key: cord-0996758-417h29ex
authors: Augusti, Paula R.; Conterato, Greicy M.M.; Denardin, Cristiane C.; Prazeres, Inês D.; Serra, Ana Teresa; Bronze, Maria R.; Emanuelli, Tatiana
title: BIOACTIVITY, BIOAVAILABILITY, AND GUT MICROBIOTA TRANSFORMATIONS OF DIETARY PHENOLIC COMPOUNDS: IMPLICATIONS FOR COVID-19
date: 2021-06-02
journal: J Nutr Biochem
DOI: 10.1016/j.jnutbio.2021.108787
sha: 32e1faac537603b1f0eb18f39a491815cef15e2c
doc_id: 996758
cord_uid: 417h29ex

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed.

The outbreak of severe acute respiratory syndrome at the end of 2019 has resulted in a huge health concern worldwide. The disease caused by coronavirus was initiated in Wuhan (China) and has spread around the world. Therefore, the World Health Organization (WHO) declared the disease as a pandemic.

Until April 28, 2021, WHO registered more than 145 million infected cases, and the number of deaths exceeded 3 million (World Health Organization, 2021) . The pathogen, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to a large family of viruses that can infect animals and humans, causing respiratory, gastrointestinal, hepatic, and neurologic diseases (Weiss & Leibowitz, 2011) . The SARS-CoV-2 has higher transmissibility and infectivity but a lower mortality rate, when compared with other coronaviruses (CoVs), such as those causing severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV) (Liu, Gayle, Wilder-Smith, & Rocklöv, 2020) .

The majority of SARS-CoV-2-infected individuals are asymptomatic or have mild symptoms, most likely due to the activation of the immune system. However, the disease evolves into acute respiratory distress syndrome (ARDS), acute cardiac complications, multiple organ dysfunction syndromes, septic shock, and death in about 20% of infected (usually people with some comorbidity) (Gattinoni et al., 2020) . These complications are believed to be associated with severe inflammatory and oxidative stress responses induced by viral replication .

Despite the severity of the disease, no effective therapy is available to improve the outcomes in patients with either suspected or confirmed COVID-19. In this context, nutritional strategies for reducing the risk or mitigating the symptoms of COVID-19 have gained considerable attention. As a non-pharmacological complementary approach, dietary supplementation of nutraceuticals and probiotics is easily available and displays no or few side effects (Iddir et al., 2020; Infusino et al., 2020) . In this regard, phenolic compounds (PC) have emerged as putative nutritional or adjunct therapeutics for COVID-19 because these compounds are associated with health benefits against several pathologies (Fraga, Croft, Kennedy, & Tomás-Barberán, 2019) .

Moreover, PC exhibit prebiotic effects, influencing the gut microbiota and attenuating gastrointestinal complications reported in COVID-19. PC are metabolized by colonic microbiota and the resulting products may be absorbed in the gut and exert beneficial effects on several organs (Singh et al., 2019) .

Despite the existing literature on the effects of PC against several viruses, only a few studies have demonstrated their action against CoVs (Annunziata et al., 2020; Mani et al., 2020) . A recent study reviewed the potential ability of PC in the prevention and therapeutics of COVID-19 by addressing molecular pathways modulated by PC (Levy, Delvin, Marcil, & Spahis, 2020) . However, this review did not discuss the impact of digestion and metabolism on the bioavailability of PC or the effects of gut microbiotaderived PC metabolites on the putative role of PC in COVID-19. Moreover, safety issues and possible drug interactions were not addressed.

This review summarizes the current evidence regarding the bioactive mechanisms of dietary PC against COVID-19 manifestations, as well as the influence of bioavailability and gut microbiota transformations on the putative effects of PC.

Moreover, safety issues and the interaction of dietary PC with drugs used to mitigate certain COVID-19 manifestations have been addressed.

The PubMed (https://pubmed.ncbi.nlm.nih.gov) and ScienceDirect (https://www.sciencedirect.com) databases were used to search articles by a combination of terms: coronavirus, COVID-19, SARS, MERS, influenza, NF-kB, cytokine storm, immunomodulation AND phenolic compounds, anthocyanins, flavonoids, isoflavones, nutrition, phytochemicals, bioactive compounds, and oxidative stress. As this was not a systematic review, exclusion and inclusion criteria were not defined. All articles up to and including August 20, 2020, were considered, and those providing relevant data for the discussion were included in the review.

CoVs are enveloped and single-stranded RNA viruses that infect a wide variety of host species. Structurally, CoVs have four structural proteins: spike (S), membrane, envelop, and nucleocapsid ( Ye, Wang, & Mao, 2020) . S protein mediates the entering of SARS-CoV-2 into the host cell through binding to the angiotensin-converting enzyme 2 (ACE2) receptor in host cells (Shang et al., 2020) . The CoV entry activates the transmembrane protease serine 2 (TMPRSS2); this, along with ACE2, is the main determinant of the entry of this virus (Shang et al., 2020) .

CoV replication is mediated by RNA polymerase to produce polyproteins. These polyproteins are processed by virus proteases, papain-like protease (PLPro), and serine main protease (chymotrypsin-like protease-3CLPro). Next, viral messenger RNA (mRNA) is used to construct viral proteins (maturation) that are subsequently released (Yuki, Fujiogi & Koutsogiannaki, 2020) . Helicase (Nsp13) is a highly conserved enzyme in all CoVs and is crucial for viral replication, making it a promising target for antiviral therapies (Romano, Ruggiero, Squeglia, Maga, & Berisio, 2020) .

