Gut Microbiome In Acute and Long COVID
Gut microbiome dysbiosis is common in acute and Long COVID. Intestinal dysbiosis (out of balance and unhealthy gut flora) is a factor implicated in both severity of acute COVID-19 and expression of Long COVID. This article will examine the supportive data behind this statement, and explain how intestinal dysbiosis may increase the risk of severe COVID and be a factor leading to Long COVID.
If I had not already been convinced there was a place for the use of probiotics in prevention, and treatment of acute COVID-19, and Long COVID, I would certainly be convinced after reading some of the studies now available. It is obvious that a healthy gut microbial community is protective, lowers symptom severity and time of illness, while dysbiosis sets the stage for a greater likelihood of contracting COVID, having more severe COVID, or ending up with Long COVID.
In this article we will focus on:
- How intestinal dysbiosis may increase the risk of severe COVID
- How intestinal dysbiosis may increase the risk of Long COVID
- Explore the evidence for using probiotics, and prebiotics for prevention, and as part of the treatment protocol for COVID-19 and Long Covid-19
Dysbiosis In a Nutshell
In dysbiosis you find commensal microbes (the good microbes) lower in number, and pathogenic microbes, which usually consist of opportunistic pathogens, in higher number. With the loss of normal gut microbes they no longer are availalbe to keep these pathogenic microbes in check and we end up with growth of microbes that don't play nicely with others. Dysbiosis may lead to an inflamed, and damaged gut lining, which becomes leaky allowing the pathogens, and endotoxins created by the pathogens to move into the bloodstream, and move around the body adding to systemic inflammation, secondary infections acute respiratory distress syndrome, multi-organ failure and even death.
Dysbiosis Is Common In Acute and Long COVID
We know there are various factors that are associated with those who have exaggerated responses to Sars CoV-2. We can add gut dysbiosis to the list. Intestinal dysbiosis is also seen in many of the comorbid diseases associated with increased risk of coronavirus infection. COVID-19 morbidity, and mortality are correlated with older age, hypertension, obesity, and diabetes mellitus type 2, which are all groups of people who are predisposed to have dysbiosis, or alterations in their gut microbial composition.
Gut Microbiome Importance In COVID
Research has shown that the microbiota in our gut reflects disease severity and dysfunction of the immune response from individuals with COVID-19.
The gut microbiome composition is significantly changed in patients with COVID-19 compared with those who do not have COVID-19. Some have suggested this disruption of the gut flora is due to antibiotics used during COVID-19, but this change in intestinal microbes appears to take place in many patients no matter if they take medication that may affect the intestinal microbiome or not.
One study has found the usual gut commensals Faecalibacterium prausnitzii, Eubacterium and Bifidobacteria were decreased and stayed low at least 30 days after the illness was resolved. Additionally, this study found the loss of these strains were associated with elevated inflammatory cytokines, and the researchers noted that the change in gut microbes accompanied the changes in inflammatory markers and severity of the illness. The researchers theorized that not only did it appear the gut microbial disruption was associated with the severity of COVID-19, but it might also be a factor in Long COVID.
Another study looked at microbiome diversity in relation to SARS-CoV-2 and found those patients who were severely affected had significantly less bacterial diversity. They specifically found decreased levels of Bifidobacterium, Faecalibacterium and Roseburium. They also found increased Bacteriodes. They theorized that the lack of Bifidobacterium genera either before or after infection caused a reduction in immune function allowing SARS-CoV-2 infection to become symptomatic and more severe. They further theorized that use of this probiotic either before, during or after infection might alter existence of symptoms, their severity and post-infectious symptoms seen with long-haul COVID.
Even the National Institute of Health (NIH) has recently added an article to their website that states, “COVID-19 disrupts the gut microbiome, allowing pathogenic bacteria to thrive. It can also affect the lining of the gut, which may allow these bacteria to enter the bloodstream and lead to dangerous secondary infections.“ Although the NIH has commented in this article that antibiotics used during COVID-19 may be causing this dysbiosis, they also note that this may not be the only factor. Studies funded by the NIH suggest SARS-CoV-2 infection itself disrupts the gut microbes causing a dysbiosis. We know that dysbiosis can lead to intestinal permeability, and indeed the NIH studies found the gut disruption during COVID led to secondary bacterial infections that the researchers believed moved from the gut through the disrupted gut lining into the bloodstream.
