Study suggests tea polyphenols may modulate COVID-19 via intestinal microbiota

The coronavirus disease 2019 (COVID-19) pandemic was declared in March 2020 and triggered the implementation of a wide range of non-pharmaceutical interventions (NPIs) to stop the spread of the virus.

This has led to over 5.8 million deaths so far, and understandably, there is much interest in identifying safe and effective antivirals to prevent and treat the disease, and reduce the global toll of the outbreak.

A new paper in the journal Foods discusses the state of current knowledge about the potential use of tea polyphenols in the prevention and treatment of COVID-19.

Introduction

Gastrointestinal involvement has been a prominent manifestation in COVID-19, and patients with gut symptoms show rapid progression and more severe disease, as well as a less favorable outcome, compared to those without it. The possibility of preventing or altering this disease trajectory by interventions targeting the gut is, therefore, a promising one.

Tea polyphenols have been shown to regulate intestinal homeostasis and the gut microbiome. In the current situation, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first attaches the cell membrane of the host cell, and then enters the cell to establish a productive infection. This is mediated via the spike antigen, which achieves attachment and membrane fusion with the host cell angiotensin-converting enzyme 2 (ACE2) receptor through its receptor-binding domain (RBD).

The spike protein also binds to a receptor called CD209L, to accomplish cell entry via caveolin and clathrin in an endocytosis-dependent manner, though this is not the dominant mechanism of infection.

While vaccine development was given top priority in order to arrest or at least mute the outbreak, the current study focused on the potential utility of gut microbiome modulation to enhance the immune response to the vaccine and thus boost vaccine efficacy. With the emergence of Omicron, a variant with the largest number of mutations known so far, scientists fear that widespread infections can cause a fresh wave of hospitalizations and deaths.

The intestinal microbiome is crucial to digestion, metabolism and the synthesis of several essential nutritional factors in the body. These microbes may help with the enzymatic breakdown of plant polysaccharides and polyphenols – the latter are also called tannins.

Tannins are found in a multitude of plant foods, including vegetables, fruits, and seeds. Tea, coffee, grapes, kidney beans, and red wine are particularly rich in tannins.

Effects on the gut wall

Dietary constituents rich in polyphenols promote health, preventing the toxic changes of environmental factors such as unhealthy diet, abundant antibiotics and undesirable lifestyle factors on the gut microbiome. Dysbiosis could lead to increased intestinal permeability and permeability of the blood-brain barrier, inflammation of the nervous system, and eventually neurodegenerative diseases.

These compounds promote probiotic growth within the gut, inhibit colonization by pathogenic bacteria, and maintain a favorable balance of microbes such as Escherichia coli, Lactobacillus, and Enterococcus within the gut.

Polyphenols also promote cardiovascular health via their metabolic or signaling pathways. They have an anti-inflammatory action, and may thus prevent inflammatory and malignant processes, often caused by the after-effects of viral infection. Their breakdown by the intestinal microbiome yields bioactive compounds that can be readily absorbed.

Some of the microbes involved in this processing of polyphenolic compounds from plant foods include Lactobacillus plantarum ZLP001, which also strengthens the intestinal epithelial barrier to promote gut mucosal integrity.

Tea polyphenols can maintain the health of the intestinal mucosal barrier, preventing gut epithelial apoptosis, reducing intestinal mucosal damage and suppressing the inhibition of TLR2 transcription induced by some bacterial toxins such as those caused by certain strains of Escherichia coli, triggering diarrhea, mucosal epithelial damage and ulceration of the epithelium with local invasion and inflammation.

These compounds reduce gastric mucosal damage caused by Helicobacter pylori, encourage regeneration of these cells, and reduce ethanol-induced production of COX2 and inducible nitric oxide synthase (iNOS) in gastric mucosa to prevent acute gastric mucosal injury.

Anti-inflammatory activity

Green tea is rich in the epicatechin EGCG, which has been studied intensively over the last few decades. Known to have antimicrobial, antioxidant and anti-inflammatory effects, as well as antitumor effects, it is claimed to be associated with lower rates of cancer, cardiovascular disease, and neurologic disease.

It inhibits many inflammatory cascades including those involved in COX2, IL-6 and IL-1β production via the tumor necrosis factor TNF-α pathway. It seems to act via its ability to suppress the initiation of the NLRP3 inflammasome, preventing the activation of its assembly process. It thus inhibits the activation of macrophages by lipopolysaccharide bacterial antigens, and spatially inhibits mitochondrial translocation during inflammasome activation.

Antiviral activity

Earlier studies reported that the use of catechin and theanthin in capsule form reduced the risk of symptomatic flu infection, and shortened the recovery time. The compound also appears useful in preventing the surface release of hepatitis B virus (HBV) antigens as well as the secretion of the viral DNA, which could lead to its development as an anti-HBV drug.

Antitumor activity

Plant polyphenols also reduce tumor risk by inducing the differentiation of tumor cells and apoptosis and regulating the tumor cell cycle, besides suppressing tumor cell proliferation. Polyphenols like quercetin, resveratrol, ethanol and grape polyphenols inhibit nitric oxide synthase and thus protect human health, as well as showing in vitro inhibition of cancer cell proliferation and differentiation.

For blocking SARS-CoV-2 entry

Besides the potent anti-inflammatory effects of EGCG, tea polyphenols can activate the protective transcription factor Nrf2 and thus inhibit SARS-CoV-2 entry into host cells via Nrf2 regulation of multiple genes, including those involved in antioxidant, immune and antiviral activity. EGCG increases the expression of type I interferon via Nrf2, while recruiting innate immune cells.

EGCG not only blocks SARS-CoV-2-receptor binding but can inhibit the viral papain-like protease as well, preventing spike activity by binding to the S1 spike subunit at the ubiquitin-binding site.

The regulation of the gut microbiota through long-term individualized dietary modification [including tea polyphenols] is a viable strategy for the prevention and intervention of COVID-19”, explained the researchers.

Since ciliated glandular gut mucosal epithelial cells are very vulnerable to the infection, due to the high ACE2 expression on these cells, the binding of this receptor in the gut cells could lead to malfunctioning of the gut cells, including malabsorption of the key molecule tryptophan, and its bioactive metabolite called nicotinamide. This amino acid can regulate the microbiome composition and modulate antimicrobial peptide expression.

The results of disrupted tryptophan homeostasis in the gut include the reduced production of antimicrobial peptides, inflammation in the intestinal mucosa, dysregulated enteric nervous system activity, and diarrhea.

EGCG also has powerful antioxidant activity that may block the oxidative stress induced by SARS-CoV-2. It could also inhibit the viral main protease Mpro, required for virus reproduction. It can block endoplasmic reticulum stress and the viral life cycle as well as suppress acute lung injury, acute respiratory distress syndrome, thrombosis, sepsis, and pulmonary fibrosis.

Conclusion

EGCG can be used as a broad-spectrum therapy for asymptomatic and symptomatic COVID-19 patients. Compared with vaccines, polyphenol interventions are not targeted and only universal. It is hoped that through the study of specific dietary intervention mechanisms, the occurrence of COVID-19 virus infections can be reduced or prevented”, the researchers concluded.

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.