After the SARS-CoV-2 infection, the increase in viral load causes an inflammatory cytokine storm, an out-of-control cytokine release, leading to a hyperinflammatory condition in the host (Mahmudpour et al., 2020) . The nuclear factor kappa B (NF-κB) plays a significant role in regulating the expression of a multitude of genes involved with immune and inflammatory responses (Xu et al., 2018) . Once activated, the NF-κB pathway also promotes T and B cell differentiation (Liu et al., 2017; Moynagh, 2005) .

One of the major pathways for NF-ĸβ activation after CoV infection is the myeloid differentiation primary response 88 (MyD88) pathway through pattern recognition receptors (PRRs). This pathway induces a variety of pro-inflammatory cytokines, including interleukin (IL)-6 and TNF-α (Hirano & Murakami, 2020; Talukdar et al., 2020) . ACE2 is endocytosed along with SARS-CoV-2, resulting in the reduction of ACE2 on cells, followed by an increase in serum angiotensin II (Ang II) (Hoffmann et al., 2020) . Ang II acts both as a vasoconstrictor and pro-inflammatory cytokine via the Ang II-receptor type 1 (AT1R). The Ang II-AT1R axis activates NF-ĸβ and induces tumor necrosis factor-α (TNF-α), epidermal growth factor receptor (EGFR), and soluble form of IL-6 receptor (sIL-6Rα) via disintegrin and metalloprotease 17 (ADAM17) (Hirano & Murakami, 2020; Hoffmann et al., 2020; Talukdar et al., 2020) .

Thus, the higher the viral load, the lower the concentration of ACE-2 due to virus binding, which causes increased levels of Ang II in the serum, thus activating the NF-ĸβ pathway. Certain glucocorticoids, such as methylprednisolone, prednisone, and dexamethasone, have been reported to inhibit NF-κβ activation and are used in the management of COVID-19 in several countries (Solinas et al., 2020) . Thus, substances with this same mechanism of action would be important putative agents for containing this disease.

The overproduction of reactive oxygen species (ROS) and deprivation of antioxidant mechanisms are crucial events for viral replication and the subsequent virusassociated disease (Checconi et al., 2020; Delgado-Roche & Mesta, 2020) . In addition, variations in cellular pH, decrease in reduced glutathione (GSH) levels, and the activity of NADPH oxidase (NOX) family are important events. The NOX4-derived ROS production is modulated by ACE2 (Checconi et al., 2020; Delgado-Roche & Mesta, 2020) . Furthermore, free radicals, such as superoxide anion radical (O 2 -), chlorine oxide (ClO -), nitric oxide (NO), and peroxynitrite (ONOO -) could be the cause of virusinduced pneumonia death (Wu, 2020) . In addition, oxidative stress occurs not only due to ROS released but also due to pro-oxidant cytokines, such as TNF-α and IL-1, released by phagocyte activation (Schwarz, 1996) .

Oxidative stress plays a crucial role in the pathogenesis of COVID-19. It perpetuates the cytokine storm as well as exacerbates hypoxia, including mitochondrial dysfunction (Cecchini & Cecchini, 2020) . The interplay between ROS and cytokine storm generates a self-sustaining cycle between the cytokine storm and oxidative stress, leading to multiorgan failure in severe COVID-19 patients whose condition progresses to sepsis and shock (Cecchini & Cecchini, 2020; Wu, 2020) .

The Nrf2-mediated antioxidant system is an essential mechanism to protect cells from oxidative injury. Under oxidative stress, the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is translocated to the nucleus and coordinately activates cytoprotective genes against oxidative stress (OS) by binding to antioxidant responsive element (ARE) in the promoter region of DNA. In addition, Nrf2 regulates the genes involved in immunity and inflammation, as well as in the mechanisms affecting viral susceptibility and replication of respiratory and non-respiratory infections (Kesic, Simmons, Bauer, & Jaspers 2011; Olagnier et al. 2014; Komaravelli, Ansar, Garofalo & Casola, 2017; Staitieh, Ding, Neveu, Spearman, Guidot, & Fan, 2017; El Kalamouni et al. 2018; Lee 2018) .

Once COVID-19 has been shown to target multiple organs through inflammatory, immune, and redox mechanisms, dietary bioactive compounds that modulate these mechanisms could be a nutritional alternative to control the disease severity.

PC have at least one aromatic ring with one or more hydroxyl groups attached.

According to their chemical structure, they can be divided into several classes: phenolic acids, tannins, lignans, flavonoids, stilbenes, coumarins, and curcuminoids (Supplementary material, Figure S1 ). They are products of the secondary metabolism of plants, providing essential functions, including protecting plants against herbivores and microbial infection, attraction for pollinators and seed-dispersing animals, allelopathic effects, UV protection, and signal molecules during the formation of nitrogen-fixing root nodules (Gould & Lister, 2006; Del Rio, Rodriguez-Mateos, Spencer, Tognolini, Borges & Crozier, 2013) . In the human diet, PC are responsible for the healthpromoting effects due to their antioxidant, anti-inflammatory, immune, and prebiotic

properties (Spencer & Crozier, 2012) . Increasing evidence suggests that modest longterm intakes of PC can have favorable effects on the incidence of chronic diseases (Mirabelli et al., 2020; Paquette, 2017; Raimundo et al., 2020) . Despite a few human intervention studies on the effect of PC to prevent and possibly treat COVID-19, these compounds have already been reported to present antiviral activity against CoV infection as well as strong antioxidant and anti-inflammatory properties, suggesting their potential role in mitigating this infectious disease.

