The COVID-19 Pandemic: Diet-Based Approaches Based on Cross-kingdom MicroRNA

Henry Olders, P.Eng, MD, FRCPC

Affiliate Member, Dept of Psychiatry, McGill University, Montreal, Canada

Abstract

For many, the current COVID-19 pandemic creates fear and anxiety, to some extent because we lack control. The virus is invisible, even people we are close to could infect us, apparently healthy people may get severely ill and die, many people are out of work because of social distancing and other measures dictated by governments, vaccines are months away, speculative medical treatments are causing medication shortages for others, and many with other illnesses are avoiding hospitals or emergency rooms.

Are there any measures which are in our control? Most certainly: handwashing, masks, social distancing. And what we eat!

Over thousands of years, traditional medicine has identified certain plants with therapeutic properties when eaten. In some cases, modern science has been able to identify the active molecule, and entrepreneurs are quick to market these compounds as dietary supplements. Unfortunately, it seems that supplements are frequently not as effective as eating the plant.

Suppose we were able to identify dietary ways to reduce our risk of being infected, or if infected to reduce illness severity or to reduce risk of infecting others? Of course, we would need to have access to those foods. Could this happen quickly enough and in sufficient quantities to make a difference? I believe so, because the food supply chain (production and distribution) is very effective and responsive. Certainly able to deliver much more rapidly than the highly regulated supply chains for pharmaceuticals, medical devices, or vaccines!

Why do I think a dietary approach is feasible? In the 1990s, scientists discovered microRNAs. These are small strands of RNA, around 22 nucleotides in length, which have been found to control many physiological processes in animals, plants, bacteria, and viruses. It appears that some plants make microRNA molecules which can be absorbed intact by mammals who eat those plants. The absorbed microRNA can then control the animal’s biological processes, possibly directly, or perhaps working indirectly through the gut microbiome. A number of these microRNAs have already been identified as able to modify the infectivity, severity, or infectiousness of other viruses, including coronaviruses.

What is needed, now, is a concerted effort involving multiple teams and laboratories to identify microRNAs which can affect the SARS-CoV-2 virus causing the current pandemic. For those microRNAs that exhibit stability to food preparation and to digestion, can we find plants which make those microRNAs? Or, can we genetically modify food plants to produce those microRNAs? The technologies to do so are already in widespread use.

And it doesn’t even have to involve plants. What about the bacteria, yeasts, or fungi we already use for food? Bacteria for making yoghurt, kombucha, or sauerkraut; yeast for baking bread or brewing beer; and mushrooms! These can also be genetically modified to produce the desired microRNAs.

Those plants or other foods can then be plugged into the existing worldwide food production and distribution chains. And finally, for even more control, people may choose to grow or make their own.

Can we expect scientists to collaborate in such a huge undertaking? Yes, because the pandemic affects everyone, and we are all in this together!

Introduction

In early 2020, the global pandemic of COVID-19 (CoronaVirus Disease 19), caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome-CoronaVirus 2) is causing massive economic and social disruptions, since, in the absence of any vaccine or effective treatment for this new disease, people are prevented from travelling or even leaving their homes; places of work or worship are shut down, stores are shuttered, flights are cancelled, and many other measures are recommended or even enforced with violence.

The rate of infection and/or serious illness may be influenced by social distancing, handwashing, and PPE (personal protective equipment). Almost certainly, genetics modifies vulnerability. And it is hoped that environment will play a role: with warmer temperatures approaching in the northern hemisphere, will the pandemic die down just like some other viral respiratory illnesses such as influenza or the common cold which are largely seasonal?

Another possible environmental influence may be our diets. For example, is there any correlation between the type of diet a person eats and their risk of infection, of severe illness, or of dying from SARS-CoV-2? This is important to know, because we have much more control over what we eat than we do over whether our hospitals have sufficient respirators or staff.

