As any war allows dazzling scientific and technical advances, it is a safe bet that this global pandemic, as well as the scientific mobilization which accompanies it, will teach us a lot about the immune system and, since it is now inseparable, about the microbiota .

Prevotella bacteria, which cause respiratory infections

What is the role of bacteria in immune stimulation ? 

The billions of bacteria that we harbor are of decisive importance for our immune defenses, we already knew it. But the nature of the interactions they have with each other, and which they also have with viruses, never ceases to surprise. 

The studies recently published on the coronavirus already show the involvement of very specific bacteria, suggesting a therapeutic as well as preventive axes . 

The intestinal ecosystem is involved in the co-infection of SARS-COV-2  

Understanding the invasive process of SARS-COV-2 is essential, and analysis of the gene expression profile of coronavirus receptors may help us. We know that these receptors (the gateways for the virus to enter the body, like ACE2), are enzymes that bind to gut cells. 

Coronaviruses constantly change their mode of binding as they evolve, and the potential target in the lungs also varies, but not in the small intestine, where it remains constant. The cells of the intestinal mucosa (enterocytes) could therefore constitute a reservoir for coronaviruses . These receptors could be more numerous in the event of an excess of non-symbiotic bacteria.      

Microbiota in subjects with Covid-19: is there a correlation ? 

Chinese researchers have looked at changes in the microbiota in the most afflicted patients (those who have died). 

The sequencing of the microbiota revealed a significant decrease in bifidobacteria and lactobacilli , the main families of symbiotic bacteria, as well as an increase in opportunistic bacteria such as Corynebacterium or Ruthenibacterium . 

The severity of hypoxemia (lack of oxygen carried in the blood) was strongly correlated with high levels of immune cells and markers of inflammation. The vicious circle between hyper-inflammation and intestinal dysbiosis seems to constitute a high risk of fatal respiratory distress . 

In the acute phase, virus DNA in the blood was only detected in 10% of patients, but it was still detected in 50 % of them in the stool. The live virus has even been identified there several times, which suggests that stool could be a mode of contamination .           

Intestinal microbiota and immune system: what is the relationship ? 

We know that the enteric immune system (GALT) sets the tone for the overall immune response in each of us, as the microbiota intestinal and microbiota lung are connected, even remotely . 

The lipopolysaccharide (LPS) molecules produced by gram negative bacteria cause the creation of a pro-inflammatory environment throughout the body. Individuals whose immune system reacts too much or too little most of the time have a disturbed intestinal ecosystem , with an abnormal distribution of microbial families, excessive permeability of the mucosa and a tendency to systematic inflammation. Food, lifestyle and the environment are clearly involved.  

The elderly are not only malnourished. They also have a more imbalanced microbiota , which tends towards systemic inflammation. We can therefore understand why this population pays the highest price for viral attacks. Numerous studies have shown that the elderly microbiota has more gram negative bacteria, which results in increased LPS levels and therefore, intestinal permeability and inflammatory risk.

Bacteria infected with the virus?

The genetic sequencing of the microbiota of several patients from Wuhan (the city in China where the epidemic began) revealed very strange phenomena, to the point that the researchers first wondered if they had made any mistakes. . Bacteria of the Prevotella genus appeared to contain SARS-COV-2 virus DNA, as if the virus had infected the bacteria . 

Shortly before, the sequencing of the microbiota of six patients from the same family in Hong Kong, severely infected, showed significant amounts of Prevotella in their stools. These observations, reproduced from other countries, suggest that SARS-COV-2 therefore behaves like a bacteriophage , a virus infecting bacteria.         

This could explain the large variations in viral load from one test to another in the same person, as if the virus was hiding somewhere. The hypothesis that emerges is that the virus infects bacteria, which then become virulent, causing in particular the sometimes fatal inflammation. The noose tightens when we learn that infections involving Prevotella are already known to cause respiratory symptoms, including acute ones .    

Prevotella to explain the absence of infection in children

A science teacher has embarked on an attempt at demonstration which could pass for eccentric if it were not also documented. He raises the fact that children, very little affected by the epidemic, have a microbiota poor in Prevotella . In adulthood, this bacterial genus, which is part of the commensal flora, becomes much more represented. 

More in women than in men for that matter, while statistics show that women are less affected by Covid-19. In this hypothesis, their immune system would be more used to keeping Prevotella at bay . Sequencing the microbiota on larger samples of the population will allow us to find out if it is right. This shows, by the way, the interest of participatory science which allows non-researchers, sometimes simple passionate citizens, to raise judicious questions. 

If it turns out that Covid-19 is indeed a mixed infection – both viral and bacterial – then the advantage of combining hydroxychloroquine and the antibiotic azithromycin , devoted by Professor Didier Raoult, takes on its full significance. meaning. In particular, azithromycin is active on Prevotella and on intracellular microbes.          

Probiotics Could Help

In the management of Covid-19, the Zhejiang Medical University has implemented, with good results, a strategy known as “four anti and two equilibria” : antiviral, anti-shock, anti-hypoxemia, anti-infectives, maintenance electrolyte balance and microbiotic balance . 

Multidisciplinary and individualized treatment was applied to each to increase the therapeutic effect. Anxiety and fear, very present in people with Covid-19, were accompanied in traditional Chinese medicine.  

Several patients have shown intestinal dysbiosis with a notable decrease in bifidobacteria and lactobacilli. A support micronutrient bowel was proposed to all, with administration of probiotics and prebiotics , to restore balance and prevent the risk of secondary infection. Antibiotic therapy was reserved for people with a long history of illness and repeated fevers.  

The Lactobacillus plantarum strain , by acting on the intestinal mucus, made it possible to prevent infection of the epithelial cells by the coronaviruses in an animal model study. In chronic inflammatory diseases, the ingestion of a high concentration probiotic complex also makes it possible to reduce the plasma levels of pro-inflammatory cytokines and to increase the levels of cytokines regulating inflammation, with modifications. the microbiota fecal compared to the control group. 

Another complex, using Lactobacillus brevis as the dominant strain, gives similar results but acting on the intestine-brain axis, through the immune, metabolic and nervous pathways. One detail, and not least, is that Lactobacillus brevis is able to prevent Prevotella from forming biofilms . These biofilms are one of the means used by bacteria to protect themselves from the immune system and antibiotics.                   

What should we remember ? 

Finally, obese people, who are more affected by Covid-19, have a microbiota which is also richer in Prevotella . If the administration of probiotics to this population gives good results in terms of improvement of the markers of obesity (fat mass, glycemia, insulin, etc.), these results are even more visible for the individuals in whom the bacteria were very present.   

The behavior of microbial populations colonizing the human body continues to be scrutinized, in particular in order to identify and understand the differences between the categories of people at risk and those who remain healthy. If the search for a treatment for Covid-19 is in full swing, a better understanding of the interactions between host, bacteria and virus could decisively direct efforts . 

In this area, we are in the middle of a pioneer era. New generation probiotics are attractive opportunities for prophylaxis and adjuvant therapy.