How to prevent COVID-19 gastrointestinal inflammation and diarrhea with flavonoids?


In this new study by researchers from University of Development Alternative (A private university)-Bangladesh, University of Tasmania, Hobart, Australia Walailak University-Thailand, University of Aveiro-Portugal and the University of Nottingham Malaysia Campus, it was found that a class of phytochemical called flavonoids including epigallocatechin, gallocatechin, baicalin, hesperetin, luteolin and quercetin could help prevent gastrointestinal inflammation and also diarrhea induced by the SARS-CoV-2 infection.

Infection by the SARS-CoV-2 virus resulting in COVID-19 disease can lead to massive inflammation in the gastrointestinal tract causing severe clinical symptoms.

SARS-CoV-2 infects lungs after binding its spike proteins with alveolar angiotensin-converting enzyme 2 (ACE2), and it also triggers inflammation in the gastrointestinal tract. SARS-CoV-2 invades the gastrointestinal tract by interacting with Toll-like receptor-4 (TLR4) that induces the expression of ACE2.

The influx of ACE2 facilitates cellular binding of more SARS-CoV-2 and causes massive gastrointestinal inflammation leading to diarrhea. Diarrhea prior to COVID-19 infection or COVID-19-induced diarrhea reportedly ends up in a poor prognosis for the patient.

Flavonoids are part of traditional remedies for gastrointestinal disorders. Preclinical studies show that flavonoids can prevent infectious diarrhea. Recent studies show flavonoids can inhibit the multiplication of SARS-CoV-2.

In combination with vitamin D, flavonoids possibly activate nuclear factor erythroid-derived-2-related factor 2 that downregulates ACE2 expression in cells.

The study findings suggest that flavonoids have the potential to prevent SARS-CoV-2 induced diarrhea.

The study findings were published in the peer reviewed journal: Frontiers in Microbiology-Virology.

The SARS-CoV-2 coronavirus , which is the virus responsible for the COVID-19 disease has infected over 228 million worldwide and caused the deaths of almost 4.7 million people.

Across the world, a huge subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive.

Unknown to many, the SARS-CoV-2 coronavirus can cause massive inflammation in the gastrointestinal (GI) tract of infected individuals, thus leading to several clinical symptoms including diarrhea.

The virus is also able to cause a variety of gastrointestinal conditions in the long term as a result of the inflammation including the possibility of cancer according to some experts.

Previous reports have found that diarrhea prior to COVID-19 infection or COVID-19-induced diarrhea often increases the patient’s odds of a poor prognosis.

Past studies have shown that flavonoids, which are a type of phytochemical, can prevent infectious diarrhea.

The COVID-19-Supplements study revealed that flavonoids can help prevent diarrhea in COVID-19 patients when combined with vitamin D. Taken together, this combination treatment can activate nuclear factor erythroid-derived-2-related factor 2 (Nrf2 transcription factor), which downregulates the expression of the angiotensin-converting enzyme 2 (ACE2) receptor in cells.

Although the COVID-19 disease  is primarily a respiratory illness, a wide range of other symptoms may appear in affected individuals. Diarrhea, for example, appears to be a common clinical symptom in some infected patients.

In fact, diarrhea has also been reported in cases of severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome (MERS), both of which are structurally similar to SARS-CoV-2.

According to a published study, current estimates indicate that 10.6% of patients will experience diarrhea during acute SARS-CoV-2 infection.

Role of flavonoids against SARS-CoV-2 induced diarrhea.

It is known that upon entry into the human host, SARS-CoV-2 triggers the immune system in an effort to prevent viral replication in the body. Initially, SARS-CoV-2 infects the human lungs after binding with the ACE2 receptor, which subsequently causes the body to increase the levels of angiotensin II in the blood. As a result, the body releases chemokines, as well as activates cytotoxic (CD8+) and helper (CD4+) T-cell lymphocytes, macrophages, and natural killer (NK) cells.

The cytotoxic T-cells produce interleukin-2 (IL-2) and interferon-gamma (IFNγ), whereas the helper T-cells release pro-inflammatory cytokines like the IL-4, IL-17, IL-21, and IFNγ. Taken together, these substances cause a massive release of mucus that may lead to severe acute respiratory distress syndrome.

It has been found that when there are increased levels of cytokines in the blood, the gut may also be affected. This inflammation may cause significant damage in the layers of the intestinal mucosa.

Further, the imbalance in the gut microbiota and damage to the mucosal cellular barriers facilitate SARS-CoV-2 multiplication and translocation into other tissues in the body. This imbalance, termed dysbiosis, causes diarrhea, mucus secretions, stomach pain, or blood in the stool.