In October 22 a review of research surrounding COVID-19 in relation to our gut microbiota and their relationship to acute COVID-19, and Long COVID-19 was published in Nature Reviews. This article examines the fact that SARS-CoV-2 can infect and replicate in the walls of intestinal tract. It has been found that 50% of fecal samples show the RNA shedding of the virus during acute infection, and the RNA shedding of the virus persists for 7 months in 3.8% of patients. Additionally, 17.6% of patients have gastrointestinal symptoms such as nausea, diarrhea, vomiting, loss of appetite, and abdominal pain that indicates the virus is infecting the gastrointestinal tract. One study found those patients with gastrointestinal symptoms tended to have a more severe disease progression and that these symptoms could proceed respiratory symptoms.
This review found 46 different human observational studies reporting changes in gut microbiota in patients with COVID-19 when compared with individuals without COVID-19. The studies come from a variety of countries. These studies show a decrease in the diversity of fecal bacteria and a decrease in the metabolites we know good bacteria produce. Specifically, there was a reduction of short chain fatty acids usually made by bacteria from Lachnospiraceae, Ruminococaceae and Eubacteriaceae families. These short chain fatty acids keep our intestinal tract cells healthy, and are important for other organs in the body. So, a decrease in these fatty acids can lead to intestinal irritation and lack of healthy intestinal function as well as affect other organs. They also noted an increase in opportunistic pathogens from Enterobacteriacea families (such as Escherichia coli and Klebsiella pneumoniae), and the Enterococcus genus (such as Enterococcus faecalis). They found of Faecalibacterium and Roseburia negatively correlated with disease severity. Specific bacteria seen to decrease that are known to have immunomodulatory activity were included F. prausnitzii and Eubacterium rectale. The data suggested that these two microorganisms seen in healthy people, but low in the severe COVID cases, might help prevent or decrease the inflammation associated with severe COVID cases.
I would add that we know many of our gut flora are involved in immunomodulatory activities in the gut, so more research will probably show other types of gut flora are also beneficial. I have seen probiotics be of great help to some individuals with COVID-19 both during the infection as well as in recovery, or in Long COVID.
A couple of studies examined the fungal biome during COVID-19, and found an increased amount of Candida albicans, and C. auris as well as Aspergillus and Penicillium species. Candida infections have specifically been a major complication for severe COVID-19 and has been associated with a high mortality rate. These people usually have a broad-spectrum antibiotic given to them during their stay at the hospital. Practitioners working with patients who have been given antibiotics as part of their treatment should consider the need to act preventatively to support these patient’s gut flora health through methods appropriate for that individual. This may include but is not limited to fermented foods, probiotics, prebiotics in the form of food, herbs or supplements, gut healing herbs and nutritional supplements, the use of bone broth, or long cooked chicken soups with a high amount of dark green vegetables to provide minerals.
The reviewers found that the abnormal gut microbial communities were associated with the hyperactive inflammatory response known as a cytokine storm, that can be seen in severe COVID-19. Most of the researchers thought the gut dysbiosis was due to the COVID infection. Indeed, we know that gut microbiota can be altered by many factors and one of those factors is disease, and many infectious organisms that affect the gut can cause dysbiosis. However, an additional idea held by some researchers is that a prior dysbiosis may already be in effect before the COVID infection in some patients and this could set the individuals up for a worse-case scenario COVID case, or at least be one factor leading to a a more severe outcome. One of the main reasons a prior dysbiosis could cause a COVID infection to be more severe is based on the fact that the intestinal tract houses 80% of our immune system in the gut wall and our microbial microbiome affects the guts immune system. It is no surprise then that any disruption of the microbiome in the gut will alter immune system activity, and may make it easier for SarsCo-V-2 to take over the intestinal environment. It is likely that both of these points of view are true. Anyone with prior dysbiosis will have a decreased ability to defend themselves from Sars-Co-V-2, and additionaly a person with a healthy intestinal microbial community could be infected by Sars-CoV-2 inducing a new dysbiosis.
Obviously, having a healthy intestinal microbial community is of great importance, and makes one wonder if using probiotics, or eating fermented food that contains a variety of healthy flora for our gut might help prevent COVID-19. It turns out London’s Kings College was interested enough in this subject to include questions about probiotics and prebiotics in an observational study involving over 400,000 people, which showed individuals taking regular probiotic supplements of Lactobacillus, and chicory (a high in inulin prebiotic) had a lower risk of catching COVID-19. They point out that this is preliminary data and a controlled study needs to be undertaken.
