Human Gut Microbiome in COVID-19 - Exploring the Therapeutic Potential of Probiotics

In general, the different components of large intestinal microbiota may be considered as exerting potentially health-promoting or pathogenic effects. In the gut, resilience is connected to the functional core microbiota (2). Immune changes brought about by the gut microbiota can influence respiratory conditions (3), Scientific evidence from studies has indicated that inhabiting gut microbiota shapes anti-viral defences and could modulate outcomes in certain viral infections (4). Differences in the gut microbial community have been demonstrated in viral infections like influenza and pneumonia. Numerous studies have even focused on modulation of gut microbial patterns and its effect on upper respiratory tract infections (URTI); bringing out through three meta-analyses reporting that probiotics can reduce severity and duration of illness (5)

SARS-CoV-2 most commonly presents as a URTI but can, in a more severe spectrum, may attack the lungs to become a threatening lower respiratory tract infection (LRTI). Whilst evidence is constantly in progress, recent meta-analyses of randomized control trials have indicated that probiotics can reduce the incidence and severity of ventilator-associated pneumonia (6)

In a study conducted and published by Mahmoodpoor et al., supplementation with probiotics shortened the duration of ventilator use in critically ill patients. (7) Similar findings have been observed in other ventilator-associated pneumonia studies, indicating that modulation of gut microbiota may also have a part to play in LRTI

There is a durable amount of evidence supporting a prophylactic role of probiotics in reducing symptoms associated with upper respiratory tract infections. Studies modelling the impact of probiotic consumption on respiratory infections in the pre-COVID-19 era have emphasized economic savings with the use of probiotic consumption in the general population (8)

By supplementation with probiotics, which means adopting a strategy towards correcting gut dysbiosis and increasing levels of positive microorganisms in the gut – can impact multiple pathways that could be of benefit in the fight against COVID-19, summarised as given below:

• Intervention with probiotics positively modulates the bacterial community in the gut, often to the detriment of potentially pathogenic microorganisms, through the production of metabolites and/or competitive exclusion. This can reduce the risk of gut- related illnesses.

• The gut microbiota secretes short-chain fatty acids (SCFA) that may have systemic effects across the body, including the provision of a cellular energy source.

• Increased SCFA levels are associated with improved integrity of tight intestinal junctions, possibly restricting the passage of endotoxin from the gut lumen; such effects may be partly mediated by cytokines. It is noteworthy that both aging and obesity - which are risk factors for COVID-19, are associated with a more vulnerable gut barrier function.

• Free fatty acid receptors can be found on dendritic cells, as such SCFA stimulation of dendrites can lead to interaction with regulatory T-cells, subsequently resulting in enhanced macrophage activity and increased anti-inflammatory cytokines.

• Macrophages are associated with pro-inflammatory status, and SCFA has been observed to down-regulate pro-inflammatory cytokine release.

In this manner, by supporting the immune responses and reducing aggressive inflammatory activity, harmonizing the gut microbiota through the use of probiotics could be a tool to aid the body in defending against COVID-19

A very promising development has been a recently completed study published by d'Ettorre et al., (9) which examined seventy COVID-19 positive patients requiring non-invasive oxygen therapy who were treated with hydroxychloroquine therapy along with antibiotics and tocilizumab; and in it, to a subgroup of 28 patients, an oral probiotic mixture was also administered. Along with clinical improvement reported in digestive symptoms, the probiotic group had an eight-fold reduction in the risk of developing respiratory failure.

Such results bring out great potential for considering to use probiotics to combat respiratory difficulties. As clinical evidence continues to develop in this direction, the role of safe and cost-effective probiotic interventions against COVID-19 infection could become more important.

It is also interestingly reported that variations in the intestinal microbiome may compromise the effectiveness of vaccine antigens - a result of chronic inflammation of the intestinal tract (10) . Falling along the same lines, a meta-analysis of probiotic studies has concluded that intervention alongside influenza vaccination can lead to elevated immunogenicity through enhancing seroconversion of inoculated persons. (11) Such data suggest interesting clinical implications for the population in the near future while the discovery of the COVID-19 vaccine is underway

In conclusion, there is currently clinical evidence progressing along the direction that modulation of gut microbiota, resolving the gut dysbiosis can positively influence COVID-19 outcomes. This is further substantiated by the positive effects of probiotics reported against other coronavirus strains (12). While studies are underway globally to assess whether altering the gut microbiota through diet and supplementation might be a feasible addition to our current COVID-19 treatment armamentarium; given the large experience of clinical usage, and evidence for beneficial effects in various clinical settings, Lactobacillus and Bifidobacterium can be safely considered (13)

Adapted from:

1 Walton GE, Gibson GR, Hunter KA. Mechanisms linking the human gut microbiome to prophylactic and treatment strategies for COVID-19. Br J Nutr. 2020 Oct 9:1-36. doi: 10.1017/S0007114520003980. Epub ahead of print. PMID: 33032673.

2 Dethlefsen L, Relman DA (2011) Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA 108, 4554-4561.

3 Enaud R, Prevel R, Ciarlo E et al. (2020) The gut-lung axis in health and respiratory diseases: A place for inter- organ and inter Kingdom crosstalks. Front Cell Infect Microbiol 10, 9 doi: 10.3389/fcimb.2020.00009

4 Pang IK, Iwasaki A (2018) Control of antiviral immunity by pattern recognition and the microbiome. Immunol Rev 245, 209-226.

5 King S, Glanville J, Sanders ME et al. (2014) The effectiveness of probiotics on length of illness in healthy children and adults who develop common acute respiratory infectious conditions: A systematic review and meta-analysis. Brit J Nutr 112, 41-54.

6 Su M, Jia Y, Li Y, Zhou D, Jia J. Probiotics for the prevention of ventilator associated pneumonia: a meta- analysis of randomized controlled trials. Respir Care 65, doi.org/10.4187/respcare.0709

7 Mahmoodpoor A, Hamishehkar H, Asghari R et al. (2019) Effect of a probiotic preparation on ventilator- associated pneumonia in critically ill patients admitted to the intensive care unit: A prospective double-blind randomized controlled trial. Nutr Clin Pract 34, 156-162

8 Lenoir-Wijnkoop I, Gerlier L, Roy D, Reid G. (2016) The clinical and economic impact of probiotics consumption on respiratory tract infections: projections for Canada, PLoS One. 11(11), e0166232. doi:10.1371/journal.pone.0166232

9 d'Ettorre G, Ceccarelli G, Marazzato et al. (2020) Challenges in the management of SARS-CoV2 infection: The role of oral bacteriotherapy as complementary therapeutic strategy to avoid the progression of COVID-19. Front Med. 7, 389. doi: 10.3389/fmed.2020.00389

10 Vitetta L, Saltzman ET, Thomsen M et al. (2017) Adjuvant probiotics and the intestinal microbiome: Enhancing vaccines and immunotherapy outcomes. Vaccines 5, 50 doi: 10.3390/vaccines5040050

11 Zimmermann P, Curtis N. (2018) The influence of probiotics on vaccine responses - A systematic review.Vaccine. 36(2), 207-213.

12 Chai W, Burwinkel M, Wang Z, et al. (2013) Antiviral effects of a probiotic Enterococcus faecium strain against transmissible gastroenteritis coronavirus. Arch Virol 158, 799-807

13 Angurana SK, Bansal A. Probiotics and COVID-19: Think about the link. Br J Nutr. 2020 Sep 14:1-26. doi: 10.1017/S000711452000361X. Epub ahead of print. PMID: 32921328.