The phytochemicals called flavonoids are commonly found in plants and vegetables. Some of the most common flavonoids include quercetin, baicalin, hesperetin, luteolin, gallocatechin, and epigallocatechin, all of which are secondary metabolites of plants. Taken together, these substances are considered antioxidant, anti-inflammatory, and antimicrobial agents.

It has been found that flavonoids can also help boost the immune system to ward off infections, as they have been found to inhibit some enzymes that are important for the SARS-CoV-2 replication.

The study findings revealed that flavonoids, particularly epigallocatechin-3-gallate found in green tea, along with vitamin D3, can activate the Nrf2 transcription factor. The activation of Nrf2 transcription factor subsequently downregulates ACE2 expression from the cellular surfaces.

Flavonoids also have the potential to alleviate COVID-19 and/or ease diarrhea. Quercetin, the most popular flavonoid, has been shown to prevent the interaction of the SARS-CoV-2 spike protein and ACE2 receptor and suppress the inflammatory markers.

The study team says that more preclinical and clinical studies are needed to further explore the full potential of these phytochemical compounds against COVID-19-induced diarrhea.

COVID-19 and diarrhea

Diarrhea appears to be a common feature in a certain percentage of infected patients, and  this has been observed  in SARS, MERS, and SARS-CoV-2 infections. Around 10.6 percent of patients reportedly had diarrhea during SARS infection; the percentage rose to 30% during MERS infection, the latter being much more deadly than SARS (D’Amico et al., 2020).

The COVID-19 induced gastrointestinal manifestations share similar viral or bacterial infection pathways in humans. Briefly, the virus or viral RNAs triggers the body’s immune system that activates rapidly to prevent viral antigens and their multiplications inside the body. SARS-CoV-2 infects human lungs after binding its spike proteins with alveolar angiotensin-converting enzyme 2 (ACE2) and causes an increase of angiotensin II in the bloodstream that triggers

the release of chemokines and activates both cytotoxic (CD8+) and helper (CD4+) T-cell  lymphocytes and activity  of macrophages and NK cells (Ye et al., 2020). Cytotoxic T-cells produce IL-2 and IFNg, and helper T-cells release proinflammatory cytokines such as IL-4, IL-17, IL-21, and IFNg. It causes massive mucus release and severe acute respiratory distress  syndrome. 

The  increased  cytokines in the bloodstream and SARS-CoV-2 invasion in the gastrointestinal tract by interacting with gut ACE2 receptors cause gastrointestinal dysbiosis. SARS-CoV-2 also binds with Toll-like receptors (TLR) (especially with TLR4).

A healthy gut contains reduced TLR4, but increased expression of TLR4 has been reported under inflammatory conditions (Dheer et al., 2016; Hug et al., 2018). SARS-CoV-2 Spike protein binding with TLR4 may cause  increased expression of ACE-II  receptors in  alveoli’s cellular surfaces and thus increase the intensity   of infection (Aboudounya & Heads, 2021).

Increased inflammation causes significant damage in the single-cell layers of intestinal mucosa and activations of macrophages, NK-cell, and T-cell lymphocytes to  release a  massive amount  of proinflammatory cytokines and chemokines. The imbalance in the gut microbiota and damage of mucosal cellular barriers facilitate multiplications of SARS-CoV-2 and translocation into other tissues. This dysbiosis triggers diarrhea, bloody diarrhea, mucus secretions, and gastro- intestinal pain (Figure 1).

Interestingly, an analysis of COVID-19 severity found a more significant percentage of diarrheal occurrence in severe patients than in less severe patients (5.8% versus 3.5%, respectively) (Guan et al., 2020). The opposite also holds true; patients with diarrhea followed by infection with the SARS-CoV-2 virus were more likely to develop acute respiratory distress and require mechanical ventilation than COVID-19 non-diarrheal patients (6.76% versus 2.08%, respectively) (Jin et al., 2020).

This would suggest a gut-lung axis where changes   in the gut biome because of COVID-19 would trigger a systemic cytokine release, which may exacerbate COVID-19 induced lung distress. On the other hand, COVID-19 does cause changes in the gut microbiota with a decrease in beneficial microorganisms and an increase in opportunistic pathogens, which can be discerned in the fecal samples of COVID-19 patients (Zuo et al., 2020).

Age, mode of delivery (normal or Caesarian), con- sumption of nutrients, antioxidants, natural antimicrobial compounds, and probiotics, along with mental well-being, can contribute to gastrointestinal microbiota (Thursby & Juge, 2017), preventing diarrhea and increase immunity against common viral and bacterial infections. Flavonoids are secondary metabolites of plants. Flavonoids such as quercetin, hesperetin, baicalin, luteolin, gallocatechin and epigallocatechin gallate are antioxidants, anti-inflammatory, and antimicrobial agents.