Studies Using Probiotics and Prebiotics During Acute COVID-19 as Well as to Prevent Long COVID-19
One interesting study screened a small group of human gut bacteria for SARS-CoV-2 antiviral molecules produced by our human microbiome. They found three bacterial metabolites capable of inhibiting SARS-CoV-2 infection. This included the nucleoside analogue N6-(Δ2-isopentenyl)adenosine, the 5-hydroxytryptamine receptor agonist tryptamine, and the pyrazine 2,5-bis(3-indolylmethyl)pyrazine which were cultured from Ruminococcus gnavus, Prevotella nigrescens, Bacteroides caccae, and Micrococcus luteus . The most potent of these, N6-(Δ2-isopentenyl)adenosine (from P nigrescens), had a 50% inhibitory concentration (IC50) of 2 μM. The researchers mentioned these metabolites had structural and functional similarities to synthetic drugs that have been considered for use in COVID-19 treatment.
The researchers only looked at a small group of bacteria. Therefore, I imagine many more bacteria would have antiviral activity to SARS-CoV-2 if they were also tested.
The bacteria in this study are not bacteria that are usually used in probiotic supplements, but it is likely that some of the very probiotics already on the market such as some of the Lactobacillus and Bifidobacteria species or the various bacteria in fermented foods, are putting out similar metabolites that may protect us from COVID-19, as we already know some of them have previously been shown to support our immune system, protect us from other pathogens as well as keep our intestinal tract healthy. Some of these species are mentioned in other research that follows.
A 2022 study treating 300 outpatients with Covid19 found the use of a probiotic formula with 50% Lactiplantibacillus plantarum (formerly called Lactobacillus arabinosus and Lactobacillus plantarum) KABPO22, KABP023, and KAPB033, plus 50% Pediococcus acidilactici KABP021 compared to placebo for 30 days found complete remission in 53.1% of individuals in the probiotic group compared to 28.1% in the placebo group. The probiotic group had reduced nasopharyngeal viral load, lung infiltrates and reduced duration of both digestive, and non-digestive symptoms, compared to placebo. The probiotic group compared to placebo had significant increase in specific IgM and IgG against SARS-CoV2.
Another study comparing hospital patients in a probiotic group (Lacticaseibacillus rhamnosus PDV 1705 ((previously Lactobacillus rhamnosus)) , Bifidobacterium bifidum PDV 0903, Bifidobacterium longum subsp. infantis PDV 1911, and Bifidobacterium longum subsp. longum PDV 2301) and patients in a non-probiotic group who all of them in each group had COVID-19 and pneumonia, were found to have no significant differences in mortality of disease duration, but those who had probiotics got hospital-acquired diarrhea from antibiotics less frequently and the probiotics were effective in treating diarrhea associated with COVID-19.
In this study, probiotics consisting of a mix of Bifidobacterium, Lactobacillus, and Enterococcus capsules were given to hospitalized patients in China looking at days to improvement, as well as fever, viral shedding and gastrointestinal symptoms in 375 patients all given standard care with 179 of the 375 patients also given the addition of the probiotics. Those given the probiotics had a significant decrease in duration of illness (17 days compared to 20 days), viral shedding (15 days compared to 18 days) and fever.
Results showed a significant reduction of digestive symptom reduction (65% in placebo compared to 88% in probiotic) and overall symptom reduction ( 70.8% in placebo compared to 88.6% in probiotic) in the group receiving a probiotic mixture of Kluyveromyces marxianus B0399 together with Lactobacillus rhamnosus CECT 30579, administered for 30 days to patients with COVID-19 compared to patients not given the gut flora.
Obviously, the use of probiotics for prevention and in the treatment of COVID-19 is something that needs more attention. Early on many practitioners found the individuals with COVID-19 often had gastrointestinal symptoms from dysbiosis, either from the illness itself, or having been given antibiotics. Therefore, probiotics, or fermented foods became a useful part of their treatment protocol, and probiotics became an important asset for regaining health quicker in these cases. I am happy to see these studies supporting what alterantive health practitioners have found to be true in practice.
