As of early March 2023, the global health impact of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been devastating, resulting in a reported 6,866,434 deaths worldwide.
Over the past three years, researchers have found strong evidence of the involvement of the gut and lung microbiomes in the development and progression of COVID-19 in patients. Dysbiosis has been shown to increase susceptibility to the disease and affect symptoms and outcomes. Addressing this imbalance with prebiotics and probiotics is an area of promising research.
This blog provides a brief overview of the latest findings on the complex etiology of SARS-CoV-2 infection (only as it pertains to gut and lung microbiota), mechanisms of action, as well as potential therapeutic interventions to improve the course of this dangerous viral infection.
COVID-19, a capsule
SARS-CoV-2 primarily invades the respiratory tract, where it binds with angiotensin 2 converting enzyme (ACE2) receptors on the lungs’ alveoli. Gastrointestinal tract symptoms, such as diarrhea and vomiting, have been observed in many cases, suggesting a role for the gut-lung axis in the disease. Elderly individuals and those with comorbidities such as hypertension and metabolic disease are more likely to experience severe symptoms and poor outcomes. Both of these cohorts are associated with an altered gut microbiota suggesting that dysbiosis influences COVID-19 severity.
COVID-19 and gut microbiota
Among many other roles, the gut microbiome acts as a key regulator of immunity and host defense mechanisms. Recent research suggests that disruption of the homeostasis between the gut microbiota and the host immune system can lead to immune dysfunction.
Communication along the gut-lung axis reflects the dysfunction. Accumulating evidence supports the importance of this bidirectional path between gut dysbiosis and inflammatory conditions in the lungs.
In a 2023 systematic review of 63 studies, researchers reported that the gut microbiota of COVID-19 patients was different when compared to healthy individuals: the former had fewer beneficial bacteria and more opportunistic pathogens. Notably, gut dysbiosis was observed in nearly all the studies. Moreover, gut dysbiosis in one study was observed to persist up to 6 months after clearance of COVID‐19 in some patients. Patients without post-acute COVID-19 syndrome showed a recovered gut microbiome profile at 6 months. Additionally, several studies in the review reported that gut microbiota composition can be a predictive factor in the severity of COVID‐19 disease. The reviewers wrote, “Further research is needed to investigate the probable bidirectional association of COVID‐19 and human microbiome.”
Nevertheless, many factors, such as “sex, age, basic health status, medication use, genetics, ethnicity, and geographic location, can affect the composition of the gut microbiota and lead to individual differences and varying responses to SARS-CoV-2 infection,” according to another review.
Covid and URT Microbiota
The immune function of the lungs and its performance against assaults such as COVID-19 respiratory is impacted by the microbiota inhabiting URT (including nasopharyngeal, oropharyngeal, and respiratory tract).
For example, in a study with moderate and severe COVID patients, pro-inflammatory bacteria in URT were higher in comparison to healthy individuals. These alterations were correlated with higher levels of pro-inflammatory cytokine (cell-signaling protein) levels, which can lead to a cytokine storm, an uncontrolled release that can cause multisystem organ failure and death.
A healthy URT microbiota has been proposed to be an early biomarker of favorable clinical progression in hospitalized COVID-19 patients.
Mechanisms
Beneficial microbes may protect hosts from viral infections by a number of direct and indirect mechanisms*:
- Enhanced mucosal barrier function
- Secretion of antiviral, antimicrobial peptides and bacteriocins
- Inhibition of viral attachment to host cells
- Modulation of antiviral innate and adaptive immune function
*For more extensive information on antiviral microbiome mechanisms, see a diagram in a comprehensive paper prepared by several members of IPA’s Scientific Committee (among others).
Dysbiotic conditions can lead to a slew of negative consequences that could impact the immune system function:
- Microbes passing through gut barriers may cause systemic inflammation
- Production of harmful metabolites
- Improper immune cell development
- Inflammation and increased pro-inflammatory cytokines
As mentioned, several studies noted that elderly people and those with comorbidities tended to have more complications. Two reasons have been proposed:
Dysbiosis: reduced microbial diversity and beneficial bacteria abundance seen in both groups have been linked to increased susceptibility and a higher risk of a cytokine storm.
Increased expression of ACE2: Angiotensin-converting enzyme 2 (ACE2) receptors appear to be important mediators between the gut microbiome and COVID-19. SARS-CoV-2 binds with these receptors, which are expressed in the gut epithelium as well the airway. Individuals with hypertension and diabetes comorbidities are often prescribed medications that can up-regulate ACE2 receptors in the gut, leading to changes in ACE2 concentration that may alter susceptibility to the virus. More research is needed to clarify this relationship.
Gut Microbiota in long COVID
At least 10% of severe SARS-CoV-2 infections exhibit extended illness called “long COVID.” The World Health Organization defines long Covid as “the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.”
Multiple organ systems are impacted and more than 200 symptoms have been reported. Gastrointestinal symptoms of long Covid may include nausea, constipation, anorexia, heartburn and abdominal pain. Hypothesized mechanisms of long COVID include microbiota disruption, immune dysregulation and numerous others. Dysbiosis—more pathogens and fewer beneficial microbes— has been reported in people with long COVID compared with non-COVID-19 controls.
In an evaluation of 154,068 people who survived the acute phase of COVID-19, an increased risk of gastrointestinal disorders “spanning several disease categories including acid disorders, functional intestinal disorders, pancreatic disorders, hepatic and biliary disease” was reported.
Probiotics & Covid-19
Many studies cited by a recent review have assessed the effects of probiotic administration in COVID‐19 patients. Because of their therapeutic potential seen in other viral respiratory infections, strains in the Lactobacillus and Bifidobacterium genera were most often used in investigations. The majority of these studies, around 13 in number, have documented a wide range of advantageous impacts of probiotics in mitigating COVID-19 symptoms, predicting the course of the disease, and determining the final outcome. Here are a few observations from the review based on the studies with COVID-19 patients.
- Three studies noted that diarrhea was effectively treated with several different probiotics.
- One study reported a shorter duration of illness and hospitalization with probiotics.
- Two studies showed that the use of probiotics in moderate and severe COVID-19 patients reduced hospital admission and death rates.
Prebiotics & Covid-19
Foods and supplements containing prebiotics, such as fiber, oligosaccharides, and polyphenols, can enhance the growth of beneficial bacteria. Prebiotics can also improve gut barrier functioning and stimulate production of beneficial metabolites.
In theory, prebiotics should be helpful in COVID-19, but further study is needed to establish evidence-based benefits.
Takeaway
The relationship between SARS-CoV-2 and the gastrointestinal and lung microbiomes is complex and not yet completely understood. It has become apparent that differences between gut and respiratory microbiota in COVID‐19 patients and healthy people can be significant. Moreover, dysbiosis has been shown to increase susceptibility and progression of the disease through several mechanisms. In long-COVID, evidence of dysbiosis and increased risk of gastrointestinal disorders suggest that gut microbiota is involved. Modulation with probiotics and prebiotics may be a promising therapy to improve COVID-19 susceptibility, progression and recovery.
For a glimpse back to IPA’s blog (March 22, 2020) written in the dark early days (pre-vaccine) read IPA’s COVID-19: A Role for Probiotics in Immunity? In addition, COVID-19 & Probiotics, a Webinar: Probiotics & the COVID-19 Market Transformation addressed the challenges and opportunities unleashed by the virus. This initial look at the landscape is still available here for viewing.
We have learned quite a bit since then.
Key references
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