Microbiome imbalances and COVID-19: the benefit of probiotics

The trillions of microbes that we harbour within our body play a decisive function in our innate and adaptative immune defences.

However, when disruption and imbalances in our microbial communities occur, issues can arise. When it comes to the gut microbiota, for example, microbial dysbiosis has been associated with inflammation and gastrointestinal conditions such as inflammatory bowel disease. 

The COVID-19 crisis also greatly expediated scientific and technical advances in the field of viral infection immunity, and significantly developed our understanding of the relationship between our immune function and microbiota.

Recent observations of beneficial interactions between our commensal bacteria, and their action against SARS-CoV-2, have surprised the human microbiome community and shown involvement of specific bacteria, suggesting the possibility of therapeutic as well as preventive actions.

Here I explore the link between human microbiome imbalances and the potential for probiotics to help prevent or support treatment for both gastrointestinal diseases and viral infections.

The protective networks of the gut and skin

Our gut and skin have an entodermic origin and function as protective barriers to environmental pollutants, allergens, toxins and pathogens such as bacteria and viruses. Both are also home to a large number of bacteria with a diverse array of functions.  Our gut microbiota plays a critical role in digestion, production of hormones and vitamins, inhibition of pathogenic growth, and in assisting with drug and toxin metabolism. Thus, the intestinal barrier prevents against loss of water and electrolytes and entry of antigens and pathogenic microorganisms into the body with tight intercellular junctions that allow only specific nutrients to pass.

More precisely, the intimate part of the gut barrier is populated by a network of immune and nervous cells, organized into two specialized structures called the ‘gut associated lymphoid tissue’ (GALT) and ‘enteric nervous system’.  The latter is also known as our ‘second brain’, due to the number of constitutive neurons and its relationship with the central nervous system. The enteric immune system sets the tone for each individual’s general immune response.

An individual’s host immune system, which routinely over- or under-reacts, is often characterized by a disturbed intestinal ecosystem, with abnormal distribution of microbial families, excessive permeability of the mucous membrane and a tendency for systematic inflammation. Food, lifestyle and various environmental factors are clearly involved.

Healthy versus unhealthy and the leaky gut

When in a healthy condition, the intestinal barrier forms a tight barrier that controls what is absorbed into the bloodstream from within. In addition, the skin barrier forms a second tight barrier for similar preventive functions, protecting against the external environment.

An unhealthy gut lining may have intercellular cracks, allowing external matter within the lumen to penetrate the bloodstream and reach the brain, lung, liver, muscles and skin. This syndrome is known to increase intestinal permeability and is also named ‘leaky gut’ – a digestive condition in which bacteria (i.e. opportunistic strains), virus and toxins are able to ’leak’ through the intestinal wall. This leaking triggers: (1) inflammation, which could be extensive and, in this case, named a ‘cytokine storm’; and (2) sub-clinical changes in the gut flora that could lead to problems within the digestive tract and beyond, including disturbances within general immune imbalance and global contamination.

The major aetiology of a leaky gut is a dysbiosis characterized by a decrease in microbial diversity with an expansion of specific bacteria populations. This disruption of the microbial community has been associated with the development of gut diseases, such as irritable bowel syndrome and bloating, and with depression and various chronic diseases. Other illnesses, including inflammatory bowel diseases and metabolic disorders, such as obesity and diabetes type II, are also associated with intestinal dysbiosis. The composition of the gut microbiota is dynamic and is influenced by numerous regulators: the microbiota itself through diversity and overall balance, diet, quality of intestinal mucosa and mucus, stress and the systemic immune system.

Infection with COVID-19 is characterized by a dysregulated immune response with an increase in the neutrophil to lymphocyte ratio (NLR), and T lymphopenia concentrations, and a concurrent decrease in CD4+ T cells [1]. Gut microbiota composition is also frequently altered in patients with COVID-19 [2,3,4,5]. These studies demonstrated significant intestinal microbial dysbiosis in patients through observation of major decreases in Lactobacillus sp. and Bifidobacterium sp. [5,6]the main families of symbiotic bacteria – as well as a decrease of strict anaerobic commensal strains, such as Faecalibacterium prausnitzii. This decrease is also associated with an increase in some opportunistic bacteria, such as Streptococcus sp. and Clostridium sp. [7,8].

