The coronavirus pandemic has reached almost every country in the world causing societies, economic and health crises where its impacts and losses can be felt across the world. 

Children are not the face of this pandemic. But they risk being among its biggest victims, as children’s lives are nonetheless being changed in profound ways. The socio-economic impacts and mitigation measures may inadvertently do more harm than good.

With the ever mutating Covid-19 virus, an effective anti viral drug or vaccine  against COVID-19 is not available. Hence, keeping good hygiene and supporting the immune system are possible prevention strategies.  Milk kefir is a natural fermented food that can enhance our immune system and suppress viral activity. 

Let us get a glimpse of how COVID-19 invade and infect humans, particularly in lungs and sometimes in our gut. 

How COVID-19 cause infections in human lung tissues

COVID-19 is transmitted primarily through the respiratory droplets of infected people, which are expelled from an infected person. Once it enters the body, COVID-19 virus attaches to ACE-2 receptor on human lung cells in order to enter and take over the cell machinery to make multiple copies of the virus itself.

COVID-19 virus suppresses the initial stage of host innate immunity, thereby escaping from being scavenged by macrophages and neutrophils so as to gain a strong foothold and produce multiple copies of the virus to mount a strong and effective infection.

The viral replication cycle can produce dramatic biochemical and structural changes in the human lung cell, which can cause oxidative stress and cell damage. During this stage, inflammation occurs in response to better fight off the virus by increasing the level of proinflammatory cytokines. Sometimes, inflammation can become too aggressive where proinflammatory cytokines (particularly IL-6 and TNF-α) are produced in an uncontrollable manner leading to “cytokine storm”.  

Cytokine storm is the leading cause of ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. The death is not primarily caused by viral spreading but by overstimulation of the immune system.

In this blog, we discuss how gut microbiome affects the severity of COVID-19 progression and how milk kefir (a gut superfood)  can tackle COVID-19 with its anti-viral and protective mechanisms ability.

Prevention of COVID-19 entry and inhibit the multiplication of COVID-19 in human cells.

COVID-19 need to enter and reach the cytoplasm of human cells to reproduce. They enter by attaching to ACE-2 receptors on the surface of human cells (particualrly lung, blood vessels and intestine cells) thereby gaining entry.
Probiotic microorganisms in milk kefir can suppress the initial stage of viral activity and viral adhesion into host cells by binding to the virus through a mechanism known as virus trapping. These preventive measures lead to an inhibition of the growth of COVID-19 and further events caused by COVID-19.

Antioxidant activity of milk kefir (protective mechanism)

COVID-19 can cause destruction by inducing oxidative stress which results in lipid peroxidation. Lipid peroxidation refers to the destruction of lipid membrane in human cells. This can result in cells and tissue damage. In the case of COVID-19, cells and tissue damage can eventually lead to lung failure.
Probiotic bacteria in milk kefir are effective trapping reactive oxygen species (ROS). Lactobacillus delbrueckii subsp. Bulgaricus and Streptococcus thermophilus scavenge ROS and free radicals, thereby inhibiting lipid peroxidation. 

In addition, fermentation products and metabolites (non-microbial) like bioactive  peptides can enhance the activity of superoxide dismutase (an enzyme that breaks down ROS) in the lung. Kefiran, an exopolysaccharide metabolite, can reduce oxidative stress by regulating the microbes to eliminate microbes associated with a heightened level of  reactive oxygen species.

Anti-inflammatory role of milk kefir in prevention of cytokine storm (protective mechanism)

COVID-19 infection itself mediates an aggressive inflammation due to the high levels of pro-inflammatory cytokines released from activated macrophages as these immune cells “eats up” the virus. The main pro-inflammatory cytokines such as IL-1β, IL-6, IL-8 and TNF-α regulate cell activation and recruiting immune cells to the site of infection to control and eradicate virus and other pathogens. 

Polysaccharides and bioactive peptides in milk kefir are anti-inflammatory agents that can inhibit the activity of pro-inflammatory cytokines in lung tissue.
In a study performed by Adiloğlu et. al., involving 18 healthy participants with consumption of kefir for 6 weeks, a reduction in serum IL-8 expression after kefir consumption is observed. This reduction inhibits more neutrophils from entering the site of inflammation e.g. lung tissues which can prevent further inflammation.

An overall level of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are also found to be reduced in affected lung tissue

Despite the possibility of pro-inflammatory cytokines causing an uncontrollable level of inflammation, pro-inflammatory response is important to fight off infection. The balance between pro- and anti- inflammatory response is therefore critical. Regulation of such cytokine response is important for keeping the haemostasis of the immune system.

We will move on to how milk kefir consumption can regulate this inflammatory response with pro-inflammatory cytokine in the next section.

Immunmodulating function of milk kefir (immune stimulation)

Bioactive peptides can activate innate immunity by stimulating macrophages and increasing phagocytosis (eating of virus by immune cells). Microbiota-derived components are required to program dendritic cells so that they can rapidly initiate immune responses to pathogens during initial stage COVID-19 infection.

MIlk kefir is also shown to boost production of clusters of T cell differentiation into CD4+ and CD8+ cells which produces a more targeted and potent anti-viral activity against COVID-19.

Kefir consumption also leads to a polarization of Th1 type response which is geared for killing pathogens and decreased Th2 type response, leading to a decrease in allergic response. As mentioned, kefir consumption leads to a reduction in IL-8, but leads to an increase in IL-5 production which stimulate IgA production in our gut for a more efficient immune response.