And, there are exciting recent developments in our understanding of how plant-based MicroRNAs can be absorbed by eating those plants, and can then modify the animal’s biology.

How does SARS-CoV-2 cause illness?

In common with other viruses, a coronavirus particle first has to enter a vulnerable cell, aided by a protease produced by the host cell. The contents of the viral particle enter the cell cytoplasm, and the RNA of the virus attaches to the host cell’s ribosomes as the first step in a complex process. Essentially, the viral RNA is translated into proteins which form the machinery for the virus to make copies of itself, using other tools provided by the host cell. Eventually, the viral progeny can be released to the outside of the host cell, ready to infect other cells.

The host organism’s immune system, if adequately functioning, recognizes the viral particle as foreign and mounts a defense. This defence typically causes inflammation, and one hypothesis is that a severe inflammation in the respiratory system causes malfunction which manifests as coughing and shortness of breath (SOB). Severe SOB, even if treated with intubation and mechanical ventilators, may cause failure of vital organs due to insufficient oxygen. Death can ensue.

Another hypothesis suggests that the virus can get into the brain by infecting nasal mucosa cells in the olfactory epithelium. Olfactory neurons have processes which extend to the outside of the skull through the cribriform plate into the olfactory epithelium. If the virus can gain entrance to these olfactory neurons, it might spread to the respiratory centres in the brain, and affect breathing.

Some individuals infected with SARS-COV-2 have reported a sudden loss of their sense of smell and taste, even before showing any other symptoms. Could this be a manifestation of viral neurotoxicity?

Bottom line: there may be more than one mechanism by which a coronavirus infection causes illness, including inflammation in the lungs, mediated by the host organism; and direct neurotoxicity.

Health effects of plant-based diets: phytochemicals vs miRNA

While much effort is currently being expended on finding a vaccine against SARS-CoV-2, or repurposing medications already approved for other conditions (eg anti-inflammatories such as hydroxychloriquine or colchicine), or attempting to use drugs still in development (eg, remdesivir¹), the focus of this article is on diet-based approaches to COVID-19.

Many studies demonstrate that eating a plant-based diet has long-term health benefits. However, attempts to ascribe these beneficial effects to certain phytochemicals in those plants, whether classified as antioxidants, flavonoids, carotenoids, polyphenols, proanthocyanidins, or other exotic names, extract those phytochemicals as purified preparations, and then give them as dietary supplements, have often had disappointing results in terms of health outcomes. It appears that eating the plant, or parts of it, is not the same as eating the chemicals that are found in the plant.

Why? Well, dose is important: polyphenols and flavonoids, considered to be antioxidants, are actually pro-oxidants when ingested in higher amounts². It has also been posited that these phytochemicals are effective only when ingested together with other compounds (possibly not yet identified) found in the plant. Yet another explanation has to do with non-nutrients found in plants, such as nondigestible fibre. Fibre is carbohydrate for which we do not have the enzymes required to break it down into its constituent glucose molecules. However, bacteria in the gut are able to ferment the fibre, producing gas as well as short-chain fatty acids (SFAs) in the process. We are able to absorb these SFAs, obtaining about 1.5 kcal/g of energy (compared to 4 kcal/g for digestible carbohydrates such as sugars and starches). More important for our health, though, is that these SFAs, particularly butyrate, are highly anti-inflammatory. Moreover, eating fibre encourages growth of the beneficial bacteria producing these anti-inflammatory compounds.

The discovery of microRNA, and especially cross-kingdom effects of these short lengths of RNA, suggest yet another possibility: plant-based miRNA may survive the digestive process and either be absorbed into our cells to influence our biologic processes, or affect our gut bacteria which then in turn produce health effects.

MicroRNA

For many years after the discovery of the DNA molecule which makes up our genes, scientists wondered why so much of our chromosomal material does not code for specific proteins, even calling it “junk DNA”. All that changed when it was discovered that these “nonsense” stretches of DNA between genes actually served to control gene expression, ie whether or not a gene was actually being used to make protein, and how much protein. Two mechanisms have been identified: siRNA (small interfering RNA), and microRNA (also called miRNA; not to be confused with mRNA, or messenger RNA).