In conclusion, several published analyses have confirmed significant alterations in the gut microbiota in the most afflicted patients. The link between hyper-inflammation (i.e. cytokine storm) and intestinal dysbiosis appears to constitute a high risk of fatal respiratory distress. In addition, the severity of hypoxemia is also strongly correlated with elevated levels of immune cells and markers of inflammation.

Gut dysbiosis and aging

During aging, numerous physiological and extrinsic changes occur. These include chronic inflammation at the clinical level and sub-clinical level (i.e. inflammation), immuno-senescence and microbiome modification [9,10]. It is recognized that the intestinal microbiota is subject to changes during the aging process [11], and an imbalanced microbiota (dysbiosis) is also observed in elderly people, which can result in high systemic inflammation.

Gut dysbiosis has been observed both during aging and as a result of severe COVID-19 infection [12,13,14]. In aging, this imbalance is characterized by a decrease of beneficial microorganisms associated with more Gram-negative bacteria, which increases LPS levels and therefore triggers intestinal permeability and inflammatory risk. This is in line with the observation that older individuals are more susceptible to SARS-CoV-2 and more severe COVID-19 [10]. In conclusion, related gut dysbiosis that occurs during SARS-COV-2 infection cannot be ignored, and leaky gut syndrome is likely to have significantly contributed to increased deaths, particularly in elderly people.

Probiotics for gastrointestinal disease and viral infection

As probiotics may provide a health benefit in the treatment of gastrointestinal diseases such as inflammatory bowel disease (based on the new LBP classification for GI), and even in some viral infections, it is assumed that the investigation of gut microbiome therapies such as probiotics may help decrease the inflammatory response of viral pathogenesis and respiratory symptoms by strengthening the host immune system, amelioration of gut microbiome, and improvement of gut. Moreover, numerous COVID-19 patients have shown intestinal dysbiosis with a notable decrease in Bifidobacteria and Lactobacilli. Supplementation with some specific strains of probiotics could be proposed. Bifidobacterium sp. could be an interesting candidate because some have already been used in the treatment of some viral infections [15].

Probiotic benefits could be directly involved in dysbiosis management, but probiotics may also provide protective effects for commensal anaerobic strains, such as F. prausnitzii, Akkermansia muciniphila and specific strains of Bifidobacterium and Lactobacillus, reducing the risk of infection. So, at this point of the COVID-19 pandemic, when no pharmacological strategies for prevention or treatment are available, attention to alternative therapies using probiotics must be considered to boost and rebalance immune homeostasis by altering the gut microbiota, which itself is altered by SARS-CoV-2 [16,17].

So, oral probiotics have a huge impact on the range and type of microbes in the gut. A diverse microbiome is a healthy microbiome, containing many different species that each play their part in immunity and health. Microbiome diversity declines as you get older, which may help to explain the age-related decline in immune response and reduced resistance against viral infections. It is therefore even more necessary to maintain a healthy microbiome throughout life to improve better innate and adaptative immune responses against virus infection.

In addition to preventive effects and to help COVID-19 vaccines efficacy, probiotics could be also of interest for vulnerable people who are fragile and aged, as intestinal dysbiosis effects are also proposed as a major factor for reduced efficacy and adverse effects of COVID-19 vaccines in susceptible individuals and in the elderly population [18,19].

Thus, the improvement of gut microbiota in at-risk populations could increase vaccine efficacies and reduce severe adverse effects. Modulation of the intestinal microbiota with Bifidobacteria and bacterial metabolites such as butyrate [13,18] could be a practical approach as an adjuvant for vaccine COVID-19 efficacy improvement in the elderly. Incorporation of probiotics with or without prebiotics, particularly inducing butyrate-producing bacteria, could be necessary requisites as important adjuvant mediators COVID-19 vaccine efficacy and the decrease of vaccine adverse effects.

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