A good antiviral agent should prevent the growth of viruses in infected cells by inhibiting their attachment, penetration, uncoating, genome replication, and gene expression. Table 1 summarizes the studies on antiviral effects of PC against CoVs.

PC are the main bioactive components of Camellia sinensis L., whose leaves are used for green and black tea preparation (Du et al., 2012) . The antiviral activity of green tea and black tea PC in the prophylaxis and treatment of COVID-19 has been recently reviewed (Mhatre, Srivastava, Naik, & Patravale, 2020) .

Molecular docking studies (computational procedures for searching ligands that fit into the protein's binding site) have revealed 3-isotheaflavin-3-gallate, theaflavin-3,3-digallate, and tannic acid as effective 3CLPro inhibitors (IC 50 < 10 µM) (Chen et al., 2005) , which would putatively affect CoV replication. Researchers reported that the gallate group attached to the 3' position is important for interaction with 3CLPro.

Another recent in silico study revealed the strong interaction of epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and gallocatechin-3-gallate (GCG) with one or both catalytic residues of 3CLPro (Ghosh, Chakraborty, Biswas, & Chowdhuri, 2020) .

Moreover, the complexes between protease and these PC were predicted to be highly stable. Theaflavin, the compound responsible for the orange/black color of black tea, is a potent inhibitor of the RNA polymerase of SARS-CoV-2 (Lung et al., 2020) . Catechin gallate (CG) and gallocatechin gallate (GCG) showed high inhibitory activity against SARS-CoV-2 N protein in a concentration-dependent manner and affected virus replication. These PC at a concentration of 0.05 µg/mL showed more than 40% inhibitory activity on a quantum dots-conjugated RNA oligonucleotide-designed chip (Roh, 2012) .

Curcumin has been suggested as a potential treatment option for patients with COVID-19 (Zahedipour et al., 2020) because it inhibits ACE2 and suppresses the entry of SARS-CoV-2 into the cells (Utomo, Ikawati, & Meiyanto, 2020) . In another molecular docking study, curcumin exhibited an inhibitory effect on SARS-CoV-2 S protein and its cellular receptor ACE2, with a higher affinity than drugs such as nafamostat and hydroxychloroquine (Maurya, Kumar, Prasad, Bhatt, & Saxena, 2020) .

At an EC 50 of higher than 10 µM, curcumin inhibited virus replication by reducing the number of S proteins present in the culture of Vero E6 cells infected with SARS-CoV (Wen et al., 2007) .

The protective effect of resveratrol against multiple viruses has been recently reviewed (Abba, Hassim, Hamzah & Noordin, 2015) . Resveratrol stably binds to the viral protein/ACE2 receptor complex of SARS-CoV-2, indicating it to be a promising agent against COVID-19 by disrupting the virus S protein (Wahedi, Ahmad, & Abbasi, 2020) . In addition, the stilbene diminished the expression of N protein in SARS-CoV-2 and reduced the apoptosis of Vero E6 cells. Moreover, resveratrol alleviated the Vero 

A recent review presented evidence for the use of quercetin along with vitamin C in the therapeutics and prophylaxis of COVID-19 (Colunga Biancatelli, Berrill, Catravas, & Marik, 2020) . Quercetin was identified by the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses of expression profiling experiments as a good therapeutic candidate against SARS-CoV-2 infection (Glinsky, 2020) . According to this system, quercetin inhibited the expression of several potential COV infection-promoting genes (Glinsky, 2020) . In addition, docking studies demonstrated that myricetin and the myricetin-containing phytomedicine Equivir bind to ACE2 receptor and prevented SARS-CoV-2-induced COVID-19 (Ngwa et al., 2020) .

Quercetin inhibited 3CLPro from MERS-CoV (IC 50 = 34.8 µM), whereas no inhibitory activity was detected against MERS-CoV PLPro (Park et al., 2017) . Other PC related to quercetin, such as myricetin and scutellarin, exhibited inhibitory action against SARS-CoV helicase .

Luteolin, a PC structurally related to quercetin, effectively inhibited the entry of wild-type SARS-CoV into Vero E6 cells (Yi et al., 2004) . In a recent study, the Chinese medicine Lianhuaqingwen, containing quercetin, luteolin, and kaempferol, inhibited the replication of SARS-CoV-2 with an IC 50 value of 411.2 µg.mL -1 in Vero E6 cells (Runfeng et al., 2020) .

Sambucus nigra extract is a source of several anthocyanins (cyanidin 3sambubioside accounting for almost half of them) and quercetin 3-rutinoside (Veberic, Jakopic, Stampar, & Schmitzer, 2009 ). S. nigra extract (0.004 g/mL) reduced the titers of infectious bronchitis virus (IBV). This virus is a pathogenic chicken coronavirus, and the impairment of the viral membrane is the most likely mechanism reported by workers, compromising the envelope structure and vesicle formation (Chen et al., 2014) . Forsythia suspensa Vahl. is widely used in traditional Chinese medicine and is rich in Forsythoside A. This PC inhibited CEK infection by IBV in a dose-dependent manner (0.16-0.64 mM). A direct virucidal effect was observed when the PC was administered before IBV but not when cells were previously infected (Li et al., 2011) .