MiRNA is a small RNA molecule of around 22 nucleotides, found in plants, animals, and some viruses, that can bind to complementary nucleotide sequences of messenger RNA, thereby “silencing” that mRNA molecule. The human genome is believed to encode around 600 miRNAs, which target about 60% of our genes, including many highly important biological functions, such as sleep duration in children³, and regulation of IGF-1⁴.

In the Moringa oleifera plant, used in traditional medicine, plant reproduction, growth/development and abiotic/biotic stress response appear to be regulated by miRNA⁵.

For example, several miRNAs have been identified as crucial to the host immune response in chicks to infection by the coronavirus responsible for avian infectious bronchitis⁶. In humans with periodontal disease, the inflammatory microRNA, miR-146a, appears to contribute to the development of coronary artery disease⁷.

Although plant miRNAs appear to function by near-perfect pairing with their mRNA targets, animal miRNAs can recognize their target mRNAs with as few as 6-8 nucleotides. Thus, a given animal miRNA may have hundreds of different mRNA targets, and a given target might be regulated by multiple miRNAs.

And while most miRNAs are inside the cell, some circulate in various biological fluids.

Importantly, extracellular miRNAs can enter cells of other species and exert biological effects in those other species. For example, the plant parasite Cuscuta campestris (dodder) produces miRNA which influences its host species’ mRNA to permit greater growth of the parasite species⁸. Similarly, a schistosome miRNA promotes host hepatic fibrosis⁹.

Cross-kingdom microRNA

While it is believed that microRNA systems evolved independently in plants and animals, it is clear that a given microRNA nucleotide sequence could have mRNA targets in other kingdoms. For example, some viruses (kingdom -viriae) have evolved to produce miRNA which targets the host cell’s genome, to benefit the virus¹⁰. Extracellular RNAs, including miRNA, secreted by bacteria responsible for periodontal disease, has been shown to increase expression of host TNF-α in a mouse model¹¹.

Fecal miRNA produced by humans and mice has been shown to downregulate bacterial growth of species such as E. Coli and F. nucleatum¹² and thus may help prevent bacterial colitis. Again using a mouse model, nanoparticles containing miRNA from ginger were taken up by gut lactobacillus rhamnosus bacteria, and induced production of IL-22, an interleukin linked to barrier improvement. This was shown to improve mouse colitis¹³. There appears to be a complex interplay between colon bacteria influencing the development of colorectal cancer, and colon mucosal tissue affecting colonic bacterial microfilms, mediated by miRNA¹⁴.

But for the purposes of this article, the finding that mammals can absorb miRNAs from ingested plants diets is particularly important. A 2017 paper reported “Plant miRNAs ingested from food can pass through the gastrointestinal (GI) tract, enter into blood, accumulate in tissues and regulate endogenous gene expression in mammals”¹⁵ and gives a number of examples. The authors suggest that plants may be useful delivery vehicles for therapeutic miRNAs, as some plant miRNA’s are robust and resistant to harsh conditions during digestion. Their lab had previously shown that preparing a decoction of honeysuckle by boiling for 30 minutes led to degradation of most of the miRNAs except for MIR2911, an atypical miRNA encoded by the honeysuckle (a well-known Chinese herb, used for treating influenza infections). MIR2911 significantly inhibited viral replication of the H1N1 virus in mice and prevented infection-induced weight loss¹⁶.

Importantly, further studies on MIR2911 found that a synthetic version was less bioavailable than the plant-derived MIR2911, possibly because the plant-based miRNA resides within a complex that is modified by the host to increase its stability¹⁷.

Biocomputational approaches have been developed to compare plant and mammalian miRNAs in order to find functional sequence homologies¹⁸. The tool they developed, MirCompare, is freely available via the web.