Lactoferrin (bioactive peptide derived from whey proteins in cow milk kefir) is a key element to combat excessive inflammation and direct host immune function. Lactoferrin can act on B cells, to allow subsequent T cells interactions that favor elevation of the production of Ig A and IgG antibodies. Such immune responses are more targetted.

Gut microbiome and development, prognosis, or post-infection of COVID-19 (long COVID and MIS-C)

It is now known that our gut communicates with our lungs via the gut-lung axis. This is performed through microbiota-derived metabolites or components that can cross the intestinal barrier and exert systemic activities in our lungs and even other organs. The change in our gut microbiome during COVID-19 and the initial state of gut health results in a difference of biomolecules produced which can lead to a different outcome of COVID-19 infection in terms of severity and post-infecetion.

Yeoh YK, Zuo T, Lui GC, et al (2021) conducted a research study with laboratory confirmed 100 patients infected with COVID-19. Blood and stools samples were collected. Gut microbiome and lung microbiome composition was found to be significantly altered in these COVID-19 patients, signifying that COVID-19 can alter our microbiome in both gut and lung. This can potentially allow for secondary infection.

Several gut commensals with known immunomodulatory potential (such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria) and anti-inflammatory commensal bacteria (such as Lachnospiraceae, Roseburia) were of low abundance in COVID-19 patients and remained low in samples collected up to 30 days after disease resolution. Furthermore, individuals who started off with gut dysbiosis prior to COVID-19 infection displayed a higher disease severity with elevated concentrations of inflammatory cytokines and blood markers (C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase) after COVID-19 infection.

After a virus is cleared, our immune system would reset back to the normal state in the case of other viral infections like influenza. However this is not the case for COVID-19 as a higher proinflammatory cytokine level than the normal has been detected even after 8 months post-COVID. Alteration of the gut microbiome by COVID-19 is believed to cause this prolonged inflammation. This persistence of inflammation results in conditions like  ‘long COVID” in adults and MIS-C in children.

The MIS-C group displayed a significantly higher relative abundance of Bacteroidetes and lower abundance of Firmicutes compared to the control group. There is a substantial change in the composition of these gut microbiota: (1) reduction of Faecalibacterium prausnitzii in children with MIS-C and COVID-19; (2) an increase of Eggerthella lenta which is related with autoimmunity; and (3) the predominance of Eubacterium dolichum is associated with metabolic dysfunctions and obesity in children with MIS-C.

Conclusion

Probiotics is known to reduce the severity of different types of infections in the gastrointestinal system  and upper respiratory tract in the case of COVID-19. They also showed that Bifidobacterium breve protected the lower respiratory tract from viral infection as well.

Microbial (probiotics) and non-microbial community of milk kefir has been shown to exhibit antiviral activity (through direct binding of the virus and enhancement of innate and adaptive immunity) yet has protective ability to reduce and prevent cellular damage due to oxidative stress and inflammation caused by COVID-19 via its antioxidant and anti-inflammatory properties.

The novel probiotic strain Lactobacillus kefiranofaciens M1 present in kefir grains has shown immunoregulatory, anti-allergic, anti-asthmatic, and anti-colitis activities in vitro and in vivo in germ-free mice.

Being the richest source of probiotics and containing valuable metabolites, milk kefir not only eliminated the cytokine storm, but also restored balance to the immune system by providing a wide variety of beneficial microbes that our gut needs. This reverse and provide immediate therapeutic solutions in response to COVID-19 making alterations to our gut microbiome which can therefore alter our immune response. The scientist in Ben-Gurion University of the Negev pointed that milk kefir is an extraordinary feat with significant therapeutic potential in prevention of prolonged inflammation that results in “long COVID” and MIS-C.

References

1. American Associates Ben-Gurion University of the Negev. (2021, April 13). Probiotic Yogurt-Based Drugs Could Help Treat COVID-19. Lab Manager. https://www.labmanager.com/news/probiotic-yogurt-based-drugs-could-help-treat-covid-19-25656
2. Burchill, E., Lymberopoulos, E., Menozzi, E., Budhdeo, S., McIlroy, J. R., Macnaughtan, J., & Sharma, N. (2021). The Unique Impact of COVID-19 on Human Gut Microbiome Research. Frontiers in Medicine, 8. https://doi.org/10.3389/fmed.2021.652464
3. Haseltine, W. A. (2022, March 14). New Clues To Long Covid: Prolonged Inflammatory Response. Forbes. Retrieved July 25, 2022, from https://www.forbes.com/sites/williamhaseltine/2022/01/25/new-clues-to-long-covid-prolonged-inflammatory-response/
4. Reham Samir Hamida, Ashwag Shami, Mohamed Abdelaal Ali, Zakiah Nasser Almohawes, Afrah E. Mohammed, Mashael Mohammed Bin-Meferij,Kefir: A protective dietary supplementation against viral infection,Biomedicine & Pharmacotherapy,Volume 133,2021,110974,ISSN 0753-3322,https://doi.org/10.1016/j.biopha.2020.110974.
5. Wang, B., Zhang, L., Wang, Y. et al. Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions. Sig Transduct Target Ther 7, 143 (2022). https://doi.org/10.1038/s41392-022-00986-0
6. Yeoh YK, Zuo T, Lui GC, et alGut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19Gut 2021;70:698-706.