I’m not one to use many curse words, but a little over a month ago I had a double “oh shit” moment. It was an excited realization (oh shit!), immediately followed by a sinking, pit-in-the-stomach feeling (ooh shiiiit).

A naturopath friend of mine had sent me a medical paper from the American Journal of Translational Medicine entitled “Could certain strains of gut bacteria play a role in the prevention and potential treatment of COVID-19 infections?”

At the time, I was deep in microbiome research, so this was a compelling read. The paper contended that the primary mechanism of a severe case of coronavirus, was due to the overreaction of an individual's immune system called a “cytokine storm,” resulting in a hyper-inflammatory response. 

The paper’s central thesis was described in it’s abstract:

“It has been established that high risk groups are more vulnerable to COVID-19 infections (age over 65, diabetes mellitus, insulin resistance & obesity)... and are aligned with chronic inflammatory disorders. Inflammation is regulated by the immune system and compelling evidence suggests that certain gastrointestinal flora act as anti-inflammatory mediators …elevated gut concentrations of a specific microbe, Bifidobacterium, which diminishes significantly with age. This reduction contributes to immune dysregulation and correlates to pathological onset of the forenamed conditions. Thus, we predict that Bifidobacterium functions as a key immunoprotective agent and prevents complications associated with COVID-19.” [1]

To me, the paper’s conclusions made a lot of sense, and I thanked her for sending it to me. But I needed to get to work, as I was just starting on my latest post, in which I shared and analyzed a recent microbiome analysis. 

Searching through past emails from my doctor, I pulled up my test results to begin writing about them. My plan was to research each individual bacterial species that was out of balance in my gut, and then trace that, I hoped, to one of the outward symptoms I experience. But when I opened the email attachment, my jaw dropped.

One of the first results on my analysis listed Bifidobacterium spp. (an abbreviation meaning “several species”). Oh shit! I found my first link!

Excited, I went back to the research study to confirm it was the same Bifidobacterium. It was! I clicked back to my results and traced my finger from this word to “NG.” I glanced down at the notes: NG was an abbreviation meaning “No Growth.” Ooh shiiit. My body was utterly absent of these “immunoprotective” strains. 

Until this moment, I had always considered myself to be a relatively healthy individual, with a robust immune system. Although I follow current “COVID” precautions and guidelines, I’ll admit I was actually personally quite unconcerned about contracting it, believing my immune system would deftly handle it. 

I was dead wrong. Suddenly I was “high risk” for a severe coronavirus infection. 

I have been reluctant to share this information with friends and family, because I did not want to worry them. Instead, I poured my own angst into countless hours of research—reading books, medical journal articles and pre-prints; listening to podcasts; talking to functional medicine practitioners. In the following post, I will trace this journey and share my findings, with the hope someone out there might find it useful.

• • •

The Nature of this Virus

Now knowing my risk, my next step was to explore what a “severe COVID infection” looked like.

A recent article in the journal Science traces the path of a standard coronavirus infection through the body: 

“When an infected person expels virus-laden droplets and someone else inhales them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It finds a welcome home in the lining of the nose… Once inside, the virus hijacks the cell’s machinery, making myriad copies of itself and invading new cells. Symptoms may be absent at this point. Or the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches.” [2]

A useful analogy for me when considering this moment of contraction, is one of “gates.” When the virus enters the upper respiratory tract is the “first gate”—the body’s first opportunity to deal with the virus, and the point at which most asymptomatic cases end.

“If the immune system doesn’t beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung’s respiratory tree end in tiny air sacs called alveoli… Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts this healthy oxygen transfer. Front-line white blood cells release inflammatory molecules, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells—pus—behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration. Some COVID-19 patients recover… others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet and they struggle ever harder to breathe. On x-rays and computed tomography scans, their lungs are riddled with white opacities where black space—air—should be. Commonly, these patients end up on ventilators. Many die. Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.” [2]

The point at which the virus gets to the lungs is the “second gate”—I see this as really the final chance for the immune system to respond appropriately before the infection turns severe. As the pathology shows, it is the nature of the immune response itself, not the coronavirus, that is the cause of complications in the lungs here.

The article paints this as an immune “over-response,” corroborating the theory of the “cytokine storm” presented in the paper my friend had sent me:

“Some clinicians suspect the driving force in many gravely ill patients’ downhill trajectories is a disastrous overreaction of the immune system known as a ‘cytokine storm’ which other viral infections are known to trigger. Cytokines are chemical signaling molecules that guide a healthy immune response; but in a cytokine storm, levels of certain cytokines soar far beyond what’s needed, and immune cells start to attack healthy tissues. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can ensue.” [2]

ARDS. Pneumonia. Blood clots. Organ failure. These are the most common harbingers of death in this pandemic—and all of them, it seems, are directly attributable to an aberrant immune response. 

