Abstract

Keywords: Dysbiosis; Probiotics; SARS-CoV-2; COVID-19

Introduction

Probiotics are live microorganisms, which if administered at adequate amounts, confer beneficial physiological effects [1]. Previous study underscored the positive impact (whether directly or indirectly) of probiotics on the ACE enzymes [2]. During the process of food fermentation, probiotics make bioactive peptides which interfere with the ACE enzymes through blocking the active sites [3,4]. The debris of the dead probiotic cells can also work as inhibitors to ACE [1], suggesting that probiotics are possibly potential blockers to the ACE receptors, which act as gateway for SARS-CoV-2 to attack gastrointestinal cells. Imai and colleagues reported that ACE blockers could be used to decrease respiratory distress syndrome [5]. The prebiotics are defined as ‘substrates that are selectively utilized by host microorganisms conferring a health benefit’ [6]. Similar to probiotics, prebiotics can be orally administered into microbially colonized body sites to reach the intestine, or by a direct way to the skin or vaginal tract [6]. Prebiotics include lactosucrose, oligosaccharides, isomaltooligosaccharides, fructans, xylooligosaccharides, resistant starch, lactobionic acid, galactomannan, arabinooligosaccharides, psyllium, polyphenols and polyunsaturated fatty acids [6-8]. The health benefits of prebiotics to the gastrointestinal tract such as stimulation of immune system and inhibition of pathogens are because of their ability to modulate the activity and composition of human microbiota [1]. Prebiotics, which enhance probiotics survivability and growth, may have an excellent potential effect against COVID-19 [1]. Prebiotics could block the ACE enzymes, which may have a direct effect on gastrointestinal symptoms caused by COVID-19 [1]. There are many ongoing registered trials aiming to investigate the efficiency of probiotics in treating COVID-19 patients [9].
Some COVID-19 patients showed intestinal microbial dysbiosis characterized by decreased probiotics such as Lactobacillus and Bifidobacterium. Prebiotic or probiotic supplementation, and nutritional support has been recommended to re-normalize the balance of intestinal microbiota and decrease the risk of secondary infection due to bacterial translocation [10]. Probiotic supplementation could be a promising strategy given previous studies of the potential application of probiotics in treatment and prevention of various viral infections [1,11,12]. The elderly and disordered microbiota patients are the most susceptible groups to COVID-19. Thus, it is suggested that probiotics supplementation in those groups could increase the ability of the gastrointestinal microbiota in modulation of immunity and help in prevention of viral infections including COVID-19 [1]. Competition with pathogens for nutrients, production of anti-microbial substances, enhancement of the intestinal epithelial barrier, and adhesion to the intestinal epithelium, and modulation of the host immune system might explain clinical success of probiotics [13,14]. Saavedra and colleagues conducted randomized control trial of 55 infants and found that enteral supplementation with a combination of Streptococcus thermophiles and Bifidobacterium bifidum decreased the incidence of diarrhea and rotavirus shedding [15], which may indicate interference with entry of the virus into cells and/or inhibition of viral replication in the intestine. Although probiotics were not administered to the respiratory tract, this mechanism may play a role in lowering dissemination of SARS-CoV-2 through the gut. Therefore, direct inhibition may be impossible at the respiratory tract. Having said that, lungs have their own microbiota and a gut-lung connection has been previously reported whereby microbe-microbe host-microbe, and immune interactions could affect the course of respiratory diseases [14,16].
Growing evidence showed that the gut-lung axis plays a pivotal role in the pathogenicity of viral and bacterial and infections, as the intestinal microbiota could enhance the activity of alveolar macrophage, thus having a prophylactic role in host defense against pneumonia [17]. Respiratory tract infections such as influenza are linked with a dysbiosis in the microbial communities of the both gastrointestinal and respiratory tracts [18,19], which could alter immune function and facilitate secondary bacterial infection [14]. Previous studies reported that COVID-19 could be associated with intestinal dysbiosis leading to inflammatory reactions and poorer response to pathogens [20,21], the case exists for probiotics that could restore gut homeostasis [22]. Arroyo and colleagues evaluated the efficacy of oral administration of Lactobacillus fermentum CECT5716 or Lactobacillus salivarius CECT5713, two lactobacilli strains isolated from breast milk, compared with the efficacy of antibiotic therapy in treatment of lactational mastitis [23]. They found that females took the probiotics improved more and had reduced recurrence of mastitis than those who took the antibiotic therapy.
