F.prau and COVID are linked in a number of ways

As we noted in our earlier blog on the gut microbiome and COVID infection, dysbiosis of the gut microbiome, including reduced numbers of Faecalibacterium prausnitzii (F. prau), has been observed in patients with COVID-19. In particular, reduced levels of F. prau was associated with increased duration and severity of COVID-19 infection symptoms (Yeoh et al., 2021). 

It is well-known that F. prau, as an important beneficial gut bacterium, has anti-inflammatory properties and affects the immune system, but how is it linked to COVID and why might those who suffer more and for longer from COVID-19 have lower levels of F. prau? 

Several mechanisms have been proposed to explain how F. prau contributes to immunity. These are: 

• enhancing the gut barrier – part of that critical first line of defence against invaders;  
• directly inducing anti-inflammatory cytokine secretion;  
• directly inhibiting the secretion of pro-inflammatory cytokines; and,  
• producing anti-inflammatory/immunomodulatory metabolites (He, Zhao, & Li, 2021).  

Anti-inflammatory and immunomodulatory effects of F. Prau 

One of the most severe symptoms/pathologies of COVID-19 is cytokine storm, characterised by huge increases in the levels of pro-inflammatory cytokines such as IL-6, INF-γ, and TNFα.

 This hyper-inflammation is associated with poor disease outcomes for COVID-19 infected patients and is presently treated with immunosuppressant medication such as the corticosteroid dexamethasone (K et al., 2021).  It has been proposed that commensal (friendly) bacteria with anti-inflammatory and immunomodulatory capabilities, such as F. prau, could potentially down-regulate the cytokine response, to decrease the harmful effects of inflammation while maintaining a positive immune response (Baindara et al., 2021). Therefore, high levels of F. prau may contribute to a reduced cytokine storm.

F. prau can decrease pro-inflammatory cytokine secretion and increase anti-inflammatory cytokines. For example, studies have shown that F. prau exposure significantly decreased pro-inflammatory cytokines, IL-6, IL-12 and TNFα, increased anti-inflammatory IL-10, and enhanced immune cell response upon exposure to a known antigen (a foreign substance that induces an immune response) (Sokol et al., 2008; Rabiei et al., 2019; Rossi et al., 2016).

F. prau is a major producer of butyrate and salicylic acid, two bacterial metabolites that have known anti-inflammatory properties.

It has been suggested that butyrate could function as a possible replacement for dexamethasone to treat the hyper-inflammation associated with COVID-19 due to its anti-inflammatory activity (K et al., 2021). Both butyrate and salicylic acid can inhibit inflammation (Ferreira-Halder, de Sousa Faria & Andrade. 2017; Elce et al., 2017; Cholan et al., 2020; Zeng et al., 2017; Kabel, Omar & Abd Elmaaboud, 2016).

Gut barrier integrity  

It is thought that disruptions in gut barrier integrity may contribute to the gastrointestinal symptoms associated with COVID-19. Kim (2021) proposes that a ‘leaky gut’, driven in part by dysbiosis, could allow the virus to leave the GI tract and enter the bloodstream. This could then lead to an increase in inflammation, and allow the virus access to other ACE2-expressing cells throughout the body such as in the heart, brain, and liver (Kim, 2021).

This would then trigger other COVID-19 symptoms such as headache, hepatic, and cardiac dysfunction (Kim, 2021). F. prau may be able to prevent this, through its ability to improve gut barrier integrity. For example, in a mouse model of low-grade inflammation in the gut, F. prau treatment significantly decreased intestinal permeability (Martín et al., 2015). F. prau treatment was also shown to increase the expression proteins which are part of the junctions between cells in the mouse colon, and this effect was associated with a decrease in inflammation (Laval et al., 2015).  

The elderly and those with underlying health conditions, including hypertension, diabetes and obesity, are more susceptible to COVID-19 infections. These populations often have disrupted gut barrier integrity (leaky gut) and dysbiosis (including low F. prau) which may be a crucial pathway that allows the COVID-19 virus to gain access to ACE2 receptors on enterocytes and leak out of the GI tract to spread throughout the body (see figure).

Once into the bloodstream, this may cause further inflammation exacerbating the leaking gut. In contrast, those with a healthy digestive tract, including good barrier integrity and a good level of butyrate-producing gut bacteria, such as F. prau, will have a higher number of immune cells. This may enable the immune system to contain the virus in the GI tract and it will subsequently pass out the back end.  

Alternatively, it has also been proposed that gut dysbiosis may result from the COVID-19 infection. Cytokines secreted during the “storm” reach the gut via the blood and/or the virus travels to the gut, leading to local inflammation, a leaky gut and dysbiosis.   

