Clinical and Scientific Rationale for Use of Probiotics as Adjuvant in COVID-19

While the clinical features of COVID-19 are associated with acute respiratory restrictions, cough, sore throat, and fever, followed by multi-organ failure and often secondary infections. (2) , it has been reported that there is a strong correlation between the progression of the disease and the composition of gut microbiota. Some patients with COVID-19 have manifested intestinal microbial dysbiosis, with a decrease in cell numbers of Lactobacillus and Bifidobacterium (3)

Hence it has been suggested that the use of probiotics might help normalize the stability of the intestinal microbiota and lower the risk of secondary infections.

Animals remain one of the most important "constituents" with the human ecosystem, with human microbiota often cited as an 'organ system' in itself, and as such, they must be considered as a primary source, or incubator, of novel viral diseases and outbreaks in humans. A particularly pertinent example of this is the COVID-19 pandemic.(4) It may be interesting to review and consider the potential of probiotics as a valuable integrative approach for treating COVID-19 infections

There have been reports indicating the successful clinical use of probiotics in the treatment of various intestinal, respiratory, and urogenital diseases caused by viruses.

The potential suggested primary mechanisms of probiotic action against viruses include direct probiotic cell interaction with the target viruses, production of antiviral metabolites and modulation of the host's immune system (5). Other possible mechanisms of actions include modulation of the host microbiota, interaction with eukaryotic epithelial cells and effects on the electrolyte potential (6).Virtually all bacteria, including Lactic Acid Bacillus (LAB) probiotics, are known to produce ribosomally synthesized substances which are protein in nature and exhibit bactericidal activity. These substances are collectively termed as bacteriocins (7). Several other bacteriocins have also been demonstrated to be active against viruses.

The potential of bacteriocins to alter the gut microbiota by targeting detrimental components without having a negative influence on beneficial microorganisms is an idealistic concept. The host is colonized by trillions of microbes in a symbiotic association, and some of these microbes could turn pathogenic during dysbiosis (8)

Probiotic strains like Lactic Acid Bacillus (LAB) produce a wide variety of antimicrobial compounds consisting of metabolites like hydrogen peroxide, short-chain fatty acids, and lactic acid to bacteriocin-like inhibitory substances (BLIS) and bacteriocins. (9). LAB also has a significant role in keeping the human and animal gut microbiome in a balanced state (10) and in maintaining the integrity of the gut wall. (11) apart from favourably modulating the immune responses.

Modulation of the immune system seems to be a valid and clinically relevant approach for the prophylaxis of viral infections, including COVID-19 (12) . The immunomodulatory properties of LAB are well documented. Intestinal strains of probiotics can alter the roles of dendritic cells (DC), monocytes/macrophages, T and B lymphocytes, thereby enhancing the phagocytosis of pathogenic bacteria (13). In vitro, studies have indicated that LAB induce the release of proinflammatory cytokines TNF-a and IL-6, thus stimulating nonspecific immunity (14)

The earliest reports of LAB inactivating viruses were published about 30 years ago. At that time, antiviral activity was mostly ascribed to protein denaturing reactions of hydrogen peroxide and lactic acid produced by Lactobacillus spp., leading to the inactivation of the human immunodeficiency virus type 1 (HIV-1) and human simplex virus type 2 (HSV-2) (15). It is known that probiotic LAB could trigger anti-inflammatory responses in the innate immune system by signalling dendritic cells (DCs) to secrete anti-inflammatory cytokines such as interleukin 10 (IL-10) (16). Probiotics can also down-regulate pro-inflammatory cytokines by interfering with inflammatory signalling pathways such as nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways.

In infection pervasive times of COVID-19, there has been a rampant increase in the use of antibiotics and antimicrobials – as repurposed agents or to prevent the secondary bacterial superinfections like azithromycin, doxycycline etc. In such clinical scenarios, there needs to be a consideration for the management of antibiotic-associated diarrhoea. Antibiotic-Associated Diarrhoea (AAD) can develop from a few hours and may last up to 2 months after antibiotic intake (17). The incidence of AAD reported could be as high as 25% (18). Probiotics like Lactobacillus strains remain one of the preferred probiotics for the management of antibiotic-associated diarrhoeas.(19)

Probiotics and their metabolites certainly have considerable potential to affect "germ warfare" against disease-causing viruses and also to be key allies in our efforts to possibly reduce the burden of viral and COVID-19 infections, and more certainly, improve clinical outcomes and recovery in times when every evidential and beneficial intervention matters to the medical fraternity and the society, at large.

Adapted from

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3 Xu, K., Cai, H., Shen, Y., Ni, Q., Chen, Y., Hu, S., et al. (2020). Management of corona virus disease-19 (COVID-19): the zhejiang experience . Zhejiang Da Xue Xue Bao Yi Xue Ban. 21:49.

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