It should be noted, however, that not all researchers believe that plant miRNAs can find their way into mammalian systems¹⁹.

MicroRNA and SARS-CoV-2

What do we know about miRNA which can help in controlling the COVID-19 pandemic?

1. Plant miRNA can have biological effects in animals;
2. Plant miRNA can have effects on our gut bacteria;
3. Gut bacteria miRNA can have effects on their host;
4. Some miRNA from plants can survive processing and digestion, and be absorbed in mammalian guts.

Additionally, plants, bacteria, fungi, or yeasts can be genetically modified to serve as “factories” for producing molecules such as miRNA.

Because plants which produce miRNA that has helpful biological effects on humans can be eaten, existing distribution systems for food can be employed. There would be no need for scarce medical personnel to administer injections or nasal sprays (as for vaccines), or for elaborate drug manufacturing facilities and distribution networks.

In fact, if suitable plants, fungi, yeasts, or bacteria can be harnessed, individuals can grow those plants or mushrooms at home, or make fermented products such as yoghurt, sauerkraut, or kombucha, with the appropriate bacteria, or even bake bread with the appropriate yeasts.

There are an enormous number of pieces in this puzzle that remain missing, the most important being: are there miRNAs which can influence:

1. The likelihood of being infected by SARS-CoV-2;
2. If someone is infected, the disease severity and risk of mortality;
3. The viral replication rate in infected persons;
4. The infectiousness of those replicated particles, including ability to remain viable.

Viruses also encode their own miRNAs to modulate the host’s response and favouring the survival and replication of the virus. This gives rise to the possibility of producing antisense oligonucleotides to silence those viral miRNAs. While such oligonucleotides can be synthesized easily enough, if there is a possibility of identifying naturally occurring short RNA antisense sequences produced by the aforementioned plants, bacteria, fungi, or yeasts, this might help to control SARS-CoV-2 on a wide, even world-wide, scale.

Fortunately, we already have some leads in finding pieces of the puzzle. As mentioned above, the honeysuckle plant produces a resistant miRNA, MIR2911, which has effects on influenza infection in a mouse model²⁰. With respect to the possibility that gut bacteria can modify viral infections, two recent studies found an association between butyrate-producing gut bacteria and less frequent development of lower respiratory tract viral infections, in hematopoietic stem cell transplant recipients²¹ and in kidney transplant recipients²².

Leads to explore

Given that the severity of COVID-19 may be related to the degree of the inflammatory response mounted by the infected individual’s immune system, we know that certain diet-based approaches can reduce inflammation. For example, some species of gut bacteria specialize in fermenting dietary fibre (non-digestible carbohydrate), in the process generating gas but also producing short-chain fatty acids (SCFA) such as butyrate²³, which suppresses inflammation and has other health benefits²⁴. One important non-digestible carbohydrate is inulin, found in appreciable quantities in certain food plants including garlic, leek, and onion, but also plantain, burdock root, chicory root, Jerusalem artichoke, and jicama. Inulin reduces glucose and insulin responses after meals²⁵, and is considered a prebiotic, meaning that it promotes the growth of beneficial gut bacteria such as those producing butyrate. Another such non-digestible carbohydrate is glucomannan, found in konjac, which has been shown to promote weight loss²⁶.

A little-explored possibility is that the prebiotic effect of certain plants in increasing anti-inflammatory gut microbes could be mediated through plant microRNA which increases growth of SCFA-producing bacteria, and possibly also suppresses growth of other, competing gut bacteria. Given that changes in diet can have very rapid effects on the composition of the gut microbiome (for example, diets high in resistant starch induced changes within 3-4 days²⁷; another study showed that an animal-based diet changed the microbiota in only a single day²⁸) it should be possible to rapidly identify specific plants and their microRNA products, and then test those microRNAs for effects on beneficial bacteria, or even directly on the host organism when consuming those plants.