Papyriflavonol A, present in Broussonetia papyrifera, is the most potent inhibitor of PLPro, with an IC 50 value of 3.7 µM (Park et al., 2017) . Other PC from the same plant (broussochalcone B, broussochalcone A, 4-hydroxyisolonchocarpin, papyriflavonol A, 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane, kazinol A, kazinol B, broussoflavan A, kazinol F, and kazinol J) were more potent against PLPro than against 3CLPro. A molecular docking study revealed that hesperidin, tangeretin, and naringenin from

Citrus sp. presented high affinity for the receptor-binding domain from S protein and the protease domain from ACE2 of the host cell (Utomo et al., 2020) .

The antioxidant capacity of PC has been widely investigated in the past years. It often forms the basis for several of their protective effects on living cells. The mechanisms underlying PC antioxidant capacity involve metal ion-chelating ability, scavenging of ROS, and protecting antioxidant defenses (Martins, Barros, & Ferreira, 2016) .

The direct scavenging ability of PC is exerted either by participating in reactions involving the donation of one electron (i.e., as an H) or by reducing hydroperoxide to alcohol. This prevents the formation of the hydroxyl or alkoxyl radical (Forman, Davies & Ursini, 2014) . The antioxidant activity of PC is directly related to their chemical structures (Amic et al., 2007) . The presence of -CH2COOH and -CH = CHCOOH groups on the benzene ring in phenolic acids enhances their antioxidant activities as compared with the -COOH group (Supplementary material, Figure S1 ). In addition, methoxyl (-OCH 3 ) and phenolic hydroxyl (-OH) groups promote the antioxidant activities of this class of PC . For flavonoids, the most important structural characteristic contributing to a high scavenging capacity is the B ring hydroxyl structure (Salehi et al., 2020) (Supplementary material, Figure S1 ). The hydroxyl groups on this ring donate hydrogen and electrons to stabilize ROS, including hydroxyl and peroxyl radicals, generating a radical form of the antioxidant with greater chemical stability than the initial radical. The formation of these relatively long-lived radicals can modify radical-mediated oxidations (Pereira, Valentão, Pereira & Andrade, 2009 ) implicated in several diseases, including SARS-CoV-2 infection. In addition, the metal-chelating ability could contribute to the antioxidant properties of PC. Flavonoids present strong nucleophilic centers with a high affinity for metal ions; they are primary catalysts responsible for ROS production by cells (Fraga, Galleano, Verstraeten, & Oteiza, 2010) .

The excessive levels of ROS along with a decrease in antioxidant defense generated by SARS-CoV-2 infection induce deleterious effects on the functions of pulmonary cells (lung epithelial and endothelium cells) and red blood cells (RBCs) (affecting cell membrane and the functionality of heme group), causing hypoxic respiratory failure observed in most severe cases of COVID-19 (Laforge et al., 2020; Miripour, Ramin, Sanati, & Makarem, 2020) . Therefore, free radical scavengers, such as PC, could be beneficial co-adjuvant therapeutics for most vulnerable patients. properties observed in several cell lines, including lung epithelial and endothelium cells, and RBCs. In particular, the stilbene resveratrol plays a potential therapeutic role in lung epithelial cells by attenuating oxidative stress generated after infection with

Pseudomonas aeruginosa (Cerqueira, Khaper, Lees, & Ulanova, 2013) and

Streptococcus pneumoniae (Zahlten et al., 2015) . The antioxidant effect of resveratrol has also been demonstrated in i) lung vascular endothelial cells, where 0.1 to 10 µM of the compound attenuated HMGB1-induced mitochondrial oxidative damage and protected the lung endothelial barrier (Dong, et al., 2015) and in ii) RBCs, where 100 µM of the compound prevented cell oxidation generated by H 2 O 2 (Revin et al., 2019) .

The antioxidant potential of resveratrol against H 2 O 2 -induced oxidative stress in RBCs is potentiated by the interaction of other PC present in red wine extract (Tedesco et al., 2000) . Table S1 (Lanping, Zaiqun, Bo, Li, & Zhongli, 2000) and the flavonoid fraction of orange and bergamot juices (that contained vicenin-2, neohesperidin, narirutin, hesperidin, naringenin, tangeritin, and nobiletin) reduced ROS generation in lung epithelial cells (Ferlazzo et al., 2015) .

The antioxidant activity of PC has been mainly investigated either in vitro or in vivo using animal models (Espín, González-Sarrías, & Tomás-Barberán, 2010; Martins, Barros & Ferreira, 2016) , whereas studies on humans, i.e., clinical trials are still limited. Table S2 ).

Recently, it has been reported that the mechanisms of action of PC include processes more than direct scavenging of ROS. For example, these compounds i) activate transcription factors involved in the Nrf2-ARE pathway and induce antioxidant enzymes, ii) exhibit xenohormetic effect, and iii) improve cell homeostasis due to their binding activity to peptides and proteins (Tressera-Rimbau et al., 2018) .

Although recent studies have reported the potential use of certain PC in the treatment of COVID-19, they were mostly focused on the antiviral activity mechanisms (Marinella, 2020 suggesting that the supplementation with quercetin was beneficial in treating respiratory viral infections (Yasui et al., 2015) . Accordingly, increased antioxidant defenses by activating Nrf2 by flavonoids have been discussed (Serafini, Peluso & Raguzzini, 2010) and likely contribute to their anti-inflammatory property. Furthermore, several other studies indicated that flavonoids modulate the inflammatory response by activating pathways that induce the transcription of antioxidant and detoxification defense systems (Rahman, Biswas & Kirkham, 2006) . This interplay between antioxidant and antiinflammatory effects of PC reinforce their putative beneficial role against manifestations of SARS-CoV-2 infection.