• • •

The Microbiome-Immune System Link

The burgeoning field of microbiome research is revealing myriad links between the gut microbiome and immune health. But there hasn’t been much mention of these in the national (or global) coronavirus conversation.

To ground this conversation, let’s look at some numbers:

While there are 7 billion of us humans on Earth, it is generally accepted that there are five million trillion trillion or (5 x 10 to the 30th power) bacteria. Additionally, there are 10 nonillion (10 to the 31st power) individual viruses on our planet, “enough to assign one to every star in the universe 100 million times over.” [4, 5]

For cognitive processing of these astronomical numbers, I’ll write these out here:

7,000,000,000 humans
5,000,000,000,000,000,000,000,000,000,000 bacteria
1,000,000,000,000,000,000,000,000,000,000 viruses

But it doesn’t stop there. We humans are vastly outnumbered, even within our own individual biology: there are more non-human cells in our bodies than there are human ones—bacteria, fungi, parasites, viruses—by a factor of up to 3x. In fact, there are at least 300 times more bacterial genes in your body than human ones. 

“Where the human genome carries some 22,000 protein-coding genes, researchers estimate that the human microbiome contributes some 8 million unique protein-coding genes or 360 times more bacterial genes than human genes. This bacterial genomic contribution is critical for human survival.” [7]

• • •

What is the immune system? 

Our immune system is divided into two types of coordinated responses, innate immunity and adaptive immunity: 

1. Innate immunity is our first line of defense. It is composed of “physical and chemical barriers, immune cells, and blood proteins that mediate inflammation (e.g. cytokines)... The cells of the innate immune system patrol our body looking for threats (e.g., microbes, microbial proteins) and devise quick immune responses when they find them that aim to destroy the foreign, damaged, or infected cells. These responses are nonspecific, but they influence subsequent specific adaptive immune responses.”

2. Adaptive immunity is “responsible for the more complex immune responses that develop when innate immunity is insufficient to manage a threat. Adaptive immunity is mediated by cells called lymphocytes… Lymphocytes survey our body continuously, looking for potential pathogens. When they come across an antigen they recognize, lymphocytes are activated, trigger a specific immune response, and proliferate, creating a pool of new lymphocytes with the same specificity… The adaptive immune system is what remembers past infections and vaccines, allowing the immune system to respond quickly when we encounter something similar again.” [6]

Where does our microbiome come into play?

The microbiome-immune system connection seems to have been ignited a few years ago, with the startling discovery that up to 80% of our bodies’ immune cells reside in our gut. While the links between our microbiota and our immune system have mushroomed since then, answering the question of how these microorganisms impact immune response has been elusive.

Indeed, the more I researched this question, the more overwhelmed I became. The mechanisms at play here are myriad and mind-bogglingly complex, and as most of the scientific reviews to date admit, generally not well understood.

However, a 2018 paper “Aspects of Gut Microbiota and Immune System Interactions in Infectious Diseases” published in the scientific journal Frontiers in Immunology, provides the crispest explanation I’ve found for some of these mechanisms, and they happen to align with both our innate and adaptive immune systems.

Our microbiome impacts our:

1. Innate Immunity, by creating and maintaining a physical barrier, in the mucus that lines our nose, throat, lungs, and intestines. 

“Through the colonization of the mucosal entry sites of pathogens, microbiota could directly prevent the invasion by foreign microbes—a process known as colonization resistance (by competing with pathogenic bacteria for adhesion sites and nutrients, but also by releasing toxic molecules to counteract pathogen colonization), as well as indirectly… microbiota provides signals to stimulate the normal development of the immune system as well as the maturation of immune cells.” [7]

2. Adaptive Immunity, through something called “Quorum Sensing” and communication with our own cells.

This mechanism consists of inter-species communication—bacterial cells in our gut are “talking to” our own human cells:

“...based on a universal chemical “language,” which provides signaling between bacteria and eukaryotic/host [i.e. human] cells. Quorum Sensing (QS) is orchestrated by small…hormone-like organic molecules called autoinducers (AIs)... A universal interspecific signal “cross talk” which contains AIs… hold a paramount role in various niches, especially in highly colonized sites, such as the gut and the oral cavity. This mechanism of communication regulates the expression of virulence genes in pathogens, with an important role in infection... [7]

In investigating the question of how, I inadvertently stumbled upon, perhaps a more compelling question: why do these microbes help us?