There is a great deal of information available on plants used in traditional medicine to treat type 2 diabetes, neurological disorders, and other common conditions. Many groups have attempted to identify the physiologically active compounds in these plants, typically by preparing plant extracts. Depending on the extraction methods used, the purified compounds could contain microRNA from the parent plant, microRNA which could play an important role in producing the physiological effects demonstrated for the extract. The extent to which this might be true has thus far not been extensively studied.

Next steps

My recommendation is that multiple research groups, laboratories, teams and individuals collaborate on coming up with diet-based interventions to address the current pandemic. The research process might proceed as follows, for a thread based on plants used in traditional medicine:

1. Identify a number of plant species having a specific desirable effect, such as neuroprotective, anti-inflammatory, or insulin-reducing;
2. For a given physiological effect, look for plant microRNAs in common for the species having that effect;
3. Using existing software developed for this purpose, search for mammalian targets for these plant microRNAs. As only short RNA sequences (6-8 nucleotides) can be in play, there may be many potential mammalian targets;
4. Out of the list of targets, identify those genes which are believed to play an important role in the physiological effect under consideration;
5. For the most promising candidates, synthesize the microRNAs involved;
6. Test these microRNAs for stability under the usual processes of food preparation and food digestion;
7. For stable microRNAs, test on animal models of COVID-19 (if available) or on animal models of similar viral diseases.
8. For promising stable microRNAs, develop platforms for producing food substances enriched in these microRNAs using rapidly-growing species such as bacteria used in fermenting foods such as yoghurt, sauerkraut, or kombucha; yeasts used for beer, wine, or bread production; algae that can be consumed directly as liquid or dried preparations; or fungi such as edible mushrooms. Food plants or herbals which can be grown indoors and have short maturation cycles might also be suitable. Ultimately, the goal is to find production platforms that can be operationalized at large scale in existing food production facilities, including for individuals at home.

Note that this last step should be started immediately, even before identification of stable microRNAs effective against COVID-19. Multiple laboratories could begin looking for production platforms for known stable plant-origin microRNAs such as the Honeysuckle-encoded MIR2911²⁹, known to have effects on influenza A viruses.

MicroRNA and other coronaviruses

In addition to the approach outlined above, which starts with traditional medicine, there is also a large fund of knowledge about viruses similar to SARS-CoV-2, with new information about SARS-CoV-2 being added daily.

The SARS epidemic of 2002-2004 and the MERS epidemic in 2012-2013 prompted studies into how coronaviruses enter into cells, how they replicate, and how these processes can be slowed or halted. For example, it has been possible to construct specific silencing RNA molecules which could inhibit gene expression of the Spike protein in cells infected with SARS-CoV³⁰. Mallick et al. have developed a complex interaction map among disease-related factors, miRNAs, and bronchoalveolar stem cells showing how SARS-CoV co-opts the miRNAs from the host cell to suppress its own replication so as to evade immune elimination until successful transmission has taken place³¹.

Using specialized software, the complete genome sequence of the MERS-CoV was analyzed to find sequences which have significant similarity with human miRNAs, with the goal of identifying potential therapeutic targets for antiviral therapies³². Another study used computational methods to rationally design four miRNA and five siRNA molecules for potentially silencing nine different MERS-CoV strains³³.

Coronaviruses possess a nucleocapsid, an essential structural protein. The nucleocapsid of the human coronavirus OC43 (one of the agents responsible for the common cold) has been found to bind miR-9, which is a negative regulator of a transcription factor. This appears to be a mechanism by which RNA viruses can evade an immune response³⁴.

Artificial intelligence algorithms have been used to identify cross-kingdom miRNAs, including viral miRNAs, which are potentially transportable into human blood circulation³⁵.

Given the potential of diet-based approaches to utilize the highly effective existing food production and food distribution chains, can we refine our research into SARS-CoV-2 to identify microRNA targets which can then be plugged into these chains? We can, and I believe we must!

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