The immunomodulatory ability of PC is evidenced by their ability to modulate the NF-kβ pathway by suppressing the activation of IKK or by preventing the binding of NF-κB to DNA. In addition, PC modulate the expression of pro-inflammatory genes and cytokine production, besides influencing several populations of immune cells (Wang, Liu, Xiao, Zhu, Wang & Yan, 2014; Wu, Wang, Pae, & Meydani, 2012) .

Natural killer ( (Yun et al., 2008) , and malvidin (Dai, Shi, Chen, Shen, & Pan, 2017) have been described to inhibit the activation of the NF-kβ pathway.

In addition to isolated PC, plant extracts containing multiple PC, namely phenolic acids, flavonoids, and even PC precursors such as quinic and shikimic acids, inhibit the NF-kβ pathway in vitro at concentrations ranging from 10 to 300 µg/mL (Pepe et al., 2018; Zhang, Hu, Jiang, Zhao, & Zhu, 2018) .

Cytokine storm, mass secretion of pro-inflammatory cytokines, is one of the µg/mL) reduced the concentration of IL-1β .

Resveratrol reduced the levels of TNF-α and IL-6 in vivo (100 mg/kg b.w./day) and in HTLV-1-infected CD4 + T lymphocytes (20-40 µg/mL) (Fuggetta et al., 2016) . Moreover, the secretion of TNF-α and IL-6 was reduced in human primary monocytes by oligonol (25 µg/mL), a lychee fruit-derived mixture of low-molecularweight PC (Lee et al., 2016) . At concentrations ranging from 10.8 to 61 µg/mL, quercetin, fisetin, apigenin, resveratrol, and rutin inhibited the production of IL-6, whereas curcumin and partially fisetin (7.4 and 11.4 µg/mL, respectively) suppressed the production of TNF-α in macrophages infected with dengue virus (DENV-2) (Jasso-Miranda et al., 2019). In addition, fisetin, apigenin, and resveratrol downregulated the production of IL-10, whereas rutin and fisetin inhibited the production of IFN-γ (Jasso-anti-inflammatory properties of dietary PC support a possible role for PC-based adjuvant nutritional strategies to combat the inflammatory storm characteristic of COVID-19, apart from mitigating the complications associated with this inflammation.

Although scarce, certain ongoing studies are investigating the therapeutic potential of PC for COVID-19 patients. In a randomized, double-blind, placebocontrolled study, COVID-19 patients receiving a daily dose of 160 mg of a nanomicellar form of curcumin for 14 days reported decreased IL-6 and IL-1β expression and secretion in serum when compared with the placebo group (Valizadeh et al., 2020) .

Currently, three clinical studies are registered at ClinicalTrials.gov using PC to target the inflammation caused by COVID-19. One of these trials will evaluate the use of a dietary supplement containing a molecular complex of quebracho, chestnut tannin extract, and vitamin B12 (Piskorz, 2020) . The second study aims to assess the use of Caesalpinia spinosa extract rich in PC, with a high antioxidant and anti-inflammatory activity, in decreasing the production of pro-inflammatory cytokines (e.g., IL-6) (Manrrique, Margarita Garcia, 2020) . The third clinical trial aims to evaluate the safety and effectiveness of colchicine and herbal phenolic monoterpene fractions when added to the standard treatment in patients with COVID-19 (Mostafaie, 2020) . No results about these trials have been published yet.

The bioavailability of dietary PC should be considered for a more comprehensive appraisal of the health-promoting effect of PC (D'Archivio, Filesi, Varì, most abundant bioactive phytochemical in the human diet, the bioavailability of dietary PC is usually extremely low, ranging from 1 to 10% of the initial amount. The bioavailability of PC depends on several factors, such as food processing (cooking After oral administration, resveratrol is absorbed by passive diffusion or by forming complexes with membrane transporters followed by release into the bloodstream. In the bloodstream, they are mainly present as a glucuronide, sulfate, or in the free form (Gambini et al., 2015) . The concentration of resveratrol in human plasma depends on the dose ingested; it is higher when administered in the morning (Almeida et al., 2009 ). In addition, its administration with ribose or piperine improves its bioavailability, whereas no changes were reported when it is ingested with or without alcohol or in combination with other PC such as quercetin (Ramírez-Garza et al., 2018) .

In contrast, its consumption with a high-fat meal compromises its bioavailability The bioavailability of quercetin is highly dependent on the type of food matrix. In particular, quercetin aglycone derived from onion skin extract powder is significantly more bioavailable than that obtained from apple skin extract (Lee & Mitchell, 2012) or even quercetin dihydrate powder-filled hard capsules (Burak et al., 2017) . The oral bioavailability of quercetin is well understood. Despite the administration of a high oral dose of quercetin, the maximum concentration of the free aglycone in plasma is only in the low nM range owing to its biotransformation during digestion, absorption, and metabolism (Almeida et al., 2018) . Therefore, it is suggested that quercetin can be administered directly by alternative routes, such as a nasal or throat spray, to treat COVID-19 patients in clinical trials (Williamson & Kerimi, 2020) .

