At present, during this current pandemic of COVID-19, no effective preventive and curative medicine is currently available. Subsequently, a healthy immune system is considered paramount and therapies addressing the immunopathology of the infection have become a major focus.
There are a number of nutrients which are essential for the normal functioning of the immune system, of which probiotics have shown effectiveness for treatment and prevention of viral infections as well as a supportive role in enhancing immune response(1) and this will be discussed in more detail below.
Human health is the outcome of a complex, interconnected network of interactions between microbes and their host(2) and there is a great deal of research which supports the view that the relationship between the host and gut microbiota is crucial for optimal health.
The human body harbours a large variety of microbial communities, interacting networks consisting of a multitude of bacteria, fungi, viruses, bacteriophages, archaea and eukaryotes, that colonise different body surfaces, including the respiratory tract as well as other areas.
Mucosal epithelial surfaces cover a huge area of the body, and those in the mouth and gastrointestinal and respiratory tracts are constantly exposed to numerous micro-organisms and serve as primary ports of entry for most infectious agents.
Although less extensively studied, evidence suggests that upper respiratory tract (URT) microbiome is a strong determinant of respiratory health.(3,4) When the microbiome is disturbed, for example by antibiotic treatment or disease state, potential pathogens such as Streptococcus pneumoniae, can overgrow, spread and ultimately result in respiratory infections.
The respiratory tract is a complex organ system that is divided into the upper respiratory tract (URT) and the lower respiratory tract (LRT). The URT includes the anterior nares (openings in the nose that connect the external environment and the nasal cavity), nasal passages, paranasal sinuses, the nasopharynx and oropharynx, and the portion of the larynx above the vocal cords, whereas the LRT includes the portion of the larynx below the vocal cords, the trachea, smaller airways (that is, bronchi and bronchioli) and alveoli.
The primary function of the respiratory tract is the exchange of oxygen and carbon dioxide. For this purpose, the adult human airways have a surface area of approximately 70m2, which is approximately forty times larger than the surface area of the skin. This entire surface is inhabited by niche-specific bacterial communities, with the highest bacterial densities observed in the URT.
Upper respiratory infections (URIs) are one of the most common reasons for doctor visits. The vast majority of upper respiratory infections are caused by viruses and are self-limiting. Examples of URT viruses may include rhinitis (inflammation of the nasal cavity), sinus infection (sinusitis or rhinosinusitis), inflammation of the sinuses located around the nose, common cold (nasopharyngitis), inflammation of the nares, pharynx, hypopharynx, uvula, and tonsils, pharyngitis (inflammation of the pharynx, uvula, and tonsils), epiglottitis (inflammation of the upper portion of the larynx or the epiglottis), laryngitis (inflammation of the larynx), laryngotracheitis (inflammation of the larynx and the trachea), and tracheitis (inflammation of the trachea). Coronaviruses are a type of virus too. There are many different kinds of coronaviruses. Some of them can cause colds or other mild respiratory (nose, throat, lung) illnesses.
Other coronaviruses can cause more serious diseases, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). COVID-19 is the disease caused by the new coronavirus that emerged in China in December 2019. It is an infectious disease caused by a newly discovered coronavirus. Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness and recover without requiring special treatment. Older people, and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness.
Coronaviruses are named for their appearance as under the microscope, the viruses look like they are covered with pointed structures that surround them like a corona, or crown.
For most respiratory bacterial pathogens, colonisation of the URT is the first step before causing an upper, lower or disseminated respiratory infection.(5) Inhibition of this first step of pathogenesis for respiratory infections by the resident microbiota, called ‘colonisation resistance’ (the mechanism whereby the intestinal microbiota protects itself against incursion by new and often harmful microorganisms), is of paramount importance to respiratory health.(6)
The commensal microbiota, which consists of micro-organisms present on mucosal surfaces covered by epithelial cells in the oral, gastrointestinal and respiratory tracts, plays an important role in protecting the body against pathogenic organisms. One of the mechanisms by which commensal and probiotic bacteria provide colonisation resistance to pathogens is by directly competing for the same niche. Some beneficial microbes acquire similar nutrients as pathogens, often more efficiently, thus hindering the replication and colonisation of infectious agents and thereby offering colonisation resistance.
