6, MCP-1) and hypoxia response genes (glucose transporter 1, HIF-1, VEGF): this exacerbates the in-flammation in adipose tissue, contributing to obesity-related implications. This chronic inflammatory state creates a natural background predisposing obese subjects to nega-tive outcomes if an additional inflammatory stimulus (such as a virus) is introduced. In H1N1 a link between obesity and higher mortality was evidenced for body mass in-dex (BMI)>45 kg/m2 (OR 4.2; CI 1.9-9.4). Most recently, these findings were supported during the COVID-19 pandemic ²: obesity tripled the risk of hospitalization of those infected with SARs-CoV-2. More than 30% adult COVID-19 hospitalizations had obe-sity as a comorbid condition ²⁰. In a healthcare cost model, 20.3% of patients with BMI>40 kg/m2 needed intensive care treatment, including invasive mechanical venti-lation compared with 6.6% of those with BMI <25 kg/m2 ²¹. In infected patients it was reported not only the presence of dysregulated inflammation but also a pro-thrombotic state ²², with evidence of venous thrombocytope-nia/thromboembolism, renal failure, and disseminated intravascular coagulation in many ARDS patients. The patients with microthrombi showed more comorbidities such as overweight/obesity (64%), hypertension (62%), and cardiovascular disease (53%) ²³. Endothelial hyper-activation enhances signaling pathways and leads to the generation of vascular adhesion molecules and proinflammatory cytokines, addressing inflammatory cells to both endothelium and underlying tissues ^24,25. Further, both endothelium and adipose tissue produce plasminogen activator inhibitor-1(PAI-1): a higher levels of PAI-1 is typical of obesity and can determine hypofibrinolysis, thus contributing to poor outcomes in these patients ^26,27.

Nutrients in COVID-19 prevention and Treatment

COVID-19 patients often suffer from harmful consequences (Table 1), because of a prominent systemic inflammation, with the outcome of COVID-19 patients being closely related to their nutritional status. In this respect, an adequate intake of nutri-ents can be helpful in order to prevent the infection and support the immune system during COVID-19 acute phase, but also in the post-acute phase, thus contrasting the various long-lasting symptoms typical of the so-called “long COVID”. For example, vitamin C contrasts inflammation and stimulates the immune response by regulating both cytokine secretion and histamine release, decreases oxidative stress, and regulates of T and B lymphocytes differentiation/proliferation ²⁸. Numerous observational studies demonstrated that insufficient levels of vitamin D are related to COVID-19 se-verity ^29-31; in addition, patients treated with a high-dose cholecalciferol supple-mentation displayed faster negativization ³², decreased access to intensive care ³³ and increased survival among COVID-19 hospitalized patients than those without supplementation ³⁴. Similarly, the glycoprotein lactoferrin can modulate the in-flammatory process by inhibiting the production of proinflammatory cytokines and by regulating the expression of iron homeostasis proteins (such as ferritin, ceruloplasmin and transferrin receptor 1) ³⁵. Among the most helpful nutrients in the prevention and treatment of COVID-19, omega-3 fatty acids can play a pivotal role, as well as in the therapy of many inflammation-related diseases. Among the physiological process-es of phlogosis resolution is the enzymatic conversion of omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into specialized pro-resolution mediators (including resolvins and protectins) participating in the resolution of phlogistic status and helping solve the cytokine storm and COVID-19 associated complications ³⁶.

