Because as many as 10% of COVID-19 patients have the symptom of diarrhea, it is hypothesized that SARS-CoV-2 can infect gastrointestinal cells.  Symptoms such as loss of appetite and nausea have been commonly found with patients as well. It is known that the GI tract overall has a high expression level of ACE 2, with the duodenum and small intestine having an especially high level of expression. Viral RNA has been found in both the sputum and feces of COVID-19 patients.  

Effects of COVID-19 on the Gastrointestinal (GI) Tract

A study of eight patients found that the lung microbial composition of COVID-19 patients is primarily made up of bacteria typically found in the oral and upper respiratory tract.  It is thought that the gut microbiota plays an important role in buttressing antiviral immunity and has been shown to reduce viral-related enteritis, severe pneumonia cases that require ventilator assistance, and can prevent the spread of influenza in lung epithelia cells.  No clinical data suggest that modulating the gut microbiota is an effective treatment for COVID-19, but it may be a relevant therapeutic target.  

Bi-directional Communication Network Between the Gut and Lung Microbiotas in COVID-19

The inflammatory mediators associated with the cytokine storm in COVID-19 leads the increased permeability of the lungs.  This allows for SARS-CoV-2 and the inflammatory mediators to enter the bloodstream and migrate from the lungs to the intestine.  SARS-CoV-2 can decrease ACE2 expression and alter the gut microbiota which can alter normal immune responses.  Additionally, the inflammatory mediators can weaken the integrity of the gut, allowing for microbes and their metabolites to leak out.  This can cause microbial dysbriosis which may contribute to why diarrhea is a common symptom of COVID-19.  

Michigan State University

The human gut is home to many types of bacteria that produce metabolites that are used to maintain homeostasis in various physiological processes, including:

- vitamin synthesis
- pathogen protection
- immunological development
- intestinal angiogenesis
- intestinal epithelium cell development

Every person has a unique and dynamic niche of microorganisms in their gut.  If the microbiota harbors harmful pathobionts or if keystone species that regulate the ecological community become threatened in some way, a condition known as microbial dysbiosis develops.  

Gut Microbiota in Homeostasis

The lung microbiota consists of microbes originating from the upper respiratory tract that migrate deeper into the respiratory system.  These microorganisms are controlled by immunological responses as well as competition from preexisting microbes.  The homeostasis involved in maintaining the lung microbiota is important in preventing and mitigating respiratory diseases.  For example, cystic fibrosis and asthma are both respiratory diseases where there is an increase in the diversity or number of bacteria in the lower respiratory tract.  

Lung Microbiota in Homeostasis

COVID-19 cytokine storms refer to the overproduction of pro-inflammatory stimuli (antigens, superantigens, adjuvants, allergens, pro-inflammatory cytokines) and/or the inadequate regulation of inflammation following severe/critical SARS-CoV-2 infection. Current evidence suggests that this chemical overproduction can have dangerous repercussions, with ties to more severe clinical outcomes. 

- Cytokine storms increase the risk of vascular hyper-permeability, acute respiratory distress syndrome (ARDS), multi-organ failure, and consequently, patient mortality 
- Cytokine storm syndromes are disorders that represent various inflammatory etiologies
- Immunomodulatory therapy for the reduction of cytokine storms could aid in the treatment process


 Cytokine Storms in COVID-19 

Ahlawat, S., & Sharma, K. K. (2020). Immunological co-ordination between gut and lungs in SARS-CoV-2 infection. Virus Research, 198103.
https://www.sciencedirect.com/science/article/pii/S0168170220308649
doi: 10.1016/j.virusres.2020.198103

Immunological co-ordination between gut and lungs in SARS-CoV-2 infection

After the gut microbiota develops, it stabilizes during adulthood.  However, its composition changes in old age.  An increase in facultative anaerobes, a change in the proportioning of bacteroidetes and firmicutes, and a decrease in bifidobacteria have all been observed in the elderly.  These phenomena are associated with age-related immune senescence and inflammation.  

