The First Steps to Understanding and Reversing Long-Covid

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This paper is dedicated to all those who suffer from acute and post-viral COVID syndrome,
as well as those who sit in the aftermath of the loss of a loved one from this disease.

May you find peace, courage, strength, and healing.
With love,

~ Cat ~

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Prologue:

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This matter is close to my heart, as I, myself am a ‘COVID long-hauler,’ working to restore my health and vitality. Over the last two years living with this condition, I have met countless others who suffer—in my view, needlessly—with a long list of terrifying symptoms which keep them up at night. Sometimes in pain, other times with worry that they may never return to their former selves. It is my firm belief that teaching the public prophylactic and restorative dietary and supplementation measures could save lives and livelihoods as well as much chagrin. 

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Out With it!

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The COVID-19 pandemic has affected most people on the planet in one way or another. It’s surprising, then, how little meaningful conversation exists around the after-effects of the virus itself. Many who fall ill find themselves unable to fully recover. For those of you who don’t already know, these are the so-called ‘covid long-haulers.’ According to researchers from UCLA, approximately 30-40% of people who get sick with covid, develop lasting symptoms of long-covid.[1] According to a meta-analysis from the University of Michigan, this amounts to over 100 million people from across the globe whose active SARS-CoV2 infection has progressed from the acute COVID-19 ‘phase’ into a long-term chronic illness that can last for months or years without full recovery.[2] Often with downstream effects that cause additional health problems. The list of symptoms is long, confusing, and can vary from person to person. This can leave doctors mystified and patients frustrated or even terrified. Symptoms can include debilitating fatigue, nausea, chronic chest pain, brain fog, excessive hair loss, crumbling bones and teeth, tremors and spasms, neuralgia (nerve pains), gastrointestinal disturbances, muscle pain, uncharacteristic depression and/or anxiety, food intolerances, rashes and welts, edema (mass swelling in the arms and ankles) memory loss and sleep disturbances. The list goes on.

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​This paper aims to remove some of the guesswork and provide clear direction and confidence to those suffering from long-covid so that months of illness don’t turn into years. I argue that rather than being entirely disparate, the long list of covid symptoms indicates aggressive damage and dysfunction to the epithelial and microbial lining of the gastrointestinal (GI) tract and that this is the systemic root that needs to be addressed to reverse this disease and restore cellular energy and homeostasis. There is no catch-all, as some cases may be more complex than others. However, due to the nature of this virus,

I believe that addressing these two things is fundamental to anyone’s recovery, regardless of their unique bio-individuality. Instead of using band-aid approaches to ‘boost the immune system’, I believe that focusing on replenishing and healing the gut is the number one priority for long-covid recovery.
This is likely to have a positive knock-on effect in all other areas of health and wellbeing.

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“Peace cannot be kept by force.

It can only be achieved by understanding.”
~ Albert Einstein

​To effectively address this illness, we need to understand what’s happening in the body in the first place.
                                                           

The Initial Infection
 

​Viruses are extremely small. SARS-CoV2—the virus which causes COVID-19 is spread through microscopic droplets expressed from an infected individual through respiration—whether that be speaking, breathing, sneezing, coughing, singing, or any other type of expression from the lungs, nose, or mouth. The lungs tend to be the primary location of infection. Here, the virus binds to receptors called ‘angiotensin-converting enzyme 2’ or ‘ACE2.’[3] The virus then enters the human cell where its genome replicates new virions (inactive complete viruses) which are then released back into the system to activate and infect more lung cells. The stress of this process can cause widespread cellular death.3 From personal experience, this feels like a tight, painful crust on the inside of your upper respiratory tract which cracks, stings, and calcifies like the lesions seen across a desert salt pan. As well as the constant feeling that you have a heavy object on your chest. ​

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For the virus to enter our system, it has to bind to these ACE2 receptor sites. While most people know that the virus affects the lungs, most don’t know that these ACE2 receptor sites also occur throughout the gastrointestinal tract. In particular in the small intestine.[4] This has serious implications in triggering intestinal permeability (leaky gut) and dysbiosis of the gut microbiome.4 Most people know about the gut microbiome, whether or not they understand its true importance. What many don’t realize, is that most of our organs actually have their own microbiomes. These communicate with one another through a series of ‘cross-talks,’ transferring bacteria, viruses, and other information between organs.[5]

