Gut Microbiome in Acute and Long COVID

 Studies Using Probiotics and Prebiotics During Acute COVID-19 as Well as to Prevent Long COVID-19

Study 1

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.

Study 2

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.

Study 3

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.

Study 4

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.

Study 5

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.

 

Practical Note

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.

 

Study 1

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.

 

Study 2

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.

 

Study 3

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.

 

Study 4

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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