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This guest editorial by Dr Sanjiv Hyoju talks about a possible connection between a diet-induced disturbance in the gut microbiome equilibrium and its impact on our immune response to viral infections like SARS-CoV-2. Dr Hyoju is a surgeon and researcher from University of Chicago, with his research focused on Microbiome, Sepsis, Obesity, Bowel leak, Infections, Inflammatory bowel disease (IBD). Dr Hyoju's article on the same topic has been published in Medical Hypotheses (Nov, 2020).
We are in the middle of COVID-19 pandemic. The latest data shows 14.5 million infections reported globally, and the disease growing at a rate of 1.4% per day. As of today, 607,266 people have died due to COVID-19, and 8.7 million people have recovered from the illness. The overall Infection Fatality Rate (IFR) of Severe Acute Respiratory Syndrome Coronavirus 2 (SAR-CoV-2) remains as low as 0.6% for the entire population. However, the Case Fatality Rate (CFR) is significantly high among older people (aged 65 and above) and with underlying comorbid conditions like obesity, diabetes mellitus, hypertension, heart disease, cancer. After observing such vulnerable populations infected with the virus it has become clear that SARS-CoV-2 induces an overwhelming inflammation leading to multiorgan damage. With this observation, one can speculate that "it's not the virus that is lethal, it's the host immune response to the virus that causes the detrimental effects and death". Hence, it is utmost important to understand the reasons behind such erratic host immune response toward virus among vulnerable populations.
Ageing and other comorbid conditions create complex disease processes involving interactions between the gut microbiome, the nervous system, the endocrine system and the immune cells. Within these interactions, the main driver is the gut microbiome which is highly influenced by dietary habits and host stress. Lately, the rapid advancements in civilization and agricultural development have introduced highly processed high-sugar, high-fat diets in our society. Subsequent epidemiological studies have demonstrated that there has been a rapid increase in the incidence of diseases such as obesity, diabetes mellitus, hypertension, cardiovascular disease, cancer, autoimmune disease and stroke, thus the name "Diseases of Civilization". Such observation has led to the conclusion that western-diet associated comorbidities harbour a disrupted microbiome which is in sharp contrast to our ancestors who survived on high-fibre, high-protein and low-sugar diet.
Disrupted microbiome in the gut has a profound effect on the brain and immune cell functions through the enteric nervous system, leading to chronic stress situations with exhausted and senescent immune cells making the host susceptible to poor outcomes following a viral infection. In an animal model, high-fat diet feeding increased the influenza A virus-associated cardiovascular damage. Similarly, the stress-animal model demonstrated increased the susceptibility to coronavirus and influenza virus. Stress animals are found to have an altered immune cell activity, making them more susceptible to viral infections and subsequent complications. Not only chronic stress but also psychological stress has been associated with an increased risk of acute coronavirus infection. In one study, it has been found that white blood cells harvested from stressed patients' plasma produced an excessive level of pro-inflammatory cytokines upon stimulation.
Our brain has two autonomic functions, sympathetic and parasympathetic. For the body homeostasis, sympathetic and parasympathetic outflow must equilibrate regularly. One of the prime drivers for maintaining such equilibrium is the gut microbiome and its microbial metabolites via the enteric nervous system, also known as the Gut-Brain Axis. Studies have shown that there is a disrupted microbiome in the western population compared to an underdeveloped non-civilized tribe. Hence, it has been speculated that this newly developed disrupted-microbiome led to a stage of disequilibrium in the autonomic function causing chronic sympathetic hyperactive immune stress that manifests as various diseases such as obesity, diabetes, and hypertension.
Though the sympathetic response is made to protect the host from detrimental effects during short term stress, such protective nature is lost during prolonged sympathetic hyperactivity driven by disrupted microbial community, making them more vulnerable to erratic stress such as viral infections. A respiratory viral infection is a stressful condition that enhances the sympathetic outflow from the brain as part of its protective mechanism. However, in a patient with a chronic sympathetic hyperactive condition, who then contracts the virus, the interaction tremendously increases sympathetic pro-inflammatory response. In simple words, it is just like pushing somebody off the edge of a cliff. Observations made in animal studies demonstrate that activation of sympathetic pro-inflammatory response has a detrimental effect; and also, an attenuation of such response by drugs such as Clonidine and Propranolol can be highly effective in preventing death from Influenza virus infection.
Although vaccine and antiviral therapy are the mainstays of treatment, development of such therapeutic modalities take time. Older populations with comorbid conditions are the group that require vaccination because of increased fatality rates. However, the immune status of the population is already impaired, as explained above. This brings up the question that "How effective will the vaccine be against SAR-CoV-2 among such populations?" Because evidence from U.S Influenza Vaccine Effectiveness Network demonstrates the overall effectiveness of the influenza vaccine to be only 45% and vaccination does not confer 100% protection. Likewise, recently published literature shows that antibodies produced against COVID-19 might not last long among those recovered. Hence, there is a possibility that SAR-CoV-2 virus may remain "as another flu-like syndromic virus with a substantial threat to the community for a longer period than expected". Given the fact that this virus is highly contagious and difficult to contain and the development of an effective vaccine will take time, FDA approved commonly available drugs like clonidine and propranolol should be considered to mitigate the impact of the disease.
Conclusion: With the advancement of civilization, consumption of western-diet leading to a disrupted microbiome will push the normal health toward chronic sympathetic hyperactive status bringing up disease condition like obesity, hypertension, diabetes mellitus, altering the immune cell response towards a pro-inflammatory phenotype leading to a worse outcome to SAR CoV-2 once infected. This virus has been otherwise well tolerated by a healthy population. Although a vaccine against the virus is the foremost armour to bring back life normal, scepticism remains high regarding the effectiveness of the vaccine. Again, another risk with this virus is a lack of long lasting immunity making the general population susceptible to re-infections.
Take home message: Here is a famous quote by the Greek physician Hippocrates "Let food be thy medicine". The World Health Organization should come up with strict legislation and program for the entire world to change the dietary habit to high fibre, low sugar and low fat. This will prevent disruption of normal microbiome, make the immune system healthy, fight against virus and prevent death. This is the most sustainable solution for current COVID-19 pandemic and also avoid similar viral pandemic in the near future.
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