Changes in the Gut Microbiota Compared Against Age-Related COVID-19 Mortality Rates

Gut-Lung Axis of COVID-19

Just as some gastrointestinal (GI) infections are accompanied by respiratory manifestations, many respiratory infections are coupled with GI symptoms.  It is thought that the organs are linked to each other's homeostasis through an immunological connection governed by the microbes within the microbiotas.  Consequently, they play a key role in shaping both normal and pathological immune responses.  

Bi-directional Communication Network Between the Gut and Lung Microbiotas

Intestinal ACE2 controls the expression of anti-microbial peptides (AMPs) and regulates intestinal homeostasis through its role in dietary amino acid uptake.  A lack of tryptophan, specifically, is thought to lead to adverse effects as it and its metabolites influence microbial ecology, microbial metabolism, and the interaction between the microbiota and its host.  Animal studies have shown that ACE2 knock outs had altered gut microbiotas, decreased AMP expression, and impaired amino acid uptake.  

ACE2 Modulates Gut Microbiota Composition

Plant fibre compounds that are indigestible for humans, but serve as food for the good bacteria in our bodies and allow the beneficial bacteria to grow and flourish. 


Prebiotics 

The highest mortality rates from SARS-CoV-2 are found  in the elderly and in people with certain comorbidities, such as diabetes. These groups tend to have less diverse gut microbiomes. 

Differences in Gut Microbial Compositions of Individuals Susceptible to Covid-19 Mortality 

New treatment strategies in addition to antiviral therapy has potential to significantly improve clinical outcome. One of those new potential treatments is immunomodulatory therapy. Immunomodulatory agents for the reduction of cytokine storms combined with antiviral agents could aid in the treatment process. 

- Corticosteroids
- Chloroquine
- Tocilizumab
- Proposed Doses for COVID-19 Immunomodulatory Therapy 

Immunomodulatory Therapy for the Reduction of Cytokine Storms and COVID-19 Treatment

Cytokines are inflammatory proteins that play a crucial role in an inflammatory response. But a response that is too strong is characterised as a "cytokine storm", which can also be harmful for the patient. It was previously thought that a cytokine storm was responsible for a severe immune response to COVID-19, but researchers compared several cytokine levels of patients with COVID-19 to patients with other diseases and found no increase in cytokine concentration. This indicates to the fact that severe COVID-19 immune responses are not liked to a cytokine storm. 
The cytokines that were tested were TNF-alpha, IL-6 and IL-8. It was found that the concentration of these cytokines in COVID-19 patients was significantly less elevated.

COVID-19 Cytokine Storm may not exist

- Acute Respiratory Distress Syndrome (ARDS)
- Cytokine Release/Storm Syndrome 
- Multi-Organ failure 
- Multisystem Inflammatory Syndromes (MIS)
- Secondary Haemophagocytic Lymphiohistocytosis
- Vascular Hyperpemeability 



Downstream Inflammatory Pathogenesis of Cytokine Storms in COVID-19

The increased production of cytokines is a result of many mechnisms, for example:

- CD14+CD16+ monocytes are triggered by activated pathogenic T helper cells to release IL-6 (a major component of the development of the cytokine storm)
- An increase in a subpopulation of CD14+IL-1β+ monocytes may increase IL-1β levels
- Th17 cells that produce IL-17 go on to recruit more monocytes/macrophages and neutrophils, which then triggers other cytokine cascades 
- Monocytes/macrophages may produce additional inflammatory cytokines
- Eosinophils can may release a large amount of cytokines, including IL-6 

Potential Mechanisms of SARS-CoV-2-induced Cytokine Storm 

- Obesity as a risk factor for cytokine storm onset
- Cytokine Storm as a risk factor for obese patient morbidity/mortality

Cytokine Storm and Obesity Relationship in COVID-19

- The target location of COVID-19 is the lung 
- The etiology attribute is "damp and toxin plague"
- The QPD concoction has 16 herbs that are lung-specific, making it a great treatment for respiratory illnesses like COVID-19. Studies have shown that it has the ability to reduce the cytokine storm triggered by SARS-CoV-2 infection.
- The aim of TCM is the holistic balance of Ying and Yang in the body., which strengthenes the body to fight infection 

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