Overview and potential role of omega-3 in COVID-19 4.1

Immunomodulating Effect

A weak and ineffectual immune system often provides the chance for pathogens to bring severe illness. Omega-3 fatty acids, present in walnuts, flaxseeds and seafood (such as sardines, halibut, tuna, salmon, mackerel, but also in marine sponges, algae, crustaceans and krill), are responsible for numerous cellular functions such as signal-ing and cell-to-cell interaction ³⁷. An adequate dietary intake of these polyunsatu-rated fatty acids can modulate the immune answer, by improving omega-6 and ome-ga-3 ratio. Their anti-phlogistic action is mediated by the inhibition of both 5-lipoxygenase/ leukotriene B4-B5 pathway and NF-κB pathway with a reduced ex-pression of cell surface adhesion molecules and a reduced production of interleukins (IL-1 and IL-6) from neutrophils ³⁸. Omega-3 were displayed to decrease the genera-tion of pro-inflammatory cytokines from macrophages infected with Pseudomonas aeruginosa ³⁹ and to increase phagocytic capacity of macrophages: in fact, microor-ganisms-mediated activation of the macrophage TLR4 signaling cascade depends on membrane lipid composition whose structures change after the incorporation of EPA and DHA ⁴⁰. A 45-days double blind randomized study divided the healthy adult volunteers in two groups: placebo versus 3g DHA daily supplementation. The supple-mented group showed a minor post-exercise stress-induced IL-2 release from periph-eral mononuclear cells⁴¹; this is certainly helpful in the resolution of upper respira-tory tract infections ⁴². Similarly, a 45-days 1.6g-1.8g daily supplementation dis-played to enhance NK cell activity ⁴³, reduce prostaglandins E2 levels and stimulate interferon-gamma secretion ⁴⁴ with a substantial immune reinforcement, potentially able to prevent and to mitigate COVID-19 infection. In the same way, an increased in-take of omega-3 determines their increased incorporation into cell membranes, thus replacing arachidonic acid: this mechanism may enhance inflammation resolution in athlete post-exercise⁴⁵ as well as in COVID-19 patients. Additionally, some potential antiviral activities of DHA-derived mediators have been reported: protectin D1 (a member of the class of specialized proresolving mediators generated by the oxygena-tion of DHA) and 17-HDHA (an autoxidation product of DHA) demonstrated to in-hibit respectively influenza A and H1N1 viral replication in mice⁴⁶. Similar results were displayed against Zika virus ⁴⁷, coxsakievirus and enterovirus with a signifi-cant viral load attenuation in human cells⁴⁸.

Antinflammatory effect

A plethora of anti-inflammatory mechanisms have been attributed to omega-3 (Table 1). Firstly, they modulate the expression of adhesion molecules and inflamma-tory cytokines by activating anti-inflammatory transcription factors (PPARα/γ) and stopping TLR4-mediated activation of NF-κB. Secondly, omega-3 are metabolized into leukotrienes (with anti-inflammatory activities) by cyclooxygenases and lipoxygenas-es. Additionally, their metabolism produces proresolving mediators (Figure 1) with powerful antiphlogistic activities, expecially resolvins, protectins and maresins: they inhibit the migration of polymorphonuclear cells and the generation of both reactive oxygen species and chemokines, stimulating tissue regeneration and restoration of tis-sue homeostasis ⁴⁹, which may be really helpful in limiting cytokine storm during COVID-19. Further, an intersection between innate immune inflammatory and mito-chondria has also been reported: the mitochondrial dysfunction can trigger uncon-trolled inflammatory answers⁵⁰ determining the secondary injury aggravation in COVID-19⁵¹. At the same time the hypersecretion of inflammatory mediators trig-gers further intracellular cascades, altering mitochondrial functions: IL-6 and IFN-γ stimulate mitochondrial ROS production and determine mitochondrial membrane permeabilization until cell death; IL-1β and TNF-α inhibit mitochondrial oxidative phosphorylation and ATP production with exacerbation of cell injury⁵². In this re-spect, omega-3 displayed overabundance of beneficial effects against inflammation in many trials. Rats on n-3 PUFA enriched diet presented a reduction not only in pulmo-nary microvascular permeability and lung neutrophil accumulation but also decreased concentrations of arachidonic acid-derived metabolites (such as prostaglandin E2 and thromboxane B2) in alveolar macrophages, compared to n-6 PUFA enriched diet ⁵³. In another study, pre-incubation with DHA of rhinovirus-infected epithelial cells de-creased the release of IL-6 and IFN-γ-inducible protein, and suppressed the vi-rus-induced inflammation⁵⁴. In intensive care unit patients (with severe sepsis or septic shock requiring mechanical ventilation), a DHA enriched diet significantly ameliorated clinical outcomes with a lower mortality rate, in comparison to the control groups⁵⁵. Similarly, a high-dose EPA diet (9 daily grams for 7 days) was evaluated in early-stage sepsis. This meta-analysis evidenced a noticeable improvement in oxy-genation of ventilated patients with acute respiratory distress syndrome. The lower rates of organ failures and severe sepsis development were associated to reduced levels of CRP, IL-6 and procalcitonin ⁵⁶ with a reduction of intensive care stay by about two days⁵⁷. Further studies defined the benefit of EPA and DHA supplementation (from 4 to 6 grams per day) in severe COVID-19, inhibiting cytokine secretion and mitigating the inflammatory state⁵⁸. This antinflammatory activity could be partic-ularly precious in high-risk populations with underlying health conditions, such as di-abetes, obesity, hypertension, oncologic diseases and old age⁵⁹, which could trigger the detrimental outcome often associated with severe COVID-19.