It is estimated that only approximately 1.68% of ingested tea catechins are present in human plasma (0.16%), urine (1.1%), and feces (0.42%) 6 h after the ingestion of tea (Warden, Smith, Beecher, Balentine, & Clevidence, 2001) . In particular, Yang et al.

reported that the maximum plasma concentrations for EGCG, EGC, and EC were 0.57, 1.60, and 0.6 µM, respectively, after the consumption of 3 g of decaffeinated green tea (Yang, Chen, Lee, Balentine, Kuo & Schantz, 1998) . To improve the bioavailability of tea catechins, several approaches have been explored. For instance, it encapsulation of tea catechins in protein-based, carbohydrate-based, and lipid-based nanoparticles improved their stability, sustainable release, and cell membrane permeation, resulting in increased bioavailability (Cai et al., 2018) . In addition, molecular modification of compounds, such as synthesizing peracetylated EGCG, increased the bioavailability of this compound because it protected hydroxyl groups on EGCG from oxidative degradation until it is deacetylated into its parent EGCG by esterases in cells, decreasing biotransformation and efflux of EGCG (Lam et al., 2004) . The coadministration of catechins with other bioactive compounds produced a synergistic effect, resulting in improved absorption and inhibition of efflux transporters (Cai et al., 2018) .

observed at concentrations ranging from 0.1 and 640 µM (Table 1 and Supplementary   material, Table S1 ). As discussed above, systemic levels of PC are usually within nM or low µM range due to their low bioavailability and extensive biotransformation during 

About 90% is implicated in the protective effect of grape seed polyphenol extract against neurodegenerative diseases . In contrast, the antioxidant and antiproliferative abilities of flavonoid metabolites, namely phenylpropionic, phenylacetic, and hydroxybenzoic acid derivatives was lower compared to their parent compounds (Dueñas, Surco-Laos, González-Manzano, González-Paramás & Santos-Buelga, 2011; Gao et al., 2006) .

The potential role of microbial-derived PC metabolites against SARS-CoV-2

infection comes from the studies on protocatechuic acid. After human intake of cranberry juice, plasma levels of protocatechuic acid increased and were more strongly correlated with the plasma antioxidant capacity than its parent PC (McKay, Chen, Zampariello & Blumberg, 2015) . In addition, the modulation of macrophage function is majorly responsible for the benefits of protocatechuic acid in the form of antiatherogenic effects of dietary cyanidin-3-glucoside in a mice model of atherosclerosis . Moreover, protocatechuic acid has been demonstrated to attenuate inflammatory response and increase viral clearance and survival rate of mice challenged with the influenza virus H9N2 (Ou et al., 2014) .

The other face of the interplay between PC and gut microbiota is the reshaping of the former by dietary phenolics in a prebiotic-like effect (Cortés-Martín et al., 2020) .

Such effect has been implicated in several phenolic-induced benefits, including improved intestinal homeostasis (Maurer et al., 2019) and immune response, among other relevant biological effects (Kawabata, Yoshioka & Terao, 2019) (Figure 2) . These prebiotic-like effects could be particularly relevant to SARS-CoV-2 therapy because gastrointestinal problems have been reported in approximately 50% of patients in a multicenter study in Hubei, diarrhea being reported in 17% of patients (Gu et al., 2020) .

The supplemental nutrition with soluble dietary fibers, which are classical prebiotics, and even with probiotics, have been recommended for nutrition therapy during the recovery of critically ill COVID-19 patients (Martindale, Patel, Taylor, Arabi, Warren & McClave, 2020 ; National Health Committee of the People's Republic of China, 2020). Moreover, COVID-19 patients exhibited intestinal dysbiosis characterized by a decrease in the diversity and abundance of gut microbiota (Gu et al., 2020; Zuo et al., 2020) , which could represent a potential target for the use of PC (Figure 2 ). Supporting this hypothesis, resveratrol (Cui et al., 2018) and certain resveratrol oligomers (Yu et al., 2019) have been demonstrated to alleviate diarrhea induced by rotavirus in animal models. The inhibition of epithelial Ca 2+ -activated Clchannels contributes to the antisecretory and anti-motility protective effects of these PC (Yu et al., 2019) (Figure 2 ).

ACE2 receptors, which are known to mediate the entry of SARS-CoV-2 into animal cells (Shang et al., 2020) , are highly expressed in the gastrointestinal epithelial cells (Harmer, Gilbert, Borman & Clark, 2002) . The reconstitution of gut microbiota in gnotobiotic rats was demonstrated to decrease colonic ACE2 expression compared to that in germ-free rats , providing evidence that colonic expression of ACE2 is modulated by gut microbiota. Since PC increased the abundance and diversity of gut microbiota in favor of the growth of probiotic bacteria (Singh et al., 2019) , reshaping of gut microbiota by PC could putatively modulate SARS-CoV-2 entry into the host (Figure 2 ).

In addition, COVID-19 severity demonstrated an association with 23 bacterial taxa from fecal samples, mostly from phylum Firmicutes (Zuo et al., 2020) . Clostridium ramosum and Clostridium hathewayi were positively associated with COVID-19 severity, while Erysipelotrichaceae bacterium exhibited a strong positive association with fecal SARS-CoV-2 load (Zuo et al., 2020) . These Clostridium species are reportedly associated with human bacteremia (Elsayed & Zhang, 2004; Forrester & Spain, 2014) . In addition, the fecal SARS-CoV-2 load of COVID-19 patients demonstrates an inverse association with certain Bacteroides species (Zuo et al., 2020) , which are been reported to reduce the expression of ACE2 in murine gut (Geva-Zatorsky et al., 2017) . These data suggest that Bacteroides species probably contribute to combating SARS-CoV-2 infection by hampering virus entry through ACE2 (Zuo et al., 2020) . According to a recent review, several PC and PC-rich foods, such as curcumin, resveratrol, polymeric proanthocyanidins, de-alcoholized red wine, and green tea, reduce the fecal Firmicutes/Bacteroides ratio (Kawabata Yoshioka & Terao, 2019) .