You may have heard of the ‘gut-brain’ axis, but have you heard of the ‘lung-gut axis?’ This means that constant transmission occurs between the microbiome of the lungs and the microbiome of the gut. Unfortunately, since the lungs and the gut together have an immense, never-ending interaction with the outside world, through the food and liquids we eat and drink and the air we breathe, these organs are most at risk of environmental contamination. Interestingly, studies have shown that lung immunity correlates with a rich and diverse gut microbiome.[6] Conversely, respiratory illnesses can trigger bowel infections.6 The protective barriers—the inner membranes and complex immune responses—both 'innate' and 'adaptive'—are vital for defending ourselves from external invasion. These protective measures work hand in hand with a complex ecosystem of microbial species in a dynamic interplay between host and bug. COVID-19 patients with previously depleted microbiomes thus have a greater risk of severe illness upon infection.6

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​Chinese researcher, Tao Zuo, and his fellow researchers write:

 “ACE2 is important in controlling intestinal inflammation and gut microbe ecology. With trillions of diverse bacteria growing in our gut, the gut microbiome has a myriad of effects on gene regulation, immune response, and metabolism. The commensal microbiota ecosystem in the gut is dynamic and can be regulated by invading viruses to facilitate a stimulatory or suppressive response. Studies have shown that respiratory viral infections may be associated with an altered gut microbiome, which predisposes patients to secondary bacterial infection.”4
 

From this, we can see the fascinating and terrifying reality that SARS CoV2 is adapted to bind with the very biological entity responsible for modulating the delicate balance of these microbiomes between the host (us) and our good (commensal) bacteria. This paves the way for secondary infection, disruption of the microbiome (dysbiosis), and intestinal permeability.
 

​Why is this important? Well, because our gut microbiome and epithelial and mucosal linings play a vital role in preserving our health. This complex interplay impacts our cellular energy (mitochondria) our metabolism, immune system, our brain, and our nervous and endocrine systems. Essentially, this is the control center that communicates external information (nutrients, toxins, feelings, etc.) with the inside world—turning the food we eat into energy and tissue, making sure everything within us runs smoothly. The microbiome and gut linings are all that stand between us and runaway, systemic inflammation as our body attempts to protect us from outside invasion. Chronic systemic inflammation of this kind is associated with autoimmune disease.

For most autoimmunity to occur, three conditions are necessary:[7]
 

1. Environmental factors such as an acute viral infection or a traumatic incident,

2. Intestinal permeability (leaky gut)

3. and finally, a genetic predisposition.

Research indicates that the SARS CoV2 infection can trigger at least two of the three requirements, thus potentially triggering an autoimmune illness in those with genetic predispositions. The initial SARS-CoV2 infection is an example of the first condition. Not only does it cause widespread damage to the epithelium of the lungs and GI tract, but it has major implications for the microbiomes of these organs. Studies have shown that patients with COVID-19 have “significant alterations in fecal microbiomes compared with controls, characterized by enrichment of opportunistic pathogens and depletion of beneficial commensals.” 4 This means it kills off the good bacteria, leaving opportunistic pathogens unchecked. 
 

With the normal Western diet, the richness and diversity of the gut microbiome are known to depreciate over time, dwindling as one gets into old age. This is believed to play a part in why the elderly have an increased risk of morbidity and complications with COVID-19. It turns out that specific species of microbes are affected.

