Muhammad Luthfi Adnan1, Miranti Dewi Pramaningtyas2
doi: http://dx.doi.org/10.5195/ijms.2020.486
Volume 8, Number 2: 121-125
Received 07 04 2020: Rev-request 07 04 2020: Rev-request 27 04 2020: Rev-request 05 05 2020: Rev-recd 14 04 2020: Rev-recd 29 04 2020: Rev-recd 06 05 2020: Accepted 06 05 2020
ABSTRACT
After the outbreak in December 2019, Coronavirus Disease (COVID-19) has become a global health problem because of its rapid spread throughout the world. To date, there are no effective therapies to treat or prevent COVID-19 infection. Probiotic bacteria are widely used to prevent gastrointestinal infections by modulating intestinal microbiota. Therefore, this literature review focuses on the potential possessed by probiotic bacteria for the prevention of future COVID-19 infections. Information was extracted from PubMed and Google Scholar using the keywords: "COVID-19", "immunomodulator", "inflammation", and "probiotic" and synthesized into this narrative review. The results showed that probiotic bacteria have immunomodulatory activity that can increase immunity against pathogens by regulating the immune system through modulation of intestinal microbiota and interactions with the lymphatic system in the digestive tract. The ability of the immune system regulation by probiotic bacteria has the effect of increasing the body's defense mechanisms against pathogens that infect the respiratory tract. However, further evidence is still needed regarding the effect of probiotic immunomodulators in combating future COVID-19 infections.
Keywords: COVID-19; Immune system; Inflammation; Probiotics (Source: MeSH-NLM).
Since its appearance in December 2019 in Wuhan, China, Coronavirus Disease (COVID-19) has become a worldwide pandemic by infecting more than 43,000 people in 28 countries as of February 11, 2020 and becoming a health problem in many countries. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and can be transmitted through patient droplets or direct contact with COVID-19 patients.1 The SARS-CoV-2 virus is a type of virus of the genus β-coronavirus that is enveloped in a non-segmented positive-sense RNA virus.2 The SARS-CoV-2 virus has the same genus as SARS-CoV, known for the SARS outbreak in 2003, and the Middle East respiratory syndrome coronavirus (MERS-CoV) which can cause deadly respiratory infections.2
Symptoms of COVID-19 patients include symptoms similar to influenza infections such as fever, coughing, muscle aches and dyspnea.3 Treatment for COVID-19 patients is still limited to giving symptomatic therapy to patients. Providing care to patients is done to prevent complications that arise. Some of the treatments that are often used include the use of invasive mechanical ventilation, systemic corticosteroids and antiviral therapy. The most common complications that arise are acute respiratory distress syndrome (ARDS), anemia, acute heart injury and secondary infection.3 However, some of the uses of the treatment are still unclear as to their effectiveness and there are currently no effective drugs for treating COVID-19.3
Treatment through immune system modulation has attracted much attention because it initiates the body's immune response to fight bacterial and viral infections.4 The use of many immunomodulating agents was developed to initiate the body's immune system against infection and reduce the risk of damage to the host due to the activity of the immune response from proinflammatory cytokines. With research on vaccines to prevent COVID-19 still in development stages, the use of immunomodulators in modulating the immune system may be useful for pathology related to viral infections.4
Recent studies have shown the immunomodulatory effects of probiotic bacteria.5 Probiotics are defined as being "living microorganisms which, when consumed in sufficient quantities, provide health benefits to the host”.5 Probiotics are widely used in the fermented food processing industry such as cheese, yoghurt or as supplements. Many studies show the health benefits of probiotics, one of which is to modulate the immune system to prevent viral infections through modulation of probiotic bacteria with the immune system in the intestinal mucosa.5
The purpose of this literature review is to discuss the immunomodulatory effects and the potential of probiotics to prevent COVID-19 infection.
A comprehensive electronic literature search was carried out using search tools from Medline (PubMed) and Google Scholar to identify relevant publications regarding COVID-19, immunomodulators, and probiotics. Database parameters performed using keywords include "COVID-19", "immunomodulator", "inflammation", and "probiotic". The literature used is full-text written in English and published within the last 10 years. The literature used consists of keywords that include "COVID-19", "immunomodulator", "inflammation", and "probiotic".
Excluded articles did not have a full-text publication or were not written in English. Inclusion criteria parameters include full-text in English, published less than 10 years ago, articles have the keywords "COVID-19", "immunomodulator", "inflammation", and "probiotic", articles studying COVID-19, probiotics, probiotic activity as an immunomodulator, and probiotic immunomodulatory activity in the respiratory tract.