Considering a cause-effect relationship between gut bacterial profile and COVID-19

prognostics, PC is expected to reduce virus load and COVID-19 severity (Figure 2) . ( Figure 2 ). This mechanism could be particularly relevant for counteracting the SARS-CoV-2-related inflammatory storm that is usually associated with ARDS (Shinde, Hansbro, Sohal, Dingle, Eri & Stanley, 2020) . It is noteworthy that soluble PC, particularly the matrix-bound PC, from fruits increased fecal SCFA production in vitro (Molino, Fernández-Miyakawa, Giovando & Rufián-Henares, 2018; Quatrin et al., 2020) as well as in vivo (Cortés-Martín et al., 2020; Maurer et al., 2019) . A fecal transfer experiment conducted recently in mice demonstrated that changes in gut microbiota were responsible for the lung pneumococcal infection secondary to influenza A virus infection (Sencio et al., 2020) . Oral supplementation with acetate, which is the predominant SCFA produced by gut microbiota, reduced the impact of this bacterial infection by modulating the activity of alveolar macrophages (Sencio et al., 2020) .

These data indicate SCFA as relevant therapeutic agents against the complications of viral respiratory infections and reinforce the involvement of the gut-lung axis in these pathologies ( Figure 2 ). The gut-lung axis comprises a two-way interaction, where the function and immune homeostasis of the lung can be affected by metabolites from gut microbiota and vice-versa (Conte & Toraldo, 2020) .

COVID-19-associated dysbiosis (Gu et al., 2020) has a potential impact on the profile of microbe-derived PC metabolites, and should, therefore, be carefully evaluated when considering PC as adjuncts for SARS-CoV-2 treatment ( Figure 2 ). Fecal

Clostridium species, which are positively associated with high-severity COVID-19

cases (Zuo et al., 2020) , have also been implicated in the gut metabolism of PC (Cortés-Martín et al., 2020) . Moreover, emerging evidence reveals that interindividual differences in the ecology of gut microbiota result in different profiles of phenolicderived postbiotics, which could have a key role in the biological effects of PC.

Different metabolic profiles, named metabotypes, were identified for ellagitannins/ellagic acid (Cortés-Martín et al., 2020) and isoflavone daidzein (Mayo et al., 2019) , indicating the relevance of personalized nutrition and pharmacological therapy.

Despite the overall decreased abundance of gut microbiota in SARS-CoV-2 patients, there is also an increased relative abundance of opportunistic bacteria in feces, such as

Rothia and Streptococcus (Gu et al., 2020) species, which are usually associated with increased susceptibility to secondary bacterial lung infection in immunocompromised patients (Maraki & Papadakis, 2015) and Moreover, the modulation of colonic ACE2 by gut microbiota reinforces that the gutlung axis is probably involved in COVID-19 infection . Therefore, dietary modulation of the gut microbiota might be a promising approach for the treatment of COVID-19 infection, as recently suggested by a study recommending dietary fiber and probiotics (Conte & Toraldo, 2020) .

As summarized in Figure 2 , the evidence discussed in this section indicates that gut microbiota probably plays a key role in the putative effects of PC against SARS-CoV-2 infection. Therefore, gut microbiota may provide metabolic pathways either for the production of specific bioactive PC-derived postbiotics or to be targeted to allow the modulation of immune response resulting in the reduction of viral infection and morbidity. Various PC-derived postbiotics exhibit high antioxidant and antiinflammatory properties, which would be potentially beneficial against SARS-CoV-2

infection. In addition, reshaping of gut microbiota by PC has been demonstrated to trigger various mechanisms that could contribute to reducing SARS-CoV-2 infection, such as the downregulation of gut ACE2 expression, upregulation of SCFA production, and control of opportunistic bacteria. The reshaping of gut microbiota by PC could even modulate the respiratory complications of SARS-CoV-2 infection via the gut-lung axis.

Besides their natural occurrence in fruits and vegetables, PC are also present in food additives for coloring and health-improving purposes. PC are also available as tablets, capsules, or powder dietary supplements. The majority of the PC do not have sufficient toxicological studies conducted on animals to define a specific acceptable daily dose (ADI) for safe consumptions by humans. However, PC and PC-rich foods are usually considered to be safe based on the empirical evidence from their regular consumption as natural food constituents and numerous animal studies revealing their beneficial effects on health. Toxicological evaluations available for a few selected PC are discussed below. In general, quercetin appears to be well tolerated in humans when consumed orally, with a considerably low incidence of adverse effects observed at doses up to 1500 mg per day (Andres et al., 2018) . In western diets, the estimated daily intake of quercetin ranges from 3 to 40 mg (aglycone equivalents), while the recommended daily doses of quercetin aglycone via dietary supplements are usually around 500 mg. In 2010, a high-purity quercetin food ingredient was considered GRAS ("Generally Recognized As Safe") under the intended conditions of use by the Food and Drug

Administration (FDA). In this appraisal, a high intake within the estimated ADI of 19 to quercetin/day for a 70-kg adult (Food and drug administration, 2010) However, a chronic toxicity study revealed that rats receiving 40, 400, or 1900 mg of quercetin per day for two years exhibited a dose-dependent increase in chronic nephropathy and a slightly increased incidence of focal hyperplasia of the renal tubule epithelium.

Moreover, a higher incidence of kidney adenomas was observed in male rats at the doses of 400 and 1900 mg quercetin/day (US Department of Health and Human Services, 1992).