The gut microbiome plays a pivotal role in systemic immune responses, including those at distant mucosal sites such as the lungs [24,25]. Administration of certain lactobacilli or bifidobacteria helps in clearance of influenza virus from the respiratory tract [24,26]. Probiotic strains increase type I interferon levels, the activity and number of T cells, NK cells, antigen presenting cells, as well as the levels of systemic and mucosal specific antibodies in the lungs [24,27,28]. Growing evidence showed that probiotic strains could regulate the dynamic balance between proinflammatory and immunoregulatory cytokines that facilitate viral clearance with minimum immune response-mediated lung damage [14]. This seems be particularly important as a way to inhibit acute respiratory distress syndrome, which is the most feared complication of COVID-19.
Chong and colleagues reported that Lactobacillus plantarum DR7 suppressed plasma pro-inflammatory cytokines (TNF-α, IFN-γ,) in middle-aged adults, and enhanced anti-inflammatory cytokines (IL-10, IL-4,) in young adults, along with decreased levels of oxidative stress and plasma peroxidation [29]. This type of modulation is considered to be very important, especially for many COVID-19 patients, who have from cytokine storm. Orally administered probiotic strains appear to involve the immune response originating from the intestine, a main site of the body’s defenses. Thus, probiotic strains, which could improve the integrity of tight junctions, for example through butyrate augmentation, a fuel for colonocytes, may in theory decrease SARS-CoV-2 invasion [14]. Zuo and colleagues found that faecal samples with signature of low-to-none SARS-CoV-2 infectivity had higher abundances of short-chain fatty acid producing bacteria, Bacteroides stercoris, Parabacteroides merdae, Lachnospiraceae bacterium 1_1_57FAA, and Alistipes onderdonkii [30]. A recent study tested the impact of short-chain fatty acids (acetate, propionate and butyrate) in the infection by SARS-CoV-2 [31]. They found that short-chain fatty acids did not change SARS-CoV-2 entry or replication in intestinal cells. These metabolites had no effect on permeability of intestinal cells and had only little effect on the synthesis of anti-viral and inflammatory mediators. Although this may seem discouraging, we propose that testing real short-chain fatty acid-producing bacteria (not short-chain fatty acids only) may give good results. Testing bacteria is different from testing metabolite, especially that there are many current pieces of research that speak about virus-bacteria interactions [32,33].
Ren and colleagues reported that faecal and oral microbial diversity was remarkably decreased in confirmed COVID-19 patients versus healthy controls [34]. They found that there was a reduction in butyric acid-producing bacteria and an increase in lipopolysaccharide- producing bacteria in COVID-19 patients in oral cavity. Researchers reported that confirmed recovery COVID-19 patients showed depletion in 47 lipid molecules, including sphingomyelin (SM)(d40:4), SM(d38:5) and monoglyceride(33:5), and enrichment of phosphatidylcholine(36:4p), phosphatidylethanolamine (PE)(16:0p/20:5) and diglyceride(20:1/18:2) versus confirmed COVID-19 patients. This is the first study that explores the alterations in the human oral and gut microbiomes and lipidomics in COVID-19 patients, which may be involved in the development and progression of COVID-19 and could be also useful as an auxiliary diagnostic tool. Previous clinical and experimental studies reported that some probiotic strains have antiviral effects against common respiratory viruses, including respiratory syncytial virus, rhinovirus, influenza [12,28,35,36]. Although these mechanisms or effects have yet to be tested on the SARS-CoV-2, this should not refute considering this new line of investigation, especially when effects of probiotics against other coronavirus strains such as transmissible gastroenteritis virus have been reported [37-40]. Research is urgently needed to assess the effect of probiotics and prebiotics against SARS-CoV-2, which may lead to a better understanding of the bacterial dynamics in the gastrointestinal tract.