The SARS-CoV-2 virus, is closely related to the SARS-CoV-1 virus that targets angiotensin-converting enzyme 2 (ACE2) cells as receptor cells in host targeting.6 The virus has an incubation period of 2-14 days during which the host is infectious.6 The greatest burden of the virus is contained in the lung organs, causing symptoms similar to pneumonia with characteristic changes in lung opacity on CT imaging. Other symptoms of COVID-19 that are similar to that of pneumonia include fever, cough, shortness of breath and sore throat.6 Some other symptoms of COVID-19 include gastrointestinal symptoms such as diarrhea, nausea and vomiting. This may be due to ACE2 receptors also found in intestinal epithelial cells. The finding of SARS-CoV-2 nucleic acid in a patient stool reveals a potential route for viral infection through feces.7
COVID-19 also impacts the body's immune system during the infection stage. For example, an increase in the ratio of neutrophils to lymphocytes (NLR) and T lymphopenia and a decrease in CD4 + T cells are found in patients with COVID-19. These findings indicate the presence of immune system dysregulation induced by viral activity targeting T lymphocytes. NLR, which is a systemic infection marker, was also found as part of a proinflammatory cytokine storm (TNF-α, IL-1, IL-6) and chemokine (IL-8) which correlated with the severity of COVID-19 patients.8 The cytopathic effect of proinflammatory cytokine activity results in systemic inflammation which has the potential to cause death.8
The emergence of cytokine storms is in this case an overzealous immune response against viral infections. Cytokine storms are a form of immune homeostasis disorder and self-tolerance through interference with regulatory T cells that play a role in the control of systemic and tissue-specific autoimmunity. The high level of proinflammatory signals in cytokine storms results in collateral host tissue damage.8 Uncontrolled cytokine storm activity in the immune system's reaction to a viral infection affects the process of remodeling airway tissue which risks increasing the severity of infection and damage to important organs causing a risk of death.9,10
Probiotics are types of bacteria that can provide health benefits to the host. Some characteristics possessed by probiotic bacteria are (1) having the ability of probiotic bacteria to survive and reproduce in the intestine; (2) having benefits for the host through growth in the host body; (3) being non-pathogenic or toxic; (4) protect against pathogens (i.e., bacteria, viruses or fungi); and (5) are resistant to transfer of antibiotic resistance. Probiotic bacteria of different strains can provide different benefits to the health of the host.11
Bacteria from the genus Lactobacillus and Bifidobacterium are widely used probiotics known as probiotic lactic acid bacteria (LAB). Probiotics work in part by binding to the intestinal mucosa and producing antimicrobial compounds, increasing the defense function of the intestinal barrier, and modulating immunity against intestinal pathogen infections.12 Probiotics have an important role to play in fighting diarrhea, antibiotic-related diarrhea, prevention of colorectal cancer, and treatment agents for gastroenteric infections caused by various pathogens such as Escherichia coli, Bacillus, Salmonella, Shigella, Vibrio cholera, Klebsiella and Pseudomonas.12
Lactobacillus and Bifidobacterium bacteria have the structure of lipoteichoic acid (LTA), surface layer associated proteins (SLAPs) and mucin binding proteins (Mubs) that bind to glycocalyx in the intestinal epithelial layer.13 Glycocalyx contains glycolipids and glycoproteins that interact with the structure layers of LTA, SLAPs and Mubs from probiotic bacteria. The composition between the structure of probiotic bacteria and intestinal mucosa has hydrophobic and adhesion properties that can synthesize the extracellular matrix components of fibronectin, collagen, and laminin.13,14 Through the mechanism of adhesion on the surface of the intestinal epithelium, probiotic bacteria exert an increased effect on the integrity of the intestinal barrier and result in maintenance of immune tolerance, decreases the translocation of pathogenic bacteria across the intestinal mucosa, and prevent phenotypic changes due to diseases such as gastrointestinal infections, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).15 The immune tolerance response from the interaction between the intestinal mucosa and the probiotic bacteria induces a balance in the microflora in the intestinal environment.16
In probiotic bacteria, antitoxins can produce a serine protease and phosphatase that degrades toxins from E. coli and Clostridioides difficile, as well as displaying the ability to destroy intersections between pathogenic bacteria with epithelium and viruses with enterocytes.17 Probiotic bacteria also can interact with other microbiota in the intestinal environment and can rehabilitate intestinal microbiota balance in diarrheal infection conditions.17