Effects of probiotics reach beyond the gut. Human clinical trials suggest that probiotics could also be effective in cases of respiratory infections, allergies, mental disorders, periodontitis etc.
Gut–lung crosstalk has been proposed in the pathogenesis of certain respiratory conditions. Two meta-analyses reported modest efficacy of probiotics in reducing the incidence and duration of respiratory tract infections of viral origin.(7,8)
Bifidobacterium species induce distinct cytokine production patterns and can suppress allergic immune responses in a strain-specific manner.(9) Multiple studies by Sagar et al. demonstrated that Bifidobacterium breve has strong anti-inflammatory properties and is capable of suppressing pulmonary airway inflammation and airway remodelling in a model of chronic allergic asthma.(10,11)
MRx-4DP0004 (a lyophilised formulation of Bifidobacterium breve proprietary strain) is an orally administered, single-strain live biotherapeutic product currently in a Phase I/II clinical trial for the treatment of patients with partly-controlled asthma. Trials with this have shown that it is able to down-regulate specific pathological aspects of the hyper-inflammatory response to viral infection without impairing viral clearance and impact particular immune cell types and pathways implicated in the hyperinflammatory response to SARS-CoV-2 infection.(9)
Both are key factors in the effective treatment of the respiratory symptoms associated with COVID-19, not only for hospitalised patients with more severe disease but potentially also in patients with milder symptoms to prevent disease progression and hospitalisation. Subsequently, a Phase II clinical trial of MRx-4DP0004 for patients hospitalised with COVID-19 is now open to enrolment, and dosing of the first patients is expected shortly.(12) This will be a randomised, double-blind, placebo-controlled trial. It will evaluate the efficacy and safety of MRx-4DP0004 in addition to standard-of-care in up to 90 patients hospitalised with symptoms indicative of COVID-19.
A recent review ‘Enhancing immunity in viral infections, with special emphasis on COVID-19’ aimed to evaluate evidence from previous clinical trials that studied nutrition-based interventions for viral diseases (with special emphasis on respiratory infections).(1) A systematic search strategy was employed and studies were considered eligible if they were controlled trials in humans, measuring immunological parameters, on viral and respiratory infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included. In the light of the current pandemic of COVID-19, the review focussed on evaluating the evidence on enhancing immunity in viral infections and concentrated on influenza-like viral infections.
The review looked at four studies on probiotics,(13–15) where Lactobacillus and Bifidobacterium strains had been used as treatments. All the studies found that probiotic supplementation either reduced the severity or shortened the duration of infection. Three of the studies showed the efficacy of Lactobacillus for treatment of respiratory tract infection of viral origin. The remaining study highlighted a significant association between Bifidobacterium and increased immune function and intestinal microbiota in the elderly.
Two randomised controlled trials showed that critically ill patients on mechanical ventilation who were given probiotics (Lactobacillus rhamnosus GG, live Bacillus subtilis, and Enterococcus faecalis) developed substantially less ventilator-associated pneumonia compared with placebo.(16,17) In spite of this, the author concluded that the efficacy of probiotics in reduction of intensive care unit mortality and inpatient mortality is uncertain.
A 2018 paper proposed to comprehensively review the effectiveness of several probiotics and paraprobiotics (sterilised probiotics) for the prevention or treatment of virally-induced infectious diseases. Discussed were the unique roles of those agents in modulating the cross-talk between commensal bacteria and the mucosal immune system. In addition, they reported that the process of viral elimination largely depends on the induction of type 1 interferons (IFNs), and that the regulation of inflammatory cytokines is mediated via pattern recognition receptors such as Toll-like receptors and retinoic-acid-inducible gene I. They further stated that studies have begun to elucidate the immunostimulatory effects of lactic acid bacteria and have reported their capacity to contribute to the prevention of viral infections such as influenza(18) and that type 1 IFNs are considered to be pivotal in mediating the protective effect of lactic acid bacteria against these infections. They concluded that although further detailed research is necessary in the future, probiotics and/or paraprobiotics are expected to be among the rational adjunctive options for the treatment of various viral diseases.(19)
One systematic review in 2014 assessed the effect of probiotics on the duration of an acute respiratory tract infection (RTI) in otherwise healthy children and adults. It evaluated probiotics that belong to the Lactobacillus and Bifidobacterium genera.(20) Studies eligible for inclusion in the systematic review were randomised controlled trials (RCT) of any duration that compared Lactobacillus and/or Bifidobacterium strains consumed orally with placebo or ‘no treatment’ in apparently healthy children (aged between 1 and 18 years) or adults who developed acute RTI at some point during the study. Acute respiratory infections were considered to include upper RTI and/or lower RTI, colds or influenza-like symptoms.