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Consent Statement/Ethical Approval

Not required.

Funding Statement

This research received no specific grant from any funding agency.

References

1. Olaimat A N, Iman Aolymat, Murad Al-Holy, Mutamed Ayyash, Mahmoud Abu Ghoush, et al. (2020) The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19. NPJ science of food 4(1): 1-7.
2. Robles Vera I, Marta Toral, Miguel Romero, Rosario Jiménez, Manuel Sánchez, et al. (2017) Antihypertensive effects of probiotics. Current hypertension reports 19(4): 26.
3. Ayyash MM, F Sherkat, N P Shah (2012) The effect of NaCl substitution with KCl on Akawi cheese: Chemical composition, proteolysis, angiotensin-converting enzyme-inhibitory activity, probiotic survival, texture profile, and sensory properties. Journal of Dairy Science 95(9): 4747-4759.
4. Ayyash M, Amin Olaimat, Anas Al Nabulsi, Shao Quan Liu (2020) Bioactive properties of novel probiotic Lactococcus lactis fermented camel sausages: Cytotoxicity, angiotensin converting enzyme inhibition, antioxidant capacity, and antidiabetic activity. Food science of animal resources 40(2): 155.
5. Imai Y, Keiji Kuba, Shuan Rao, Yi Huan, Feng Guo, et al. (2005) Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436(7047): 112-116.
6. Gibson G R, Robert Hutkins, Mary Ellen Sanders, Susan L Prescott, Raylene A Reimer, et al. (2017) Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nature reviews Gastroenterology & hepatology 14(8): 491.
7. Guarino M P L, Annamaria Altomare, Sara Emerenziani, Claudia Di Rosa, Mentore Ribolsi, et al. (2020) Mechanisms of action of prebiotics and their effects on gastro-intestinal disorders in adults. Nutrients 12(4): 1037.
8. Davani Davari D, Manica Negahdaripour, Iman Karimzadeh, Mostafa Seifan, Milad Mohkam, et al. (2019) Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods 8(3): 92.
9. Infusino F, Massimiliano Marazzato, Massimo Mancone, Francesco Fedele, Claudio Maria Mastroianni et al. (2020) Diet supplementation, probiotics, and nutraceuticals in SARS-CoV-2 infection: a scoping review. Nutrients 12(6): 1718.
10. Xu K, Hongliu Cai, Yihong Shen, Qin Ni, Yu Chen, et al. (2020) Management of corona virus disease-19 (COVID-19): the Zhejiang experience. Journal of Zhejiang University (medical science) 49(1).
11. Ceccarelli G, Maura Statzu, Letizia Santinelli, Claudia Pinacchio, Camilla Bitossi, et al. (2019) Challenges in the management of HIV infection: update on the role of probiotic supplementation as a possible complementary therapeutic strategy for cART treated people living with HIV/AIDS. Expert opinion on biological therapy 19(9): 949-965.
12. Luoto R, Olli Ruuskanen, Matti Waris, Marko Kalliomäki, Seppo Salminen, et al. (2014) Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology 133(2): 405-413.
13. Bermudez-Brito M, Plaza-Díaz J, Muñoz-Quezada S, Gómez Llorente C, Gil A (2012) Probiotic mechanisms of action. Annals of Nutrition and Metabolism 61(2): 160-174.
14. Baud D, Varvara Dimopoulou Agri, Glenn R Gibson, Gregor Reid, Eric Giannoni (2020) Using probiotics to flatten the curve of coronavirus disease COVID-2019 pandemic. Frontiers in public health 8: 186.
15. Saavedra J M, N A Bauman, I Oung, J A Perman, R H Yolken (1994) Feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. The lancet 344(8929): 1046-1049.
16. Enaud R, Renaud Prevel, Eleonora Ciarlo, Fabien Beaufils, Gregoire Wieërs, et al. (2020) The gut-lung axis in health and respiratory diseases: a place for inter-organ and inter-kingdom crosstalks. Frontiers in cellular and infection microbiology 10: 9.
17. Stavropoulou E, E Bezirtzoglou (2020) Probiotics in medicine: a long debate. Frontiers in Immunology 11: 2192.
18. Sencio V, Adeline Barthelemy, Luciana P Tavares, Marina G Machado, Daphnée Soulard, et al. (2020) Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production. Cell reports 30(9): 2934-2947.
19. Hanada S, Mina Pirzadeh, Kyle Y Carver, Jane C Deng (2018) Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. Frontiers in immunology 9: 2640.
20. Gao QY, Y X Chen, JY Fang (2020) 2019 Novel coronavirus infection and gastrointestinal tract. Journal of digestive diseases 21(3): 125-126.
21. Xu K, H Cai, Y Shen, Qin Ni, Yu Chen, et al. (2020) [Management of corona virus disease-19 (COVID-19): the Zhejiang experience], Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical sciences 49(1).
22. Di Pierro F (2020) A possible probiotic (S. salivarius K12) approach to improve oral and lung microbiotas and raise defenses against SAR S-CoV-2. Minerva medica 111(3): 281-283.
23. Arroyo R, Virginia Martín, Antonio Maldonado, Esther Jiménez, Leónides Fernández, et al. (2010) Treatment of infectious mastitis during lactation: antibiotics versus oral administration of Lactobacilli isolated from breast milk. Clinical Infectious Diseases 50(12): 1551-1558.