Gut Flora in Long Covid-19
We saw previously that 50% of fecal samples in one study showed the RNA shedding of the virus during acute infection, and the RNA shedding of the virus persisted in this study for 7 months in 3.8% of patients even when the oropharyngeal shedding had ceased. This would suggest possible viral activity affecting the gut still at this time and could be one of the factors in Long Covid-19.
We know that many studies support the idea that dysbiosis is an issue in acute COVID-19 and appears to be associated with more severe symptoms of COVID-19. The following studies specifically look at the postconvalescence, examining the intestinal microbial community in Long Covid-19 cases.
This study looked at changes in number and diversity of gut flora in patients with COVID-19 using 16S rDNA sequencing. The samples were taken during the acute phase, during recovery phase (from viral clearance to 2 weeks after discharge from the hospital), and in postconvalescence (6 months after hospital discharge).
Patients with lower microbial number and less microbial diversity in postconvalescence had higher CRP levels (marker of inflammation) and had more severity of illness during the acute phase suggesting a correlation between gut dysbiosis, inflammatory response and COVID-19 severity. It was found that lower diversity of gut microbiota in postconvalescence patients was associated with worse lung function.
A study demonstrated a correlation between Long COVID-19 symptoms and gut dysbiosis at one year after discharge from the hospital. In a group of recovered patients, the researchers did a comparison of those with symptoms of Long COVID-19 compared to those who were asymptomatic regarding their gut microbiota analysis. Those with Long Covid-19 symptoms had significantly decreased number and diversity of intestinal flora compared to those who were asymptomatic. They also had significantly reduced short chain fatty acid producing bacteria specifically. The altered gut microbiota was significantly correlated with the clinical indices of the recovery stage.
A study of 126 people with average duration of symptoms for 108 days, were given 30 days of a blend of the probiotic Lactobacillus and the prebiotic called inulin, in a capsule. Gut symptoms improved in 82% of those who reported them at baseline. Participants had significant gastrointestinal and non-gastrointestinal symptoms improve as well as improved overall well-being in the 30 day time period. Products containing Lactobacillus species and inulin are quite commonly sold, making it easy for individuals to find such a product.
A prospective study was undertaken looking at the fecal microbiome of 106 patients with a variety of symptoms indicative of severe COVID-19 . They were followed up to 6 months after admission and compared with 68 non-COVID-19 controls. At 6 months, 76% of patients had Long Covid and the most common symptoms were fatigue, poor memory and hair loss. The gut microbiota composition found at admission was associated with the occurrence of Long COVID. Patients without Long COVID showed a recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls which did not. Those with Long COVID had higher levels of Ruminococcus gnavus, Bacterioides vulgatus and lower levels of Faecalibacterium prausnitzii. The researchers found persistent respiratory symptoms that were correlated with opportunistic gut pathogens (opportunistic microbes are microbes already living in the gut that take advantage when an opportunity arises, that allows them to grow out of control ) while neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens (microbes acquired from the hospital or other medical treatment facility). At 6 months the biggest loss of butyrate-producing bacteria was seen in Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii.
Recent Study on Alleviation of Long Covid symptoms By Altering Microbiome
A recent study not yet published by Raphaela Iris Lau of 463 patients with Long COVID-19 symptoms were given 6 months of a combination prebiotic and probiotic supplement called symbiotic (SIM01). Compared to controls, the treated patients reported digestive complaints were improved in 70.2% of SIM01 recipients compared with 54.1% of controls, fatigue was improved in 62.8% of SIM01 recipients compared with 42.6% of controls, memory loss was improved in 42.0% of SIM01 recipients compared with 26.9% of controls, concentration and general unwellness was improved in 77.3% of SIM01 recipients compared with 59.0% of the controls.
Gut microbiota in general
We now know that the “good gut bugs” in our large intestine support our digestive tract health, and protect us from pathogens, but it goes beyond our gut. They modulate our immune system, and regulate the nervous system. They are involved in the gut-liver axis, gut-brain axis, gut-skin, and probably in the gut-lung axis. Certainly, we have seen that gut bacteria can enhance immune system activity through increasing macrophage activity in the lungs, providing a protective effect against pneumonia. Studies have demonstrated that respiratory infections are associated with both the type of gut bacteria and how they are functioning. Therefore, some researchers now talk about a gut-lung axis and future research will surely substantiate this. I usually consider the gut microbial community when I want to prevent, or treat an infectious lung condition. In prevention and treatment of COVID-19, and Long COVID-19, I believe it is important to make sure the gut microbial community is in good shape and they are all playing nicely together. Besides supporting the respiratory tract, a healthy gut microbiome has also been shown to support cardiovascular health, which as we know can be another issue for individuals with COVID-19.