Beyond the microbiome homeostasis effects of probiotics, their ability to fermentation non-digestible polysaccharides is an important attribute which is thought to affect host metabolism in a meaningful manner. Disorders caused by intestinal microbiota dysbiosis correlate with the onset of hypertension, obesity, and metabolic syndrome.18 With this interaction activity between intestinal microbiota and host metabolism, probiotic bacteria may have potential as antihypertensive and hypocholesterolemic interventions in metabolic syndrome.18,19
Some probiotic bacteria display an immunomodulatory function, regulating the production of two types of cytokines namely anti-inflammatory cytokines such as interleukin-10 (IL-10) and proinflammatory cytokines such as interleukin-6 (IL-6). In addition, the immunomodulatory activity of probiotics also works by balancing the T-helper (Th)1 / Th2 immune response through interactions on antigen-presenting cells (APC) in lymphocyte-dense Peyer's patches on part of the intestinal epithelium.20,21 The ability to initiate immune system modulation from probiotics may minimize epithelial injury resulting from the inflammatory response.22
The immunobiotic ability of Lactobacillus and Bifidobacterium bacteria through the production of lactic acid can modulate the immune response in the intestinal mucosa by interacting with Toll-like Receptor 2 (TLR2).21 Probiotic interactions in the intestinal environment induce a Th1 immune response that results in the production of interferon cytokines (IFN)-β and activate the bactericidal activity of macrophages.23 The host of intestinal probiotic interactions triggers lymphatic maturation, epithelial repair through endotoxin signaling and promotes intestinal microbial mucosal tolerance.24
The ability of probiotic bacteria to modulate the host immune system through activation of natural killer cells, dendritic cells, intraepithelial lymphocyte cells and macrophages that have an important role in the innate immune system. Probiotic bacteria work by binding to aryl hydrocarbon receptors and activating macrophages and dendritic cells so that there is a stimulus to release TNF-α proinflammatory cytokines from epithelial cells and enhance the immune system. Research conducted by Villena et al. (2014) showed the defense mechanism of intestinal cells through the administration of probiotic bacteria through immunoregulators with the production of proinflammatory cytokines such as IL-6 and TNF-α in response to pathogens and the production of anti-inflammatory cytokines IL-10.21
Besides their immunomodulator role in the immune system, probiotics have anti-inflammatory potential through bioactive peptide compounds.25 The compounds produced from these probiotic bacteria can restore intestinal permeabilities. Also, the probiotic activity suppresses the activity of Th2 cells to produce IgE, interleukin-4 (IL-4) and IL-13 preventing asthma and allergic reactions.25,26 Anti-inflammatory activity in the lungs plays a role in decreasing lung inflammation such as decreasing the levels of proinflammatory cytokines and C-reactive protein (CRP).27
Probiotic bacteria produce metabolites in the form of short-chain fatty acids (SCFA) consisting of acetate, propionate, and butyrate which are widely present in the colon epithelium. Parts of the butyrate are used as energy by the colonocytes while the rest of the other SCFA are absorbed into the portal circulation through the intestine.28 The SCFA metabolite binds specifically to the G-protein-coupled receptor43 / free fatty acid receptor 2 (GPR43 / FFAR2), GPR41 / FFAR3 and GPR109A. Interactions on these receptors result in the development of macrophages and increase the differentiation of dendritic cell precursors that can migrate to the lungs and change the regulator T cells with Th2 cells.29
Interaction between the intestinal relationship with the lungs is mediated by the lymphatic system through the TLR4 dependency mechanism and produces IgA associated with gut-associated lymphoid tissue (GALT).30 These probiotic bacteria will induce regulatory T cells and initiate T helper 17 (Th17) production and Th1 immune memory response.30 The circulation of the lymphatic system from the gut-lung axis enables Th17 cells to be transferred from the intestinal mucosa to the bronchial epithelial mucosa in lymph nodes in the airways. Besides suppressing the activity of pathogens that attack the respiratory system, the activity of probiotic interactions in the intestine with the airways prevents damage to the airway tissue by controlling the defense of the host immune system in the lungs.30