Figure 1: The connection n-3 PUFAs, inflammation and COVID-19 outcomes: Click here to view Figure

N-3 PUFAs can replace the pro-inflammatory arachidonic acid in cell membranes or be metabo-lized to specialized pro-resolving mediators (SPMs): this down-regulates the NF-kB pathways and inhibits the synthesis of pro-inflammatory cytokines.

Anti-Arrhythmic, Vasodilator and Anti-thrombotic Effect

While systemic inflammation, respiratory complications and multi-organ dys-function determine a noticeable morbidity and mortality, cardiovascular complica-tions (such as myocarditis, acute myocardial infarction, dysrhythmias and thrombo-embolic accidents) during COVID-19 can also occur ⁶⁰ typically in older subjects with comorbidities. However numerous cases of large vessels occlusion were reported also in young patients ⁶¹ because of significant coagulation anomalies, such as in-creased d-dimer, prolonged prothrombin time, and abnormal platelet levels ⁶². Omega-3 are known to contrast cardiovascular risk factors, such as hypertension, hy-perlipidemia and abnormal heart rhythm ⁶³ reducing the risk of cardiac death for both hemodialysis or atrial fibrillation patients and healthy subjects without anamnes-tic cardiovascular diseases ⁶⁴. In fact, they penetrate into cell membranes altering the lipid raft structure and function: this leads to improved intracellular organelle and cellular functions, higher arrhythmic thresholds, modified autonomic tone and atten-uated hypertension. Their anti-arrhythmic action can be explained by different mech-anisms: the modulation of L-type calcium, sodium and potassium channels ⁶⁵, the inhibition of thromboxane generation ⁶⁶, the capability to lower the plasmatic con-centration of non-esterified fatty-acids, which had previously displayed proarrhythmic activities ⁶⁷. Additionally, omega-3 inhibit chemotactic answer of immune cells and adhesion molecules interaction/expression on endothelial cells, thus contrasting the development of blood clots in vessels: this mechanism, together with the an-ti-inflammatory activity, can explain the anti-thrombotic properties of omega-3 (Table 1). These mechanisms, responsible for omega-3 anti-atherogenic effects ⁶⁸, may con-trast the development of blood clots in arteries during COVID-19, considering its pro-coagulant status and high risk of thromboembolic complications ⁶⁹. Another re-search in a Japanese population evidenced that higher fish intakes were inversely as-sociated with intracerebral hemorrhaging ⁷⁰. Omega-3 may influence membrane fluidity, interacting with Peroxisome Proliferator-Activated Receptors (PPARs) an-drepresent a substrate for lipoxygenase, cicloxygenase and cytochrome P450 ⁷¹. As a result, n-3 PUFAs can induce hemodynamic modifications, improve endothelial func-tion and arterial compliance, decrease arrhythmias risk, and inhibit inflammatory pathways. Strong evidence suggests that DHA is more efficient in decreasing blood pressure, heart rate, platelet aggregation, and improving both the endothelial health and HDL/LDL ratio ⁷¹ thus decreasing global cardiovascular risk, so that the daily supplementation of omega-3 can be recommended for cardiovascular prevention.

