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COVID-19 affects more than just your lungs: new insights into how our gut microbes could be used to

With over 16.7 million confirmed cases and 650,000 deaths worldwide, the burden of the COVID-19 virus (also known as SARS-Cov-2) continues to grow. Therefore, it is of no surprise that there has been an urgency in the medical community to delve deeper into how this virus behaves and what factors are critical in determining it's severity. We already know from studying other diseases, that viruses, even those in the respiratory tract, can influence the microbes that call our bodies home, with emerging evidence now linking COVID-19 with the gut microbiome.

But what exactly does this mean for COVID-19 and how can we better understand this interesting interaction to combat this growing public health crisis?

Viruses and the microbiome

It has already been established that the our gut microbes control our immune system; a hangover from our evolutionary past to ensure we tolerate good bacteria and eradicate bad bacteria. In fact, our gut microbiome is extremely efficient at controlling our immune system by tightly regulating the development of immune cells, including specialised regulatory T cells and innate lymphoid cells that are critical in keeping our gut and lungs healthy. While this link is certainly present, the specific cellular processes that control it are unclear.

Whilst scientists are trying to uncover the exact link between gut microbes and our immune system, more evidence is being published to show there is a strong link between immunity and the gut microbiome. For example allergy-associated asthma has been indicated to influence the gut microbiome, with mice treated with antibiotics (to damage the microbiome) exhibiting exacerbated immune responses and increased susceptibility to lung inflammation. Similar effects have also been seen outside of the lungs, with the inflammatory mechanisms that control atherosclerosis (hardening of plague in arteries) also linked with the microbiome. Researchers were able to show that by supporting the health of gut microbes, the severity of atherosclerosis, caused by a high-fat western diet, was reduced. Additionally, a large area of gut microbiome interest is also cancer, with the gut microbiome's influence on immune properties thought to accelerate cancer development and also control how well that person responds to treatments such as chemotherapy.

While these findings have prompted enthusiastic investigation of how the microbiome can be harnessed to predict, prevent or treat these diseases, it remains challenging to determine if the microbiota actually contributes to the development of these diseases, or if these diseases are responsible for changes in the microbiota… that’s right, the old chicken and the egg conundrum!

COVID-19 in the gut… a lost virus or an unknown mechanism?

The COVID-19 virus uses special receptors, called ACE2, to enter host cells. Therefore, the distribution of these receptors within each of us is critical in determining the impact of COVID-19. The ACE2 receptors are known to be highly expressed in lung AT2 cells and cells of the upper oesophagus. Importantly though, they are also expressed on the cells that line our gastrointestinal tract. It is therefore not surprising that COVID-19 has been reported to cause digestive symptoms, including diarrhoea, with 1 in 8 COVID-19 patients experiencing gastrointestinal symptoms. Furthermore, 2 in 5 patients present with diarrhoea and a fever before the development of respiratory symptoms, suggesting diarrhoea could be an early indicator of disease and the need to quarantine. Interestingly, despite COVID-19 being a predominantly respiratory virus, rectal swabs and stool specimens have also tested positive for COVID-19. In fact, one study reported almost 25% of stool samples were positive whilst still producing negative results in the respiratory tests! These findings are the first to show that COVID-19 may truly have an effect on the microenvironment of our gut, and for this reason, it’s interaction with the microbiome has become the topic of intense interest.

Figure 1.Gut microbiota in healthy Vs. COVID-19 patients (Zuo et al. 2020)

Figure 1.Gut microbiota in healthy Vs. COVID-19 patients. Image source: Zuo et al., 2020 Gastroenterology.

What are the microbial changes in COVID-19 patients?

From reading this blog, you will know that the gut is full of billions, if not trillions, of bacteria which typically fall along a spectrum from “good” to “bad”. COVID-19 has already been shown to drastically change the types of bacteria found in our gut, which in turn, changes how our immune system works and may make us more or less susceptible to the virus.

Most recently, a study conducted by Zuo and colleagues in 'Gastroenterology', reported that the abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi strongly correlated with the severity of COVID-19, as shown in Figure 1. Furthermore, Erysipelotrichaceae bacterium, a bacterium most commonly implicated with inflammation in the gut, had the strongest positive correlation with COVID-19 presence in faecal samples and virus’ severity. Conversely, Faecalibacterium prausnitzii, the all-around good guy in terms of gastrointestinal health, had an inverse correlation between COVID-19 severity and abundance. Interestingly, a cluster of microbes (Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis and Bacteroides ovatus) were also shown to regulate the expression of ACE2 receptors, therefore impairing the ability of COVID-19 to enter the gut.

While much of this data remains associative (i.e. we cannot confirm a causal relationship), these findings strongly reinforce the link between the microbiome and COVID-19, revealing new avenues for controlling this deadly disease.

How does this evidence help people with COVID-19?

Emerging evidence strongly suggests that the communication between the gut and lungs (termed the ‘lung-gut axis’) is critical in determining the severity of COVID-19. So, what does this mean for the future of COVID-19 and will it help us control who is at risk and how severe their disease is? Several studies have started to speculate that this new understanding of how the microbiome regulates COVID-19 could help predict who might be at risk of severe infection as well as improve outcomes for people already infected. Some scientists have suggested that pre- and probiotics, both of which support a healthy microbiome, may decrease disease severity by strengthening the immune system. Predicting who is at risk may be more challenging in reality, but if approached carefully, the composition of a person’s gut microbiota could be used to guide isolation practices and facilitate the delivery of more effective therapies.

Whilst much of this information remains speculative having just scratched the surface of this interesting interaction, the discovery that the microbiome could help to in the diagnosis and treatment of COVID-19 is a major finding. If the suggestions by scientists in this area are feasible, exploiting the microbiome to control the virus may be a huge step forward in our fight against this pandemic and may offer additional benefits alongside traditional vaccines.

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