Researchers have found that COVID-19 patients have something of a microbial ‘footprint’ that is distinct from both healthy controls and those with other illnesses such as influenza A, pneumonia, or the common cold.4 We could go in-depth into this, but for this paper, suffice to say the following:

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Compared to healthy controls, Wanyin Tao and his team of researchers discovered that “compared with healthy controls…Streptococcus, Clostridium, Lactobacillus, and Bifidobacterium increased whereas…Bacteroides, Roseburia, Faecalibacterium, Coprococcus, and Parabacteroides were decreased in SARS-CoV-2-infected patients.”[8] This may sound like gibberish to most ears, but the increased prevalence of Streptococcus, for example, is associated with an increased risk of secondary infection and ‘bacteremia,’ which occurs when secondary bacterial infection leaches into the bloodstream and infects multiple other organ systems.4These bacteria are implicated in various disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis.[9]

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​In their clinical study, Tao Zuo and his research team found that even after the coronavirus cleared, the microbiomes of most of their COVID19 patients did not recover. Many of these patients displayed a progressive worsening of their microbiome over time.4 It seems the more damaged your microbiome is, the more toxic the local terrain (your gut ecosystem) becomes, as pathogenic and opportunistic species run amok in the altered ecology. Creating something of a vicious cycle in the gut.[10] Unfortunately, this increases the risk of the second condition necessary for most autoimmune diseases: Intestinal permeability. Herein lies the true clincher: the ultimate ‘can of worms.’

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​Intestinal permeability or leaky gut occurs when the epithelial and mucosal linings of the small intestine become so worn down, loose, and damaged that large molecules (and pathogens) can pass undeterred from your gut into your bloodstream. This has huge implications for the well-being of the entire system. It can impact the pH of your blood, (and thus the porosity of the bones which leach calcium into the bloodstream to restore even slight changes in pH—hence those crumbling bones and teeth) your cellular and mitochondrial health, as well as brain and endocrine function. Blood quality and the prevalence of systemic inflammation have huge implications on the body as it tries to protect itself from an endless onslaught of secondary ‘invaders.’ Intestinal permeability is responsible for most food sensitivities and intolerances for this reason, since microscopic food particles which pass into the bloodstream trigger an immune response.

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​Two major species of beneficial bacteria have (among others) been found to be severely depleted in COVID-19 patients. One of these is the species “Alistipes onderdonkii,” which is involved in the metabolism of the serotonin precursor, tryptophan, as well as in the homeostasis of both the gut and the immune system.4 Since the neurotransmitter Serotonin is responsible for modulating mood, sleep, cognition, and memory, this could explain why so many ‘long-haulers’ suffer from uncharacteristic depression, anxiety, sleeplessness, brain fog, and short-term memory loss. Inflammation itself could also play a significant role, here.

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​The second species, Faecalibacterium prausnitzii has anti-inflammatory properties which seem to influence a group of proteins collectively called ‘zonulin.’10 Zonulin is responsible for the regulation of ‘tight junctions’ between the epithelial cells of the small intestine.10 Long story short, the more zonulin you have in your small intestine, the looser these cellular junctions and the higher your rate of intestinal permeability. The more Ruminococcaceae and Faecalibacterium you have, the lower your levels of zonulin. This suggests that these butyrate-producing bacteria play a significant role in decreasing zonulin levels and intestinal permeability, thus dampening systemic inflammation.10 Ruminococcaceae also seem to help process and clean up microbial excrement known collectively as ‘metabolites.’[11]

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​A host of other conditions can be connected to systemic inflammation, microbial dysbiosis, excess zonulin, and, intestinal permeability. Several chronic illnesses to which zonulin has been linked as a biomarker of intestinal permeability include ADHD, autism, celiac disease, ME/CFS, inflammatory bowel diseases, IBS, HIV, all types of diabetes, major depressive disorders, multiple sclerosis, Schizophrenia, non-alcoholic fatty liver disease, and non-celiac gluten sensitivity, among others.10

​Unfortunately, intestinal permeability does more than increasing the risk of systemic infection, inflammation, and toxicity. In a vicious cycle of catch-22, it also reduces the body’s capacity to absorb essential nutrients, causing further deficiency and pathology in the body. My functional nutrition teacher, Andrea Nakayama says “It’s not just what you eat, but what your body can do with what you eat.” In other words, you may be eating the right foods, but if your body is in such a state of disarray that you cannot assimilate the nutrients into your system, then you could be deficient in the nutrients you think you’re getting frequently. In leaky gut syndrome, the microvilli of the small intestine—which are responsible for the uptake of nutrients, become stubby and damaged. Each micro-villi in the small intestine is responsible for the absorption of different nutrients. Therefore, nutrient deficiencies that lead to a vast array of illnesses and conditions are often related to which villi or sections of the small intestine have been damaged or compromised. This can affect things as diverse as brain function, osteoporosis, and cognitive decline, right down to anemia and vitamin D deficiency. Most importantly, I believe it has direct consequences on our body’s ability to regenerate soft tissue and neurological tissue.