Results from a majority of the trials demonstrated a significant difference in favour of probiotics, suggesting fewer numbers of days of illness per person compared with that in participants who had taken a placebo.
In conclusion, the systematic review provided evidence from a number of good-quality randomised controlled trials that the average duration of respiratory illness episodes, the number of days of illness per person and the number of days absent from day care/work/school are significantly reduced with probiotic treatment compared with placebo.
Generally it has been found that multi-strain probiotics or multispecies probiotics may have advantages over single strain products.(21) The reason being, since probiotics are expected to influence multi-factorial diseases demanding a variety of probiotic properties, the synergistic actions or additive effect of several strains may be advantageous.
If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Helen) by phone or email at any time.
Amanda Williams and the Cytoplan Editorial Team
- Jayawardena R, Sooriyaarachchi P, Chourdakis M, Jeewandara C, Ranasinghe P. Enhancing immunity in viral infections, with special emphasis on COVID-19: A review. Diabetes Metab Syndr Clin Res Rev. 2020 Jul 1;14(4):367–82.
- Vayssier-Taussat M, Albina E, Citti C, Cosson JF, Jacques MA, Lebrun MH, et al. Shifting the paradigm from pathogens to pathobiome new concepts in the light of meta-omics [Internet]. Vol. 5, Frontiers in Cellular and Infection Microbiology. Frontiers Research Foundation; 2014 [cited 2020 Jun 26]. Available from: https://pubmed.ncbi.nlm.nih.gov/24634890/
- de Steenhuijsen Piters WAA, Sanders EAM, Bogaert D. The role of the local microbial ecosystem in respiratory health and disease [Internet]. Vol. 370, Philosophical Transactions of the Royal Society B: Biological Sciences. Royal Society of London; 2015 [cited 2020 Jun 29]. Available from: /pmc/articles/PMC4528492/?report=abstract
- Charlson ES, Chen J, Custers-Allen R, Bittinger K, Li H, Sinha R, et al. Disordered microbial communities in the upper respiratory tract of cigarette smokers. PLoS One [Internet]. 2010 [cited 2020 Jun 29];5(12). Available from: /pmc/articles/PMC3004851/?report=abstract
- Bogaert D, De Groot R, Hermans PWM. Streptococcus pneumoniae colonisation: The key to pneumococcal disease [Internet]. Vol. 4, Lancet Infectious Diseases. Lancet Infect Dis; 2004 [cited 2020 Jun 29]. p. 144–54. Available from: https://pubmed.ncbi.nlm.nih.gov/14998500/
- Man WH, De Steenhuijsen Piters WAA, Bogaert D. The microbiota of the respiratory tract: Gatekeeper to respiratory health. Vol. 15, Nature Reviews Microbiology. Nature Publishing Group; 2017. p. 259–70.
- Hao Q, Lu Z, Dong BR, Huang CQ, Wu T. Probiotics for preventing acute upper respiratory tract infections. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2011.