COVID-19 infection attacks the lung tissue and activates inflammation in the airways.31 The results from serum sampling of COVID-19 patients has shown an increase in the number of proinflammatory cytokines such as IL-1B, IL-6, IL-15, IL-15, IL-17 IFN-γ and TNF-α.31 This leads to the emergence of cytokine storms and correlates with the severity of the disease.31 The emergence of cytokine storms can lead to pulmonary fibrosis and damage to respiratory organs.32 This inflammatory stimulus-response may be due to the activation of the Th1 cell response.33
The potential effect of probiotics in influencing the activity of cytokine storms due to COVID-19 infection may be through interactions in the gut microbiota with the immune system.34 Disruption to the intestinal microbiota environment results in an imbalance of Th1 / Th2 cells, which results in the production of proinflammatory cytokine storms in the lungs.34 Through modulation of intestinal microbiota, there is a shift in the balance between Th1 / Th2 cells which could theoretically reduce the inflammatory response in the respiratory tract, thereby reducing the severity of disease.34
The activity of modulating intestinal microbiota through administration of probiotic bacteria has an impact on controlling the lung immune system response to viral infections. Probiotic bacteria can reduce the excessive inflammatory response in the face of viral infections by influencing T cells to produce IFN-γ.35 The activity of probiotic bacteria in regulating the immune system is carried out through interactions with regulatory T cells in Peyer's patches on the intestinal surface thereby preventing excessive cytokine storm activity in fighting viral infections.36
In addition to stimulating the regulation of Th1 / Th2 cell balance, the activity of probiotic bacteria can initiate a defense system in the airway mucosa.37 As a result of the response of proinflammatory cytokines in the airway mucosal epithelium, airway remodeling activity causes narrowing of the airways. Airway remodeling arising from pro-inflammatory cytokines can lead to breathing difficulties and a worsening of patient condition.38 Prevention of airway remodeling due to viral infection creates therapeutic targets for probiotic bacteria to potentially prevent worsening the condition of patients in COVID-19.39,40
With the development of therapies and vaccines for the prevention of COVID-19 infection still ongoing, the immunomodulatory effects of probiotic bacteria may have the potential to help with COVID-19 infection. The ability of probiotic bacteria to regulate the gut microbiota may in turn modulate immune system in a manner which could be useful in COVID-19. The findings from previous studies still need further research on broader subject matter to ensure the safety of therapy, so that the immunomodulatory potential of the probiotic bacteria can be maximized in the fight against COVID-19 infection in the future.
None.
The Authors have no funding, financial relationships or conflicts of interest to disclose.
Conceptualization: MLA. Methodology: MLA. Software: MLA. Validation: MLA. Formal Analysis: MLA. Data Curation: MLA. Investigation: MLA. Resources: MLA. Writing – Original Draft: MLA. Writing – Review & Editing: MLA. Visualization: MLA. Supervision: MDP. Project Administration: MLA. Funding Acquisition: MLA.
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Muhammad Luthfi Adnan, 1 Medical Student, Universitas Islam Indonesia, Sleman, Indonesia
Miranti Dewi Pramaningtyas, 2 Master of Science, Department of Physiology, Universitas Islam Indonesia, Sleman, Indonesia
Francisco Javier Bonilla-Escobar, Editor
Mihnea-Alexandru Găman, Editor
Andrew Stanton Kucey, Student Editor
About the Author: Muhammad Luthfi Adnan is currently a 4th year medical student of Faculty of Medicine, The Universitas Islam Indonesia of a 6-years medical program. His several research studies have been published at the 7th International Congress on Lipid Metabolism & Atherosclerosis (ICoLA 2018) in Seoul, South Korea, the Indonesia International (Bio)Medical Students’ Congress (INAMSC) 2019 in Jakarta, Indonesia and the 30th European Student Conference (ESC) 2019 in Berlin, Germany.
Correspondence: Muhammad Luthfi Adnan, Address: Kaliurang St No. Km. 14,5, Krawitan, Umbulmartani, Ngemplak, Sleman Regency, Indonesia. Email: 16711133@students.uii.ac.id
Cite as: Adnan ML, Pramaningtyas MD. Probiotics as Promising Immunomodulatory Agents to Prevent COVID-19 Infection: A Narrative Review. Int J Med Students. 2020 May-Aug;8(2):121-5.
Copyright © 2020 Muhammad Luthfi Adnan, Miranti Dewi Pramaningtyas
This work is licensed under a Creative Commons Attribution 4.0 International License.
International Journal of Medical Students, VOLUME 8, NUMBER 2, August 2020