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This could be why diseases like long-COVID and chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) can have such a diversity of manifestations between individuals. Of course, then there is the issue of the cytokine storm—which is the reaction and overreaction of the body towards the infection, and subsequently itself. A few major agents have been identified: IL2R, IL6, IL8, and IL18. These have long-lasting impacts but have especially been found in severe cases involving hospitalization.[12]

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​In addition to all this, the gut contains more neurons than your spinal cord or peripheral nervous system[13] It also contains every chemical substance that helps run and control your brain. Including neurotransmitters like serotonin, dopamine, oxytocin, glutamate, and norepinephrine.13 This could explain why this kind of inflammation and degeneration in the gut may cause strange nerve pains and tremors, depression and anxiety, brain fog, and difficulty sleeping. Some sufferers also report feeling an ‘impending sense of doom,’ which I believe comes from a crash in the feel-good neurotransmitters normally generated in the gut. This is outside the scope of this paper, but I encourage those interested to look further into the topic of ‘psychobiotics’ (the role of probiotics in controlling and forming our mood and aspects of our personality.) You may also be curious to learn about the stimulation of the Vagus nerve and enteric nervous system to switch on the ‘rest and digest’ response.

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“The highest activity a human being can attain is learning for understanding
because to understand is to be free.”

~ Baruch Spinoza

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​Finding Solutions

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​See how much it helps to properly understand “what’s going on in there?” Now that we have a little more insight, we have some direction as to how to go about healing it. It’s important to remember that SARS CoV2 is a virus, not a bacterium. As such, it may be impossible to ‘kill’ once it is inside your system. My understanding is that viruses exist in the grey area between the living and nonliving. Rather than having cells, they are a collection of RNA or DNA that can only replicate within the living structure of a cellular organism. So, instead of focusing on the virus itself, whether or not we vaccinate, it makes sense to restore the damage and rebuild the resilience of the entire system. Now that we know what has gone awry, we know what needs to be done: heal the damaged microbial, mucosal, and epithelial elements of the GI and respiratory tracts to heal intestinal permeability, restore microbial equilibrium and stem systemic inflammation.

 
I have put together four steps to simplify the process in the reader’s mind.

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1. Stop the fire: Elimination diet.
   Remove all foods that exacerbate inflammation and dysbiosis in the gut. These can vary from person to person, which is why this diet is a process of personal discovery. In general, as a rule, gluten, dairy, corn, soy, sugar, and highly processed meats and carbohydrates as well as the deadly nightshade family (tomatoes, peppers, chilis, eggplant, and often white potatoes) nuts, yeasts, and oranges should all be removed. Grains and legumes are also common aggravators that are removed.
    

2. Reconstitute the microbiome with both targeted and diverse butyrate-producing bacteria.
   Butyrate is produced when microbial action on dietary fiber produces short-chain fatty acids which help protect the gut and lungs from an allergic reaction or intolerance.6 This step includes reducing meat, sugar, and alcohol and moving towards an increase in whole, fresh, organic vegetables and other prebiotic fibers so the new probiotics can gain a decent footing inside you. Interestingly, diets high in fat and sugar appear to have deleterious impacts on the microbiome, causing difficulty sleeping, among other things.6 Studies also found remarkable differences between the microbiomes of plant versus animal-based diets. Lactobacillus rhamnosus and Saccharomyces boulardii are widely used for targeting leaky gut and dysbiosis.5 Use activated charcoal capsules to address occasional nausea and digestive bitters to address digestive distress while supporting the liver. Bifidobacterium lactis, Bifidobacterium breve, Bifidobacterium bifidum, Ruminococcus obeum, Blautia coccoides, Faecalibacterium prausnitzii and Lactobacillus casei (specifically Shirota) are other species that are worth introducing.6
    