Use of fermented products, or probiotics may have a place in protecting our respiratory tract, cardiovascular system, and gut from COVID-19.
Our gut microbiota are immense in number. There are approximately 1011-1012 microorganisms per gram of content in the intestinal lumen (inside the intestinal tube). They have a total biomass of more than 1 kg in weight. Sometimes they are damaged or killed by drugs, enviornmental toxins, illness, or our poor lifestyle choices. It behooves us to protect, and grow them with good lifestyle choices and by feeding them foods that help them thrive.
The suggestion to use probiotics to replace microbes in our gut was first brought up over a century ago when Elie Metchnikoff first theorized that the bacteria in yogurt could protect us from bad health and senility. In the 1980s, when I was a fledging naturopathic student, naturopaths were commonly using yogurt and Lactobacillus acidophillus as a probiotic, as well as other fermented foods. However, most of the rest of the medical community still did not understand that using fermented foods, or Lactobacillus supplements could enhance gut resilience as well as general health. Yogurt was the only major source of healthy microbes in a fermented food that was easily available in the 80s to purchase and you could only get live yogurt from a health food store usually.
Today in the 2020’s, things have changed. The microbiome project showed the world that we are teeming with microbes, and that we are dependent on many of them for our health. We found out that there are a vast array of microbes including bacteria, fungus, archea, protists, viruses and perhaps even worms that are necessary for our health. Bacteria being the main gut inhabitant that has been the most studied and used medicinally. This has opened the eyes of the entire medical establishment, and created a booming business for those who want to make, and sell live fermented foods as well as probiotics. You can usually find live yogurts, and live sauerkraut in many foods stores, as well as probiotics and prebiotics. Probiotics are the actual microbes that are sold, while prebiotics are foods that feed our gut bacteria. These are usually water soluble fiber, that are found in foods such as apples, pears, figs, peaches, passion fruit, okra, flax seeds, oats, beans, marshmallow root herb as well as many other foods and herbs. All water soluble fiber products will feed your gut bacteria.
How Probiotics Help Us
This is by no means an exhaustive list.
- They compete with pathogenic microbes in various manners
- They compete for space in the gut with pathogenic microbes
- They compete for nutrients with the pathogens
- They make metabolites that lower the amount of pathogenic microbes
- Some have been shown to produce organic acids, bacteriocins and other antibacterial products which stimulate intestinal mucins and help prevent the implantation of pathogens in the gut wall
- They make nutrients needed in the digestive tract to support the epithelial cells
- Thiamine, folate, biotin, riboflavin, pantothenic acid and vitamin K2
- They make molecules we need for our body to function normally
- They support mucosal integrity and intestinal barrier function
- Make butyrate and other short chain fatty acids needed by gut cells, but some short chain acids are also used by other organs.
- They help regulate gut motility
- They help regulate the central nervous system
- They support healthy skin
- Those with dysbiosis are more likely to have food allergies
- They lower high blood pressure
- They prevent osteoporosis by increasing bone density and prevention of secondary osteoporosis
- They lower plasma total cholesterol, LDL cholesterol and VLDL cholesterol
- They support a healthy immune system
- They stimulate receptors of innate immunity, toll like receptors that cause production of pro-inflammatory cytokines that induce phagocytosis by macrophages.
- They stimulate the secretion of IgA and regulatory T cells
- They help protect us from antibiotics inducing dysbiosis
Last Words On Gut Microbiome In COVID-19
Gut flora are very important to us, and I often consider that we are feeding them when we eat, rather than feeding ourselves. If we feed our intestinal flora with food that supports them, they in turn are more capable of protecting us when we are under physical, mental, and emotional stress common in todays world. Taking care of our gut flora keeps us more resilient, and capable of fighting off illness in general. Additionally, the studies we examined in this article show us our efforts to support our gut microbial community may be repaid in their protecting us from COVID-19 through prevention of infection, less severity of symptoms, and better recovery during acute COVID, with less chance of long COVID.
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