COVID infections and the link to the gut microbiome­­

Recent research into COVID-19 has found that the composition of the gut microbiome may influence the severity and duration of infections and how the immune system responds.

COVID-19 is primarily a respiratory illness, but gastrointestinal symptoms, including nausea, abdominal pain, vomiting and diarrhoea are also commonly reported: indicating the involvement of the gut.  

The COVID-19 virus invades cells by a process that starts with the virus binding to a cell surface receptor called ACE2 (Gao et al., 2020). While this receptor is found in high levels on the surfaces of cells lining the lungs (lung epithelium), it is also found in high levels in the intestines (intestinal epithelium) (Uno, 2020).

 In the gut, ACE2 is linked to the gut microbiome and plays a role in gut inflammation (Gao et al., 2020; Garg et al., 2020). 

COVID-19 viral material has been detected in stool samples, even after respiratory tract samples test negative. This all shows that the COVID-19 virus can and does invade the intestinal epithelium. 

In order for the COVID-19 virus to invade intestinal epithelial cells, it must survive transit through the stomach, and resist stomach acid. Individuals on proton pump inhibitors (which reduce stomach acidity) are at risk of increased COVID-19 symptom severity and duration (Lee et al., 2021; Lee et al., 2020; Zhou et al., 2020).

Similarly, susceptibility to the virus is age-related (Zimmerman & Curtis, 2020), and increased age is associated with decreased stomach acidity (Uno, 2020), as well as decreased overall immune function and microbial dysbiosis (Amsterdam & Ostrov, 2018). 

The makeup of the gut microbiome also plays a role in COVID-19 incidence and severity.

In a recent study, researchers from the Chinese University of Hong Kong (Yeoh et al., 2021) analysed blood and stool samples and medical records from 100 people with COVID-19 infections, and 78 people without COVID-19 who were taking part in a microbiome study before the pandemic. 

Analysis of the stool samples showed that the make-up of the gut microbiome differed significantly between patients with and without COVID-19, irrespective of whether they had been treated with drugs, including antibiotics. 

COVID-19 patients had higher numbers than people without the infection of several bacterial species including Ruminococcus gnavus, Ruminococcus torques and Bacteroides dorei. The COVID-19 patients also had far fewer of the bacterial species that have been shown to improve immune system responses, such as Bifidobacterium adolescentis, Faecalibacterium prausnitzii (F. prau) and Eubacterium rectale. Lower numbers of F. prau and Bifidobacterium bifidum were particularly associated with the severity of COVID-19 symptoms. 

A previous study showed COVID-19 patients had lower numbers of several bacterial species, including E. rectale and F. prau compared to healthy individuals (Zuo et al., 2020). 

Again, F. prau, and a bacterium called Alistipes, most strongly negatively correlated with disease severity. These COVID-19 patients were also shown to have greater numbers of opportunistic pathogens known to cause bacteraemia (presence of bacteria in the bloodstream), and greater numbers of species known to upregulate ACE2 numbers in the gut. This microbial dysbiosis persisted during and after hospitalisation of the patients.  A further study investigated gut microbiome differences in patients with COVID-19 and influenza A (H1N1) compared to healthy people (Gu et al., 2020). 

People with COVID-19 or H1N1 had lower microbial diversity (a measure of microbial ecosystem robustness), and the relative abundance of Streptococcus and Escherichia/Shigella was significantly higher in COVID-19 and H1N1 patients, respectively. A lower relative abundance of beneficial gut microbes, including Faecalibacterium was also observed in both COVID-19 and H1N1 patients.  

The depletion of key bacterial species in the gut microbiota of COVID-19 patients was also associated with increased concentrations of inflammatory cytokines (Yeoh et al., 2021), suggesting the gut microbiome is influencing the immune system’s response to the COVID-19 infection. Imbalances in the make-up of the microbiome may also be implicated in persistent inflammatory symptoms, dubbed ‘long COVID’. 

The collective research suggests that bolstering of beneficial gut species depleted in COVID-19 such as F. prau through the use of prebiotics and/or probiotics could serve as a way to reduce the duration and severity of the disease.

However, F. prau is highly oxygen sensitive and cannot be viably delivered for consumption in adequate live numbers in a probiotic supplement format.

A better proposition are prebiotics: food which survives digestion and reaches our large intestine to selectively increase the numbers of gut bacteria that confer health benefits. Diet has been shown to increase F. prau numbers (Singh et al., 2017), particularly high carbohydrate/low glycemic impact diets (Fava et al., 2013).

In terms of selectively increasing F. prau, Livaux® from New Zealand gold kiwifruit is a natural prebiotic clinically shown to increase F. prau levels in individuals with low baseline levels (Blatchford et al., 2017).

