Immunity and virus infections

Immunity
The gut microbiome plays an important role in the education and function of the immune system (1,2). The gut bacteria partly determine the basic tone of the immune system (3) and thus influence the crucial balance that exists between sufficient resistance and sufficient inhibition of inflammation (4-6). The gut microbiome thus plays a role in the acquired immunity and how effectively the immune system can respond to pathogens, but also in the extent to which immune responses remain within limits (7). It is striking that many non-communicable diseases such as type 2 diabetes are characterized by an overactive immune system in the form of low-grade inflammation (8-10), while at the same time there are indications that the acute immune response in viral infections is insufficient (11,12). Finally, research into the effect of antibiotics (13) and probiotics (14) on the immune response to vaccinations endorse the role of the microbiome in immunity. In short, a disturbed microbiome can lead to the immune system not being able to respond effectively enough to infections and to the inflammatory response being too strong or too long.

Virus infections
It is not surprising that virus infections affect the intestine and thus the intestinal microbiome, given the often occurring intestinal complaints. Although the research is still in its infancy, there is also evidence of an inverse relationship, in which the microbiome helps determine the response to and the course of viral infections (15). Treatment with different types of antibiotics in laboratory animals has shown that the composition of the gut microbiome influences the course of an infection with the flu virus (16,17). On the other hand, laboratory animal and human research show that certain probiotic strains can favorably influence the course of influenza virus infection (18).

Pneumonia
Recent research focuses on the so-called gut-lung axis, which is the result of a complex interaction between micro-organisms and with, among other things, the immune system of the host (19,20). In this light, it is interesting that a Cochrane review concludes that there is cautious evidence that probiotics can reduce respiratory infections and have a beneficial effect on the course. Another Cochrane review concludes that there is some evidence that probiotics may reduce the risk of ventilator-associated pneumonia, although the quality of the included studies is low (21). Collectively, these findings suggest that the gut microbiome may affect infections and inflammation in the lungs.

Topical
In light of the current pandemic, the literature has been examined to see whether the aforementioned influence of the gut microbiome on immunity and infections may also play a role in the disease caused by infection with the SARS-CoV-2 coronavirus.

Gastrointestinal complaints
In more than 200 Covid-19 patients admitted to three hospitals in China, more than half had gastrointestinal complaints (22). Below the authors also counted decreased appetite, which is not very specific for gastrointestinal complaints. If only diarrhea, vomiting and abdominal pain are considered, these complaints occurred in 19% of the patients.

Virus in the stool
In several studies, the SARS-CoV-2 virus has been found in stool samples (23, 24). The fact that the RIVM has also found the virus in sewage water confirms the presence of the virus in faeces (25). Detection in feces leads to suspicion that infection with the virus could occur not only via airborne droplets but also via the fecal-oral route (26), implying that infection can also pass through the gastrointestinal tract.

Smell and infection of neurons
The UK Association of ENT Physicians published a notice on March 21 mentioning loss of sense of smell as a possible symptom of Covid-19 (27). The report mentions that in South Korea (where a great many people have been tested) in about 30% of the infected individuals, reduced sense of smell was the main complaint with an otherwise mild clinical picture. One possible cause of this reduced sense of smell is that the SARS-CoV-2 virus can get into the brain (28). Researchers also think this may be related to the breathing problems found in severe cases, because the respiratory center in the brainstem may be affected (29). Antigens against SARS-CoV-2 have been found in the brain stem, and in SARS-CoV (the coronavirus that was circulated in 2003) and MERS-CoV (the coronavirus that broke out in 2012), the brain stem was also among the most infected part of the brain (29).
The blood-brain barrier is an important anatomical layer that protects much (but not all areas) of the brain by selectively allowing or blocking substances (30). As in the intestinal epithelium tight junctions play an important role in this. The tight junctions in the gut epithelium are regulated by zonulin (31), which is also used as a marker for increased gut wall permeability (32,33). The gut microbiome has an important role in regulating the permeability of the gut wall, including through expression of tight junctions (31,33). Intriguingly, recent research shows that tight junctions in the blood-brain barrier also respond to zonulin (34). Increased intestinal permeability can also lead to bacterial substances, such as LPS, in the circulation that themselves, whether or not via an inflammatory reaction, also adversely affect the blood-brain barrier (33,35,36).

References

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