Either way, treating the dysbiosis in the gut by supplementation with probiotics and/or prebiotics may rectify the issue allowing the body’s defences to eliminate the virus (Conte & Toraldo, 2020). In particular, those prebiotics or probiotics which can increase F. prau, such as Livaux® gold kiwifruit powder, may help to bring balance back to the gut, reduce inflammation and support the body’s natural immune system to fight off the virus.  

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.

Low levels of F. prau linked to more severe COVID infection

Livaux® prebiotic powder, from New Zealand gold kiwifruit, has been clinically shown to increase Faecalibacterium prausnitzii (F. prau) numbers in individuals with low F. prau levels (1). Research show that low levels of F. prau are associated with increased SARS-CoV-2 (Covid-19) virus symptom severity and duration. This finding is covered in a recent NutraIngredients article (2). 

Covid-19 invades cells by a process starting with binding the ACE2 receptor (3). This receptor is found in highest levels on the surfaces of cells of the lungs, and on the surfaces of the cells lining the intestines (4). In the intestines, ACE2 is linked to inflammation and the gut microbiome (5). Covid-19 is known to cause gastrointestinal disturbances, with high incidence of diarrhoea and microbiome dysbiosis (3-9). Viral material has been detected in faeces, even after the respiratory tract tests negative, illustrating the risk of faecal-oral transmission (3) and an urgent need to address these gastrointestinal issues (10). 

In order for the Covid-19 virus to invade intestinal epithelial cells, it must survive transit through the stomach acid. Indeed, individuals on proton pump inhibitors (which reduce stomach acidity) are at risk of increased Covid-19 symptom severity and duration (11-13). Similarly, susceptibility to the virus is age-related (14), and increased age is associated with decreased stomach acidity (4), as well as decreased overall immune function and microbial dysbiosis (15). 

The microbial dysbiosis associated with Covid-19 is well documented, and the bacteria most commonly inversely correlating with presence or severity of Covid-19 symptoms is F. prau.  

For example, recently patients with Covid-19 were shown to have significantly underrepresented F. prau, Eubacterium rectale and Bifidobacterium adolescentis, with the strongest inverse correlations with severity being numbers of F. prau and Bifidobacterium bifidum (16).  

A previous study showed Covid-19 patients had lower numbers of Eubacterium rectale, Ruminococcus obeum, Lachnospiraceae bacterium 1_1_57FAA and F. prau (17). Again, F. prau most strongly negatively correlated with severity, in addition to Alistipes (17). These patients were also shown to have greater numbers of opportunistic pathogens known to cause bacteraemia such as Clostridium hathewayi, Actinomyces viscosus, Bacteroides nordii, and Coprococcus species known to upregulate ACE2 in the gut (17).  

A similar association of increased viral disease severity with lower F. prau has been seen in flu (H1N1) patients (18).  

Decreases in F. prau numbers have not been shown to be associated with infectivity. In another study, individuals with high Covid-19 infectivity had lower abundances of Parabacteroides merdae, Bacteroides stercoris, Alistipes onderdonkii and Lachnospiraceae bacterium 1_1_57FAA (19). However, given that lower numbers of F. prau, Alistipes and Lachnospiraceae bacterium 1_1_57FAA were common across multiple independent studies, this suggests these bacteria occupy guilds that are relevant to mitigating the severity of Covid-19 symptoms. 

Modulating the gut microbiome may be a solution to decrease risk and severity of Covid-19 infection (20, 21) What can be done to address microbiome dysbiosis and increase F. prau numbers? Decreased hygiene and cleanliness has been associated with an increased microbial diversity and decreased Covid-19 susceptibility (22). Conversely, social distancing and its commensurate decrease in microbial transfer and acquisition has been posited to lead to a dangerous decrease in microbial diversity (23). However, decreasing hygiene and social distancing are dangerous, as they are associated with other larger risks (22, 23). A more viable alternative to increase microbial diversity for decreased Covid-19 symptom severity is through food (20). 

The use of probiotics, live microorganisms that confer health benefits when consumed, has been suggested as a viable strategy (20). Indeed, The Natural Health Committee of China has promoted this course of action (20). Similarly, some of the researchers who first definitely established the link between Covid-19 severity and gut microbiota have attempted to create probiotic supplements for this purpose (24). However, F. prau is highly oxygen sensitive and cannot be viably delivered for consumption in adequate live numbers. 

Prebiotics, food which survives digestion and reaches our large intestine to selectively increase the numbers of gut bacteria that confer health benefits, are a better proposition. Diet has been shown to increase F. prau numbers (25), particularly high carbohydrate/low glycemic impact diets (26). In terms of selectively increasing F. prau, Livaux® from New Zealand gold kiwifruit is the only prebiotic clinically shown to increase F. prau levels in individuals with low baseline levels (1). This effect has also been demonstrated in vitro (27). Livaux contains high methoxy pectin, and high methoxy pectic galacturonic acid is a substrate used by F. prau (28).