This effect has also been demonstrated in vitro (Duysburgh et al., 2019). Livaux contains high methoxy pectin, which is known to be a substrate (food) used for growth by F. prau (Lopez-Siles et al., 2011). 

Gut microbiome and Immunity

Our immune system is very complex and provides the vital function of protecting us from invaders/pathogens, such as viruses, bacteria, parasites, fungi, toxins, etc. A good analogy for the immune system is a bank – the bank has various mechanisms to protect all the valuables inside (our blood and organs) from robbers (the pathogens).

Our immune system uses two types of immunity to protect us – innate (non-specific) immunity and adaptive (specific) immunity.

Innate immunity is what we are born with and includes external and internal defences to keep out the robbers or to apprehend and eliminate them if they do get into the bank.

The external defences are represented by the bank’s walls – these are the physical and chemical barriers of the innate immune system, for example:

• Our skin and gut epithelium (digestive tract walls) – the main physical barriers that cover our body’s surfaces.
• Saliva and tears – these contain antibacterial enzymes to break down bacteria and can be used to flush/wash them out of our mouth and eyes.
• Mucus – this thick fluid lines our respiratory and digestive tracts and can trap dirt and microbes.
• Stomach acid – the low pH of the acid in our stomach can kill acid-intolerant microbes

The bank’s security guards represent the internal defences. These are the components of the inflammatory response including defence compounds, such as cytokines and defensins, and white blood cells, namely phagocytes (which include macrophages, dendritic cells and neutrophils) and natural killer cells. Phagocytes eat and destroy other cells by a process called phagocytosis – the phagocytes identify and respond to pathogens and infected/dead/damaged cells, bind to them, and then engulf and destroy them.

Our adaptive immunity is developed over time and is based on having exposure to things, like a disease/virus or a vaccine. If the robbers get past the bank walls and overwhelm the security guards, then the security guards (macrophages and dendritic cells) trigger the alarm system (they become antigen presenting cells (APCs)) to call for backup from the police – the lymphocytes, known as T and B cells.

The police can deploy additional weapons to fight off or capture the robbers. For example, T cells, through the cell-mediated response, are activated by the APCs and then differentiate into various types of T cells to help fight the infection – cytotoxic T cells directly attach to and kill pathogens and virus-infected cells, while helper T cells stimulate the response of B cells and macrophages.

APCs and T helper cells stimulate B cells, which produce antibodies to bind and neutralise pathogens. The antibodies are specific to a particular antigen and once bound to that antigen on a cell/pathogen,

they are effectively in handcuffs/jail – the cell/pathogen is no longer able to move, reproduce and infect other cells.

While this is going on, memory T and B cells (our CCTV capturing footage of the robbers) are produced and remain in the lymphatic tissue so that if the same robber returns they are able to form a stronger, faster response.

How does our gut microbiome fit with our immune system?

The human body actually contains about the same number of bacterial cells as human ones. Within and on our body are trillions of microbes, collectively known as microbiota, or when the genetic material of these microbes is included, this is the microbiome, however the two words tend to be used interchangeably these days.

Approximately 95% of the trillions of microbes we host, reside in our gut. This gut microbiome is of particular interest to us being of great importance for not only our intestinal health, but our immune, mental and general health and wellbeing (Martin, Bermudez-Humaran, & Langella, 2018).

The gut microbiome interacts with the human body and plays a vital role in:

• Normal gut development
• Promotion of fat storage
• Promotion of blood vessel formation
• Modulation of bone density
• Synthesis of vitamins and amino acids
• Modification of the nervous system (gut-brain axis)
• Breaking down food compounds
• The immune system.

The gut microbiome can affect and support the immune system in several ways.

Before we get into that, let’s set the scene. Our gastrointestinal tract has several key components: the gut epithelium (a layer of intestinal epithelial cells that form part of our bank’s walls), the intestinal lumen, and the lamina propria. Lining the epithelium is mucus and within the lumen are the beneficial microbes and pathogens. Within the lamina propria are the cells of our immune system, including dendritic cells and macrophages (those security guards).

The beneficial bacteria provide resistance to pathogens (robbers). This can be via direct or indirect mechanisms (Kamada, Seo, Chen, & Nunez, 2013).

The beneficial microbes also help to modulate, develop and train the immune system (i.e. training of the security guards and police). Microbial colonisation of the gastrointestinal tract appears to start before birth, however, the largest share of colonisation occurs after birth with microbes mainly originating from the mother. The first 1000 days after birth are the most critical with delivery mode, breastfeeding, the introduction of solids, and environmental factors all playing a role in the development and diversification of the gut microbiome. The commensal microorganisms (resident, ‘good’ microbes)

interact with the host and help the immune system differentiate between them (they become like “self”) and the pathogenic bacteria through toll-like receptors (TLRs).