Impact on respiratory system

The role of omega-3 in respiratory affections has already been evidenced in asthma and exercise-induced bronchoconstriction where the presence of epithelial in-jury and phlogosis in the airways was found ⁷². A decreased bronchial phlogosis due to an omega-3 dietary supplementation was clearly reported ^73,74. For example, the low incidence of asthma and other chronic respiratory diseases in Eskimos may be due to the great intake of fat fish among this population ⁷⁵. More specifically, a daily ad-ministration of 3.2 grams of EPA and 2.0 grams of DHA for 3 weeks decreased the concentration of pro-inflammatory cytokines (IL-1β and TNF-α) in the sputum also displaying that both fish oil and anti-leukotrienes medication were independently ef-fective in mitigating hyperpnea-induced and exercise-induced bronchoconstriction as well as airway inflammation ⁷⁶. A randomized clinical trial evidenced that a high daily omega-3 dietary intake mitigated lung inflammation with a meliorated oxygena-tion in critical acute lung injury: the meta-analysis of outcome data displayed that the use of an inflammation-modulating diet in patients with acute respiratory distress syndrome increased ventilator-free days and significantly decreased mortality at 28-day interval ⁷⁷. Similarly, an open-label trial showed the efficacy of parenteral nutrition with fish oil in modulating inflammatory response and cytokine production in patients with respiratory distress during sepsis: after 3 days the omega-3/omega-6 ratio was reversed with EPA and DHA prevalent over arachidonic acid, and omega-3 incorporation into mononuclear leukocyte membranes. Additionally, critical patients with acute lung injury and acute respiratory distress syndrome are prone not only to a major risk of sepsis but also to cardiac arrest: omega-3 can promote resolution of in-flammation and precondition the heart against septic cardiomyopathy because of their antioxidant and immuno-modulating activity ⁷⁸.

Effect on the Renin Angiotensin Aldosterone system

Renin Angiotensin Aldosterone system (RAAS) has been focused on for several years because of its pivotal role in the physiology and pathophysiology of cardiovas-cular disease: it is involved in blood pressure regulation, fluid, and electrolyte balance through action on kidney and blood vessels. Angiotensin converting enzyme (ACE), is a critical regulator of RAAS by converting Angiotensin I (Ang-I) to Angiotensin II (Ang-II), which is the most powerful biologically active product of RAAS. Ang-II in-creases blood pressure stimulates aldosterone secretion, which results in sodium reab-sorption and potassium excretion. However, a second ACE (ACE2) is a negative regu-lator of RAAS: it opposes the effect of ACE in the heart, kidneys, and lungs and con-verts Ang-II to Angiotensin, which is a vasodilator, antihypertrophic, antithrombotic peptide ⁷⁹. In fact, in almost all the cardiovascular pathological conditions there is a disturbance in ACE/ACE2 ratio, usually due to a down-regulation in ACE2 levels.

Additionally, ACE2 serves as a receptor for SARS-CoV-2 entry into target cells by binding of the spike protein to ACE2 and a specific transmembrane serine protease 2 (TMPRSS2) required for the spike protein priming, which also leads to down-regulation of ACE2⁸⁰. Interestingly, poor outcomes of COVID-19 have been observed in patients with pre-existing cardiovascular diseases, who have already defi-ciency in ACE2 and increased ACE/ACE2 ratio⁸¹.
Omega-3 supplementation was associated to a significant decrease in serum levels of both ACE/ACE2 ratio and ACE (Table 1), displaying that they may reduce suscepti-bility to COVID-19 and reduce disease severity and its complication ⁸².

Table 1: Potential molecular mechanisms of omega-3 PUFAs on COVID-19 complications

Conclusion

This review highlights the molecular mechanisms of omega-3 PUFAs mediated resistance against COVID-19 based on available evidence. In addition to preserving or repairing the brain structure and function by interacting with phospholipid metabo-lism and the known shift in the pattern of lipid metabolites to a more an-ti-inflammatory metabolite profile, omega-3 PUFAs and/or their biologically active metabolites have the potential to improve oxidative stress, and immune dysregulation; maladaptation of the RAAS and coagulation system; and psychosocial stress from changes in health, financial status, or social life. Despite these promising effects of omega-3 PUFAs, additional epidemiological, experimental, and RCTs are needed to test, validate, and translate these proposed effects in the context of long COVID.

The administration of omega-3 fatty acids in COVID-19 patients aims to target both the improvement of health status and the prevention of potential complications: their anti-inflammatory action can stimulate macrophage phagocytic effort, disable enveloped virus, modulate cell signaling, attenuate coagulopathy, shift the lipid me-tabolites towards an anti-inflammatory pattern and globally mitigate an uncontrolled immune response secondary to the infection.

Acknowledgment

The authors acknowledge the Department of Medical, Oral and Biotech-nological Sciences, of University G. D’Annunzio for the support.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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