It appears these microorganisms are quite content living in the warm, moist environs of our skin, nose, mouth, lungs and intestines, and are willing to defend their happy home against outside invaders.

So given this strong, symbiotic Why, and considering the 200 million year history of mammals on Earth, a lineage from which us modern humans are descended, it makes sense that the How may be elusive, obscured by the complexity that comes with millions of generations of mammalian evolution, while living among nonillions of bacteria and viruses.

This evolutionary perspective on the immune system was actually an easier concept to grasp (and I really wish I had discovered this before spending countless hours wading through dense medical journal papers):

Our immune system has co-evolved along with a diverse gut flora, not only to create defenses against pathogens, but also to develop tolerance for beneficial microbes. As a consequence, the immune system and the gut microbiota developed a mutualistic relationship, regulating one another and cooperating to support each other. The importance of this interaction is clearly highlighted by the fact that 70–80% of the body’s immune cells are found in the gut. This communication and mutual regulation is maintained throughout life… In normal conditions, the immune system promotes the growth of beneficial microbes and helps maintain a stable microbial community, while in return, a healthy microbiota produces molecular signals that support the development of immune cells and contribute to the fine tuning of immune responses. A healthy crosstalk between the gut microbiota and the immune system supports protective responses against pathogens… [6]

• • •

Probiotics: A Pro-Immune Health Approach

Numerous studies have shown a link between certain strains of commensal (AKA expected, “good”) gut flora, and reduced risk and severity of Upper Respiratory Tract Infections (RTIs). With respect to the Coronavirus, the upper respiratory tract would correspond to the “first gate” analogy I described earlier, our immune system’s first shot at containing and expelling the virus. 

In a May 2020 review published in the medical journal Frontiers, entitled “Using Probiotics to Flatten the Curve of Coronavirus Disease COVID-2019 Pandemic,” the authors summarize a number of studies showing probiotics can not only reduce the risk of viral infection, but also lessen the severity of illness post-infection :

• “Viruses are etiologic agents of over 90% of upper RTIs. The positive impact of probiotics on prevention of upper RTIs is documented in a number of studies. A meta-analysis of 12 RCTs (randomized controlled trials) including 3,720 adults and children reported a two-fold lower risk of developing upper RTI in subjects taking probiotics, and a small but significant reduction in disease severity in those infected. 

• A randomized, double-blind, placebo-controlled intervention study of 479 adults showed that Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, and Bifidobacterium bifidum MF 20/5 ...lowered not only the duration of common cold episodes but also days with fever. 

• The impact of probiotics on prevention of upper RTIs caused by specific viruses has also been documented. An RCT including 94 preterm infants showed that… Lactobacillus rhamnosus GG given between 3 and 60 days of life lowered the incidence of clinically defined virus-associated RTI by 2- to 3-fold compared to placebo. 

• The incidence of influenza RTI was reduced following consumption of Lactobacillus brevis in an open label study of 1,783 school children

• Pertinent to the pandemic affecting adults more than children, these positive findings were confirmed in an RCT that included 27 elderly subjects receiving Bifidobacterium longum or placebo. [8]

This paper draws the following conclusion with respect to probiotics and “first-gate” Coronavirus infection:

...lactic acid bacteria, from which many probiotics are selected, are part of the upper respiratory tract microbiota in healthy people. This makes their use for contributing to slow down progression of the coronavirus pandemic worthy of consideration. [8]

But what happens if the virus passes the first-gate, and “marches down the windpipe to attack the lungs?” Probiotics have been shown to help here at the “second gate” too:

• “Probiotics have also been used to prevent bacterial lower RTIs in critically ill adults. Meta-analyses of RCTs including close to 2,000 patients found that probiotic strains reduce the incidence of ventilator-associated pneumonia.”