3. Take supplements that are known to promote the protection and healing of the inner ‘wet’ skins and mucosal linings.
   This step includes introducing a greater diversity of essential amino acids (the building blocks of proteins) and antioxidants. These include things like L-glutamine powder, N-Acetyl Cysteine (NAC), vitamin E, vitamin A, vitamin C, and intravenous or nebulized glutathione.[14] Herbs like slippery elm and marshmallow root powder together in a cold infusion, as well as aloe vera juice and essential fats such as Omega 3, coconut, olive, avocado, hemp, and flax oils, and vitamin D3 can be supportive of healing, too. Studies show that vitamin D insufficiency plays a huge role in the severity of active COVID-19, and may account for nine out of ten COVID deaths.[15] I would go so far as to say, if you take nothing else, take D3, and L-Glutamine. Please speak with your doctor about safe and optimal dosage for you and your family.
    

4. Take strident measures to improve sleep and reduce stress.
   Sleep is a great detoxicant. It has wonderful restorative and regenerative properties. Unfortunately, it can often elude us when we need it most. It’s important to reduce stress in every possible way, without excuse. We often take on more than we can chew because we feel we have to. Learning to rest and recuperate is a skill that has to be learned in the process of unlearning decades of habitual behavior, identities, and a sense of responsibility. Learn to ask for help.
    

There is a great deal of information that I have not included because each involves a rabbit hole of complexity to parse through. There’s the issue of small intestine bacterial overgrowth (SIBO) in some patients, as well as the conversation around cortisol, adrenal fatigue, and mitochondrial dysfunction which may impact the ease of recovery in some individuals. Given more time and resources, I would like to get a more in-depth understanding of each of these issues and how to mitigate them, independently and in relation to one another. Finally, there’s the last ‘leg’ of the ‘autoimmune trifecta:’ the role of inherited genetic predisposition. The science of epigenetics states that genes within a genetic profile can be ‘switched on and off’ through lifestyle factors such as diet, sleep, stress management, and environmental toxic load. Understanding and flagging genetic profiles such as the MTHFR and others mentioned in Dr. Ben Lynch’s book ‘Dirty Genes’ may add invaluable insight as to how to fully heal and regain optimal energy and vitality after this illness. Despite all this, evidence suggests that addressing the two most distinctive and prevalent systemic issues of intestinal permeability and microbial dysbiosis is key to addressing all of these other issues. 

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I believe the most valuable intelligence comes from making the complicated simple. Understanding is the key.

​In conclusion, rather than chasing a host of disparate symptoms, it helps to understand the systemic issues at play, and how they are triggered by the initial SARS CoV2 infection. We now understand that the virus binds to the ACE2 receptor cells in the lungs and GI tract and that a series of ‘cross-talks’ occurs between the gut and the lungs, allowing for pulmonary infection to spread to the digestive system where it can wreak havoc by destroying the microbial ecosystem’s balance, leaving pathogenic and opportunistic species unchecked. This can lead to secondary infections and systemic ‘bacteremia,’ where infection seeps into the blood and contaminates other organs. We understand that specific bacterial species associated with the regulation of zonulin, which plays a key role in intestinal permeability, are vastly depleted in the COVID-19 microbial profile when compared to multiple controls. We understand that for most autoimmune diseases to occur, three conditions need to exist; an environmental infection (like SARS CoV2), intestinal permeability, and genetic predisposition. We have come to understand that by entering the human cell through the ACE2 receptor sites, two of these three conditions are created by ensuing events in the gut. These, when met with an individual with genetic predisposition, already depleted microbial profile, or chronic excessive cortisol levels, can together cause the advent of autoimmune disease and thus the COVID long-hauler phenomenon.

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​To address the illness from the root, we need to focus on dampening the fire by removing inflammatory foods, rejuvenating the microbiome, regenerating the epithelial and mucosal lining of the lungs and GI tract, and taking strident measures to improve sleep, reduce stress and incorporate behavioral changes that include rest, relaxation, simplification, sense of identity and sense of responsibility. While there is a great deal more to this story, I believe that addressing these issues are the greatest needle-movers, the flood-gates, if you will, to healing and restoring energy, vitality, and homeostasis.