Resveratrol, which has a low dietary intake of 6 to 8 mg/day (Chachay et al., 2011) , is present in commercial dietary supplements at 50-500 mg of trans-resveratrol (Sangeetha, Eazhisai Vallabi, Sali, Thanka, & Vasanthi, 2013) . In a study, resveratrol and a nutraceutical formulation containing resveratrol (Longevinex) did not exhibit any sign of toxicity in Sprague-Dawley rats receiving daily doses of 50 and 100 mg for 28 days. Another formulation containing a high-purity trans-resveratrol (resVida®) exhibited low oral toxicity, although high doses (2-3 g/kg b.w./day) appeared to adversely target the kidneys and the bladder in animals. Frequent gastrointestinal discomfort/diarrhea was observed in humans receiving high doses (2.5 g or 5 g per day)

of resveratrol for 29 days (Vang et al., 2011) . On the basis of NOAEL, in animal studies, a daily dose of 450 mg of resveratrol was considered safe for a 60-kg individual, using a 10-fold safety factor (Williams, Burdock, Edwards, Beck, & Bausch, 2009 ).

Curcumin is reported to be effective, safe, and tolerable against various chronic diseases in human trials (Kunnumakkara et al., 2017) . Clinical trials involving healthy human subjects revealed that curcumin induced a 50% contraction of the gall bladder at the dosage of 40 mg/day (Rasyid, Rahman, Jaalam, & Lelo, 2002) . Despite this, JECFA (The Joint FAO/WHO Expert Committee on Food Additives) and EFSA (European Food Safety Authority) established an ADI of up to 3 mg/kg b.w. for curcumin which is equivalent to 210 mg/day for a 70-kg adult (Kocaadam & Şanlier, 2017) .

EGCG is the major PC in green tea. The toxicological studies have demonstrated a pattern of hepatotoxicity associated with the intake amounts of 140 to 1000 mg/day of EGCG (Oketch-Rabah et al., 2020) . A 13-week study on rats and dogs reported a NOAEL of 500 mg/kg b.w./day for EGCG (Isbrucker, Edwards, Wolz, Davidovich, & Bausch, 2006) . Considering the purity and safety factor calculations, this study generated an ADI of 4.6 mg/kg b.w./day for EGCG, which is equivalent to 322 mg EGCG/day for a 70-kg adult. Other studies on EGCG toxicity conducted in both animals and humans were reviewed recently, and an intake of 338 mg EGCG/day was reported to be safe (Hu, Webster, Cao, & Shao, 2018) . Furthermore, European regulatory agencies have proposed daily EGCG limits for supplements, which range from 300 to 1600 mg/day (Yates, Erdman, Shao, Dolan, & Griffiths, 2017) .

Although existing studies indicate high doses to be safe for most dietary PC, relevant concerns are expected when using dietary PC as adjuvant therapy for pregnant COVID-19 patients. It is recommended that the consumption of PC-rich foods and supplements be restricted during the 3 rd trimester of pregnancy due to their association with ductal constriction in fetal heart (Hahn et al., 2017) . This effect is probably mediated by anti-inflammatory mechanisms and is shared by non-steroidal antiinflammatory drugs (Hahn et al., 2017) . Therefore, the possible occurrence of toxicity during PC nutritional approaches for COVID-19 therapeutics should be considered prior to reporting a final statement regarding the clinical use of PC.

The When formulating a PC-based nutritional strategy for COVID-19 therapy, the interaction of PC with numerous therapeutic drugs, such as those used for controlling COVID-19 manifestations (antivirals, antibiotics, and glucocorticoids), must be considered. Green tea extract (containing 100 µM of EGCG) has been demonstrated to inhibit the drug transporters OATP1A1 and OATP1A2 in vitro (Knop et al., 2015) .

Since these transporter proteins are involved in the transport of fluoroquinolones and antiretrovirals, green tea extract should be avoided when using these drugs (Asher et al., 2017) . On the other hand, onion and garlic extracts that are rich in PC potentiated the efficacy of streptomycin and chloramphenicol in vitro (Mahomoodally, Ramcharun & Zengin, 2018 (Andres et al., 2018) . Regarding diabetes management, quercetin (10 mg/kg) increased the bioavailability of intravenous and oral-administered pioglitazone by 25%-75% in female rats (Umathe et al., 2008) . However, current evidence on the interactions of PC with these drugs is scarce and, therefore, caution in PC intake is advised for subjects under these therapies.

As depicted in Figure 3, 

While the present study offers much useful information regarding the putative role of PC in COVID-19 manifestations, an important limitation of this study has to be noted, i.e., the lack of clinical trials evaluating the use of PC compounds in COVID-19

patients. So far, only one clinical trial has been concluded, revealing the positive effects of curcumin (in a nano-micellar form) in reducing the inflammatory manifestations in COVID-19 patients (Valizadeh et al., 2020) . Although other clinical trials are currently being conducted, they concern the effects of PC-containing plant extracts and not the effects of isolated PC.

Therefore, further studies investigating the antiviral effects of PC in animal models or clinical trials are required to further corroborate the promising in silico and in vitro findings regarding the antiviral effects of certain PC. Moreover, as PC could exhibit a certain level of toxicity and may interact with drugs used in COVID-19 management, in vivo studies determining the safe dose levels of PC for therapeutic use should be conducted. Once this evaluation is completed, the next step should be to perform human clinical trials to determine the safety of using PC in humans.

Several of the potential protective mechanisms of PC against COVID-19 infection probably depend on the two-way interaction between PC and gut microbiota.

Therefore, further comprehension of how COVID-19 affects gut microbiota and the impact of these changes on PC transformation during digestion would also be useful for designing the rational use of PC as adjuncts for COVID-19 therapy. 

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