• A recent study in mice has shown that oral administration of Lactobacillus acidophilus CMCC878, started 24 h after pulmonary (i.e. lung) inoculation of [pathogens] reduced bacterial load in the lungs, and decreased lung damage and systemic inflammation.” [8]

This multi-stage immuno-protective effect has been documented by other studies as well, with specific regulatory action on the dreaded “cytokine storm”:

“Probiotics can interfere with the viral cycle by acting at several steps, interfering with some aspect of viral replication or pathogenesis, or protecting the mucosal barrier function. Also, immunomodulation at the level of innate and adaptive responses has emerged as a major mechanism for antiviral effects. By means of several mechanisms that are still poorly understood, probiotics can modulate specific host pathways and affect the synthesis of many cytokines (e.g., IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-γ, and TNF-α)… Thus, the adjuvant effect of probiotics has been documented for vaccination against several viral pathogens such as hepatitis B, poliovirus, or influenza, giving rise to increased IgG and IgA titers

— from “Intestinal Microbiota and Susceptibility to Viral Infections: Role of Probiotics” in the journal  Probiotics, Prebiotics, and Synbiotics [9]

There’s a lot of alphabet soup in there, but the important thing to take away is that these cytokines (IL-6, TNF-a, etc.) are a feature of our innate immune system—they are trying to protect us from pathogens like this coronavirus. But without certain good bacteria to regulate them, they can get out of hand (i.e. “storm” the infection sites), triggering a hyper-inflammatory state.

The paper that originally took me down this rabbit hole of research, corroborates these mechanisms, and posits that a healthy and varied set of Bifidobacterium species in the gut temper this immune system “overreaction” and prevent a cytokine storm:

“IL-6 is a marker of disease severity in COVID-19 patients and is responsible for initiating this cytokine release syndrome. Physicians treating these patients are now testing levels of IL-6... the serum IL-6 levels were found to be markedly elevated and predictors of severity of pneumonia. Additionally, the risk for respiratory failure was observed when levels of IL-6 exceeded 80 pg/ml ...Elevated IL-6 levels were also strongly associated with the need for a mechanical respirator. This suggests that the increased mortality of these patients might be attributed to the hyper-inflammatory immune reaction. Evidence of increased IFN-𝛄, and TNF-α have also been well documented in COVID-19 positive patients. Along with IL-6, TNF-α, and IFN-γ are also involved in lung tissue damage… [1]

Through various pathways, as the above graphic suggests, the study authors indicate that Bifidobacterium species down-regulate IL-6 and TNF-a, the primary culprits in cytokine storms, and upregulate other immune cells like Natural Killer (NK) cells and IFN-a:

“Furthermore, supportive evidence shows that cytotoxic lymphocytes such as natural killer cells (NK) are low or exhausted among COVID-19 patients with mild symptoms and severe symptoms (respectively)... This trail of logic concludes with the supposition that individuals with a populous gut microbiome, replete with Bifidobacterium will also have higher serum IFNɑ and presumably elevated NK cells capable of mitigating infections. Decreasing concentrations of B. longum, B.infantis & changing NK cell phenotypes have been reported with age, while enhancement of NK activity in aged persons who are given the forenamed microbes has been reported… the reestablishment of the gut microbiome via daily supplementation is a practical and effective method for viral remediation. [1]

Almost from Day 1, the mystique surrounding this Coronavirus was by virtue of its unique pathology in who it affects: while people of all ages contract the virus at similar rates, children are generally unaffected (asymptomatic), whereas the elderly are at the highest risk for a severe infection.

Many theories have been offered, but more than six months into this global pandemic, this attribute remains a head-scratcher for doctors and scientists alike. This paper offered the most compelling explanation for it I’ve come across yet:

“Bifidobacterium levels decline with age, becoming significantly reduced in the adult population and virtually absent in the high-risk groups mentioned… Equally evident is the difference in the specific strains among the age groups. B. longum, B. infantis, B. catenulatum, and B. breve are the abundant species in babies and healthy children. B. breve is highest in breast fed infants and has shown significant anti-inflammatory properties. B. infantis has also shown significant positive immunoprotective effects. The majority of the adult gut Bifidobacterum, on the other hand, shows less colonization of these strains and is mainly colonized by B. angulatum and B. adolescentis. Many studies have linked age related changes in microbiota to decreased immunity. Of particular interest, in a study of Chinese and Italian centenarians, the level of Bifidobacterium was higher than that found in the younger elderly population, suggesting that longevity may be partly attributed to a higher level of this flora.” [1]

As a final note: the microbiome is a difficult system to study. The experiments discussed here all relied on supplementation of probiotics to correlate between certain probiotic strains and beneficial outcomes. However, all probiotic supplements are not created equal, and the ideal scenario is that an individuals microbiome is already replete with a healthy balance of these microbial strains to the extent that outside supplementation is unnecessary. One way to foster this balance is through diet, as I’ll discuss in my next post, Wanderer’s Guide to: Coronavirus.

•••

Thank you for reading. If you feel called, please share with a loved one to continue the conversation.