24. Zelaya H, Susana Alvarez, Haruki Kitazawa, Julio Villena (2016) Respiratory antiviral immunity and immunobiotics: beneficial effects on inflammation-coagulation interaction during influenza virus infection. Frontiers in immunology 7: 633.
25. Abt MC, Lisa C Osborne, Laurel A Monticelli, Travis A Doering, Theresa Alenghat, et al. (2012) Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37(1): 158-170.
26. Ichinohe T, Iris K Pang, Yosuke Kumamoto, David R Peaper, John H Ho, et al. (2011) Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proceedings of the National Academy of Sciences 108(13): 5354-5359.
27. De Vrese M, Petra Winkler, Peter Rautenberg, Timm Harder, Christian Noah, et al. (2005) Effect of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on common cold episodes: a double blind, randomized, controlled trial. Clinical nutrition 24(4): 481-491.
28. Namba K, Michiko Hatano, Tomoko Yaeshima, Mitsunori Takase, Kunihiko Suzuki (2010) Effects of Bifidobacterium longum BB536 administration on influenza infection, influenza vaccine antibody titer, and cell-mediated immunity in the elderly. Bioscience, biotechnology, and biochemistry 74(5): 939-945.
29. Chong H X, Nur Asmaa' A Yusoff, Yan-Yan Hor, Lee-Ching Lew, Mohamad Hafis Jaafar, et al. (2019) Lactobacillus plantarum DR7 improved upper respiratory tract infections via enhancing immune and inflammatory parameters: A randomized, double-blind, placebo-controlled study. Journal of dairy science 102(6): 4783-4797.
30. Zuo T, Qin Liu, Fen Zhang, Grace Chung Yan Lui, Eugene Yk Tso, et al. (2021) Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 70(2): 276-284.
31. Pascoal L B, Patrícia Brito Rodrigues, Lívia Moreira Genaro, Arilson Bernardo Dos Santos Pereira Gomes, Daniel Augusto ToledoTeixeira, et al. (2021) Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples. Gut Microbes 13(1): 1-9.
32. Almand EA, MD Moore, L A Jaykus (2017) Virus-bacteria interactions: an emerging topic in human infection. Viruses 9(3): 58.
33. Dawley C, K E Gibson (2019) Virus-Bacteria Interactions: Implications for Prevention and Control of Human Enteric Viruses from Environment to Host. Foodborne pathogens and disease 16(2): 81-89.
34. Ren Z, Haiyu Wang, Guangying Cui, Haifeng Lu, Ling Wang, et al. (2021) Alterations in the human oral and gut microbiomes and lipidomics in COVID-19. Gut 70(7): 1253-1265.
35. Waki N, M Matsumoto, Y Fukui, H Suganuma (2014) Effects of probiotic Lactobacillus brevis KB 290 on incidence of influenza infection among schoolchildren: an open‐label pilot study. Letters in applied microbiology 59(6): 565-571.
36. Turner R, J A Woodfolk, L Borish, J W Steinke, J T Patrie, et al. (2017) Effect of probiotic on innate inflammatory response and viral shedding in experimental rhinovirus infection-a randomised controlled trial. Beneficial microbes 8(2): 207.
37. Seo B J, Mi Ran Mun, V J Rejish Kumar, Chul Joong Kim, Insun Lee (2010) Putative probiotic Lactobacillus spp. from porcine gastrointestinal tract inhibit transmissible gastroenteritis coronavirus and enteric bacterial pathogens. Tropical animal health and production 42(8): 1855-1860.
38. Chai W, Michael Burwinkel, Zhenya Wang, Christiane Palissa, Bettina Esch, et al. (2013) Antiviral effects of a probiotic Enterococcus faecium strain against transmissible gastroenteritis coronavirus. Archives of virology 158(4): 799-807.
39. Liu Y S, Qiong Liu, Yanlong Jiang, Wentao Yang, Haibin Huang, et al., (2020) Surface-displayed porcine IFN-λ3 in Lactobacillus plantarum inhibits porcine enteric coronavirus infection of porcine intestinal epithelial cells. Journal of microbiology and biotechnology 30(4): 515-525.
40. Wang K, Ling Ran, Tao Yan, Zheng Niu, Zifei Kan, et al. (2019) Anti-TGEV miller strain infection effect of Lactobacillus plantarum supernatant based on the JAK-STAT1 signaling pathway. Frontiers in microbiology 10: 2540.

Abstract

Probiotics are live microorganisms, which if administered at adequate amounts, confer beneficial physiological effects [1]. Previous study underscored the positive impact (whether directly or indirectly) of probiotics on the ACE enzymes [2]. During the process of food fermentation, probiotics make bioactive peptides which interfere with the ACE enzymes through blocking the active sites [3,4]. The debris of the dead probiotic cells can also work as inhibitors to ACE [1], suggesting that probiotics are possibly potential blockers to the ACE receptors, which act as gateway for SARS-CoV-2 to attack gastrointestinal cells. Imai and colleagues reported that ACE blockers could be used to decrease respiratory distress syndrome [5]. The prebiotics are defined as ‘substrates that are selectively utilized by host microorganisms conferring a health benefit’ [6].

Keywords: Dysbiosis; Probiotics; SARS-CoV-2; COVID-19