It’s a Two-Way Street

The interaction with the immune system is not just one-way and the condition of both the gut microbiome and the immune system affects that of the other. Unbalanced and poor gut microbiomes can lead to immune health issues such as autoimmunity, allergies and metabolic disorders, and a poor immune system can also cause poor and unbalanced microbiomes. For example, in inflammatory bowel disease (IBD), mutations in genes involved in the immune system can disrupt the gut microbiome, causing dysbiosis, and the loss of protective bacteria and/or the accumulation of pathogens (dysbiosis) leads to chronic inflammation (Kamada, Seo, Chen, & Nunez, 2013).

Likewise, a diverse, rich and balanced microbiome supports a normal immune system which in turn supports a diverse, rich and balanced microbiome. This is referred to as homeostasis, whereby the beneficial microbiota, such as the likes of Faecalibacterium prausnitzii, have anti-inflammatory effects and promote regulatory immune responses involving T regulatory cells, interleukin-10 (IL-10) and antimicrobial compounds, and the immune system, especially via IgA production, helps to promote a rich and balanced bacterial community by keeping pathogenic bacteria at bay.

How to keep your gut microbiome and immune system happy

In order to help sustain your gut microbiota and immune system, you should consume prebiotics. Prebiotics, in the form of dietary fibre, such as kiwifruit pectin, are food for good gut bacteria. The bacteria ferment the dietary fibre to generate energy allowing them to grow and produce essential short-chain fatty acids. More beneficial bacteria and their byproducts mean they are able to outcompete the pathogens and support the immune system.

Eating a range of complex prebiotics, like Livaux gold kiwifruit powder with its complex kiwi fruit pectin, allows for the growth of a range of beneficial gut bacteria resulting in a desirable rich, diverse and balanced gut microbiome and healthy immune system.

The importance of diversity in the gut microbiome

Did you know that humans contain trillions of microbes (microorganisms) in and on the body? This includes some 1000 different bacterial species and means that we contain about 10-fold more microbes than human cells.

These microbes are collectively referred to as “microbiota”, or alternatively as the “microbiome” when their genes are also considered. The vast majority (approx. 95%) of these microbes are located in the gut and they weigh about 2 kg. The types of microbes differ depending on their location in or on the body and everyone’s microbiome is unique, like a fingerprint.

The human gastrointestinal tract hosts one of the most complex ecosystems, the gut microbiome, and it is key to maintaining homeostasis/balance of a healthy individual.

In order to do this, a diverse gut microbiome is required.

When we talk about diversity, there are two types that are commonly measured, and these are known as alpha and beta diversity.

• Alpha diversity is the diversity within a habitat, for example, the number and types of gut bacteria that a particular person has. Ideally a person will have high alpha diversity within their gut, so a good range of different types of microbes within their gut.
• Beta diversity is the diversity between This is important when comparing the gut microbiomes of people with different genetics and/or dietary habits to see how different/similar they are.

The concept of alpha and beta diversity is nicely depicted by the microbiomes of the BaAka pygmies and Bantu people of Africa compared to that of US Americans.

Firstly, if we look at them individually, the BaAka pygmies and Bantu people have a high level of alpha diversity, with many different bacterial species in their guts. US Americans however have low alpha diversity, typically hosting fewer types of bacterial species.

When we compare the groups, the BaAka pygmies and Bantu have low beta diversity between them, in other words, their microbiomes are similar – these two peoples live in a similar location and are exposed to similar diets, but there are some differences and this is likely due to diet (the pygmies are hunter-gatherers, whereas the Bantu have access to agricultural food).

Compared to the US Americans with their Western diet (which is high in processed foods and low in dietary fibre from fruit and vegetables), there is high beta diversity between the groups.

But why is diversity important? The microbes in the gut conduct various important functions, including:

• the production of essential nutrients, such as vitamins and amino acids;
• metabolism of indigestible food compounds;
• protection against pathogen colonisation;
• Protection against injury to the epithelium lining the gastrointestinal tract; and,
• influence over central physiological functions such as the development and training of the immune system, angiogenesis (blood vessel formation) and fat storage.

Different bacteria produce different enzymes and byproducts which have different roles in the body, so we need a good range of bacteria to ensure good coverage of these functions. A diverse microbiota is also more adaptable and resistant to being upset by antibiotics, pathogens or other invaders.

The best way to nourish a diverse gut microbiome is to feed it with a variety of complex dietary fibre, such as that found in grains, nuts, vegetables and fruit. Fruit products, such as Livaux from whole gold kiwifruit, contains complex dietary fibre and other essential nutrients which help the gut microbiome to thrive.