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References

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​ [1] Yoo, S.M., Liu, T.C., Motwani, Y. et al. Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort. J GEN INTERN MED (2022). https://doi.org/10.1007/s11606-022-07523-3. Accessed May 24, 2022

2 Global Prevalence of Post-Acute Sequelae of COVID-19 (PASC) or Long COVID: A Meta-Analysis and Systematic Review

Chen Chen, Spencer R. Haupert, Lauren Zimmermann, Xu Shi, Lars G. Fritsche, Bhramar Mukherjee

medRxiv 2021.11.15.21266377; DOI: https://doi.org/10.1101/2021.11.15.21266377 (Has not yet been peer-reviewed.) Accessed May 24, 2022

[3] Khatiwada S, Subedi A. Lung microbiome and Coronavirus Disease 2019 (COVID-19): Possible link and implications. Human Microbiome Journal. https://doi.org/10.1016/j.humic.2020.100073. Published August 5, 2020. Accessed May 24, 2022.

[4] Zuo T, Zhang F, Lui GCY, et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology. 2020;159(3):944-955.e8. doi:10.1053/j.gastro.2020.05.048. Accessed May 24, 2022

[5] Enaud R, Prevel R, Ciarlo E, et al. The gut-lung axis in health and respiratory diseases: A place for Inter-organ and inter-kingdom crosstalks. Frontiers. https://www.frontiersin.org/articles/10.3389/fcimb.2020.00009/full. Published February 19, 2020. Accessed May 24, 2022.

[6] Dhar D, Mohanty A. Gut microbiota and Covid-19- possible link and implications. Virus Research. 2020;285(198018). doi:10.1016/j.virusres.2020.198018. Accessed May 24, 2022

[7] Andrew W. Campbell, "Autoimmunity and the Gut", Autoimmune Diseases, vol. 2014, Article ID 152428, 12 pages, 2014. https://doi.org/10.1155/2014/152428. Accessed May 24, 2022

[8] Tao W, Zhang G, Wang X, et al. Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18. Medicine in Microecology. 2020;5:100023. doi:10.1016/j.medmic.2020.100023.

[9] Bush LM, Vazquez-Pertejo MT. Streptococcal infections - Infectious Diseases. Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-cocci/streptococcal-infections. Published April 18, 2022. Accessed May 24, 2022.

[10] Fasano A. All disease begins in the (leaky) gut: Role of zonulin-mediated gut permeability in the pathogenesis of some... F1000Research. https://f1000research.com/articles/9-69/v1. Published January 31, 2020. Accessed May 24, 2022.

[11] Punzalan C, Qamar A. Probiotics for the treatment of liver disease. The Microbiota in Gastrointestinal Pathophysiology. 2017:373-381. doi:10.1016/b978-0-12-804024-9.00040-9

[12] Dance A. What is a cytokine storm? Knowable Magazine | Annual Reviews. https://knowablemagazine.org/article/health-disease/2020/what-cytokine-storm?gclid=CjwKCAjwiOv7BRBREiwAXHbv3K1teuwNBWNrdVntB4EBN9dbo3f8qmqK-diLGSa_r1LoKRGY1zTkDxoCTU4QAvD_BwE. Accessed May 24, 2022.

[13] Hadhazy A. Think twice: How the gut's "Second brain" influences mood and well-being. Scientific American. https://www.scientificamerican.com/article/gut-second-brain/#:~:text=The%20second%20brain%20contains%20some,our%20gut%20and%20its%20contents. Published February 12, 2010. Accessed May 24, 2022.

[14] Regenerative Medicine: Healing Chronic Pain and Addressing COVID-19. Mark Hyman. Ultimate Wellness. YouTube; 2020. https://www.youtube.com/watch?v=UbSdX-G8ZXw&t=1s. Accessed May 24, 2022.

[15] Brenner H, Schöttker B. Vitamin D insufficiency may account for almost nine of ten COVID-19 deaths: Time to act. comment on: “vitamin D deficiency and outcome of COVID-19 patients”. nutrients 2020, 12, 2757. Nutrients. 2020;12(12):3642. doi:10.3390/nu12123642