These  compounds  can  boost  the immunity of people against viruses as they  inhibit  some enzymes (e.g. Papain Like protease (PLpro), RNA- dependent RNA polymerase (RdRp), Chymotrypsin-Like Protease (3CLpro), and NTPase/helicase), which are essential for the replication and transcription of  SARS-CoV-2  (Russo et al., 2020; Mouffouk et al., 2021).

Flavonoids like epigallocatechin-3-gallate (from green tea) along with vitamin D3 consumption are believed to activate the nuclear factor erythroid-derived 2-related factor 2 (Nrf2 transcription factor) that down-regulates ACE2 expression from the cellular surfaces and may protect cells against SARS-CoV-2 infection (Mendonca & Soliman, 2020). This interaction would help develop immunity against infections, reduce oxidative stress, and release proinflammatory cytokines caused by the virus (Figure 1).

Role of flavonoids against COVID-19 induced diarrhea

Flavonoids can act against COVID-19 induced diarrhea in three ways. It can alleviate COVID-19, it can alleviate diarrhea,    or it can alleviate both COVID-19 and  diarrhea. Amelioration of acute and chronic diarrhea by flavonoids has been attributed to reducing intestinal motility and reducing  chronic gut intestinal inflammatory injury (Gálvez et al., 2001).

It has been shown repeatedly that various flavonoids can ameliorate diarrhea through a number of mechanisms. For instance, Psidium guajava has been traditionally used to prevent gastrointestinal disorders in many countries, and flavonoids like quercetin (from Psidium guajava) prevent Shigella and Escherichia coli-induced diarrhea (Hirudkar et al., 2020). Incidentally, quercetin may also inhibit viral entry into host cells and in silico studies have shown that the flavonoid can inhibit Mpro of SARS-CoV-2 (Brito et al., 2021).

A similar observation is applicable also for baicalein, a flavonoid present in  Scutellaria baicalensis. Baicalein has been shown to inhibit SARS-CoV-2 and its 3C-like protease replication in vitro (Liu et al., 2021b), and suppress colonic motility (Kim  et  al., 2019). In senna extract-induced acute diarrhea in BALB/c mice, flavonoids from Malus pumila leaves lowered diarrhea index and decreased the levels of inflammatory cytokines like interleukin 6 (IL-6), interleukin 12 (IL-12), and tumor necrosis factor-a (TNF-a).

This ameliorating effect was reported to be caused by ten flavonoids, namely rutin, hyperoside, isoquercitrin, taxifolin, quercitrin, hesperidin, myricetin, baicalin, neohesperidin dihydrochalcone and quercetin (Yi et al., 2020). Incidentally most of these flavonoids have been variously reported to be able to bind and inhibit various integral proteins of SARS-CoV-2  necessary for viral entry and replication in human cells (Alzaabi et al., 2021). Thus, flavonoids can have a dual effect of alleviating diarrhea through inhibitory effects on causative agents (like SARS-CoV-2) as well as contractile inhibitions (Zhang et al., 2003).

Quercetin, Luteolin and Quercetin 7-rhamnoside showed efficacy against porcine epidemic diarrhea virus (Choi et al., 2009), as these compounds interfere the viral replication at initial stage and thus similarly it can work against SARS- CoV-2 induced diarrhoea.

In silico studies exhibit that quercetin interacts firmly with SARS-CoV-2 spike proteins (Colunga Biancatelli et al., 2020; Derosa et al., 2021), and the compound showed potent inhibition against 3CLpro and PLpro enzymes of SARS-CoV-2 (Derosa et al., 2021). Noticeably, its efficacy after oral consumption is limited by its poor solubility and bioavailability, which can be improved by developing a complex with phospholipids like lecithin as it was done in a randomized clinical trial (Di Pierro et al., 2021).     

In this clinical study, daily oral intake of 1 g quercetin improved symptoms, reduced fatigue, improved appetite and overall health conditions of non-critical COVID-19 patients (Di Pierro et al., 2021). Flavonoids such as quercetin can inhibit interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-a and other proinflammatory markers from  inflamed  GI  lumen or other organs (especially lung and other parts of the respiratory system) affected by viral or bacterial infections, which are major symptoms of COVID-19 (Huang et al., 2020; Bastaminejad et al., 2021). The compound (quercetin) also displayed efficacy against lung infections (Heinz et al., 2010; Wang et al., 2018).