- King S, Glanville J, Sanders ME, Fitzgerald A, Varley D. Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: A systematic review and meta-analysis. Br J Nutr [Internet]. 2014 Jul 14 [cited 2020 Jun 29];112(1):41–54. Available from: /pmc/articles/PMC4054664/?report=abstract
- Raftis EJ, Delday MI, Cowie P, McCluskey SM, Singh MD, Ettorre A, et al. Bifidobacterium breve MRx0004 protects against airway inflammation in a severe asthma model by suppressing both neutrophil and eosinophil lung infiltration. Sci Rep [Internet]. 2018 Dec 1 [cited 2020 Jul 6];8(1). Available from: /pmc/articles/PMC6089914/?report=abstract
- Sagar S, Vos AP, Morgan ME, Garssen J, Georgiou NA, Boon L, et al. The combination of Bifidobacterium breve with non-digestible oligosaccharides suppresses airway inflammation in a murine model for chronic asthma. Biochim Biophys Acta – Mol Basis Dis [Internet]. 2014 Apr [cited 2020 Jul 6];1842(4):573–83. Available from: https://pubmed.ncbi.nlm.nih.gov/24440361/
- Sagar S, Morgan ME, Chen S, Vos AP, Garssen J, van Bergenhenegouwen J, et al. Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma. Respir Res [Internet]. 2014 Apr 16 [cited 2020 Jul 6];15(1):46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24735374
- Pharma 4D. A Study for Efficacy and Safety of Live Biotherapeutic MRx4DP0004 to Treat COVID-19 – Full Text View – ClinicalTrials.gov [Internet]. 2020 [cited 2020 Jul 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT04363372
- Akatsu H, Iwabuchi N, Xiao J, Matsuyama Z, Kurihara R, Okuda K, et al. Clinical Effects of Probiotic Bifidobacterium longum BB536 on Immune Function and Intestinal Microbiota in Elderly Patients Receiving Enteral Tube Feeding. J Parenter Enter Nutr [Internet]. 2013 Sep 27 [cited 2020 Jun 26];37(5):631–40. Available from: http://doi.wiley.com/10.1177/0148607112467819
- de Vrese M, Winkler P, Rautenberg P, Harder T, Noah C, Laue C, et al. Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double blind, randomized, controlled trial. Vaccine. 2006 Nov 10;24(44–46):6670–4.
- Berggren A, Lazou Ahrén I, Larsson N, Önning G. Randomised, double-blind and placebo-controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections. Eur J Nutr [Internet]. 2011 Apr 28 [cited 2020 Jun 26];50(3):203–10. Available from: https://link.springer.com/article/10.1007/s00394-010-0127-6
- Zeng J, Wang CT, Zhang FS, Qi F, Wang SF, Ma S, et al. Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial. Intensive Care Med [Internet]. 2016 Jun 1 [cited 2020 Jun 29];42(6):1018–28. Available from: https://pubmed.ncbi.nlm.nih.gov/27043237/
- Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: A blinded, randomized, controlled trial. Am J Respir Crit Care Med [Internet]. 2010 Oct 15 [cited 2020 Jun 29];182(8):1058–64. Available from: /pmc/articles/PMC2970846/?report=abstract
- Lehtoranta L, Pitkäranta A, Korpela R. Probiotics in respiratory virus infections [Internet]. Vol. 33, European Journal of Clinical Microbiology and Infectious Diseases. Springer Verlag; 2014 [cited 2020 Jun 29]. p. 1289–302. Available from: /pmc/articles/PMC7088122/?report=abstract
- Kanauchi O, Andoh A, AbuBakar S, Yamamoto N. Probiotics and Paraprobiotics in Viral Infection: Clinical Application and Effects on the Innate and Acquired Immune Systems. Curr Pharm Des [Internet]. 2018 Jan 18 [cited 2020 Jun 26];24(6):710. Available from: /pmc/articles/PMC6006794/?report=abstract
- King S, Glanville J, Sanders ME, Fitzgerald A, Varley D. Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: A systematic review and meta-analysis. Br J Nutr. 2014 Jul 14;112(1):41–54.
- Timmerman HM, Koning CJM, Mulder L, Rombouts FM, Beynen AC. Monostrain, multistrain and multispecies probiotics – A comparison of functionality and efficacy [Internet]. Vol. 96, International Journal of Food Microbiology. Int J Food Microbiol; 2004 [cited 2020 Jun 23]. p. 219–33. Available from: https://pubmed.ncbi.nlm.nih.gov/15454313/