Nigella sativa oil or extract (key flavonoids: Quercetin, kaempferol and quercitrin) showed efficacy against diarrhea and protective effects on rodents’ gastric and cecal tissues (Eida et al., 2015; Toma et al., 2015). Another clinical study showed (ID: NCT04401202 in that oral treatment of essential oil of Nigella sativa (500 mg/capsule,

twice daily) for ten days moderately improved symptoms of COVID-19 in non-critical patients against patients treated with the standard form of care (Koshak et al., 2020). COVID-19 patients treated with quercetin-rich traditional Chinese herbs reportedly experienced improved immunity against SARS-CoV-2 and less hospitalization (Luo et al., 2020). Various other flavonoids like (-)-Gallocatechin gallate (GCG), (-)- Epigallocatechin-3-O-gallate (EGCG), Kaempferol, Luteolin, and Puerarin showed promising effects against COVID-19 infections (Table 1).

These flavonoids act against the SARS- CoV-2 by three major ways:

(1) inhibition of interactions between ACE-2 of host cells and SARS-CoV-2 spike proteins,

(ii) inhibition of SARS-CoV-2 protease enzymes like 3CLpro and PLpro and its replication process, and

(iii) inhibition of proinflammatory cytokines (e.g. IL-6, IL-17, TNF- α ) caused by SARS-CoV-2 infection (Figure 1, Table 1). SARS-CoV-2 produces inflammation in gastrointestinal tract, lungs and other organs. Flavonoids have antidiarrheal, anti-inflammatory and antiviral properties, as shown in preclinical, preliminary clinical and in silico studies (Colunga Biancatelli et al., 2020; Hirudkar et al., 2020; D’Ascanio et al., 2021; Derosa et al., 2021; Di Pierro et al., 2021).

Flavonoids can not only alleviate inflammation through down-regulation of pro-inflammatory cytokines (Ginwala et al., 2019) but also disrupt the lipid raft and inhibit TLR4 signaling (Pei et al., 2020). Thus, flavonoid compounds may provide good therapeutic or supplementary reliefs against SARS-CoV-2 induced diarrhea (Figure 1).

To date, any evidence of the role of flavonoids against SARS-CoV-2 induced diarrhea is preliminary, and more importantly, in vitro preclinical and clinical studies are essential to explore the full potential of these compounds against SARS-CoV-2-induced diarrhea. On the other hand, a number of flavonoids have anti-diarrheal effects, as demonstrated in non-COVID-19 patients (Chen et al., 2014).

It has been suggested that “flavonoids may ameliorate acute and chronic diarrhea by inhibition of intestinal motility and secretion and may also be helpful in reducing chronic inflammatory injury in the gut by protecting it from oxidative stress and preserving mucosal function” (Galvez et al., 2001).

Flavonoids have been used in traditional medicines over the centuries, and these compounds have antimicrobial, antiviral, and gastro-entero-protective effects and may be potential therapeutics for SARS-CoV-2-induced diarrhea. From that viewpoint, flavonoids deserve a closer examination for their potentially beneficial effects in improving COVID-19 prognosis when diarrhea is a comorbidity.

Table  1.  Role  of  flavonoids  against  SARS-CoV-2  associated infections

Names of flavonoidsRole against SARS-CoV-2Reference
(-)-Epigallocatechin-3-O-gallateInhibited SARS-CoV-2 spike protein interaction with ACE2(Wang et al., 2021)
(EGCG)receptor (in silico) 
(-)-Gallocatechin gallate (GCG)Inhibited 3CLpro and PLpro proteins (in silico)(Swargiary et al., 2020)
KaempferolInhibited COVID-19 enzymes 3CLpro and PLpro (in silico)(He et al., 2020; Khan et al., 2021)
Luteolin1. Reduced proinflammatory cytokines (e.g. TNF-α, IL-1β, IL-6, and so on)
2. Prevented Toll-like receptor 4 (TLR4)/TNF receptor-associated factor 6/nuclear transcription factor-kB (NF-kB) signaling pathway of inflammation
(Yang et al., 2020)

Puerarin                                           1.  Inhibited  SARS-CoV-2  spike  protein  interaction with ACE2 receprot (in silico)
2. It suppressed inflammatory markers (e.g. TNF-α, IL-2, IL-17, mitogen-activated protein kinase (MAPK), peroxisome-proliferator activator receptor γ (PPARγ) and nitric oxide synthase 3 (NOS3))
(Qin et al., 2021)
QuercetinInhibited SARS-CoV-2 spike protein interactions with ACE2 receptor (in silico)(Di Pierro et al., 2021)
QuercetinInhibited COVID-19 enzymes 3CLpro and PLpro (in silico)(Derosa et al., 2021)
QuercetinReduced proinflammatory cytokines (e.g. IL-6, IL-17, TNF-a)(Bastaminejad & Bakhtiyari, 2020; Huang et al., 2020)
LuteolinImproved smell or taste disorders of patients with post-COVID-19 infections (clinal study)(D’Ascanio et al., 2021)
QuercetinQuercetin reduced the length of hospital stay and severity of infections in SARS-CoV-2 infected patients with mild and moderate symptoms (clinical study)(Di Pierro et al., 2021)

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