key: cord-265729-prgj36g0
authors: Lehtoranta, L.; Pitkäranta, A.; Korpela, R.
title: Probiotics in respiratory virus infections
date: 2014-03-18
journal: Eur J Clin Microbiol Infect Dis
DOI: 10.1007/s10096-014-2086-y
sha: 
doc_id: 265729
cord_uid: prgj36g0

Viral respiratory infections are the most common diseases in humans. A large range of etiologic agents challenge the development of efficient therapies. Research suggests that probiotics are able to decrease the risk or duration of respiratory infection symptoms. However, the antiviral mechanisms of probiotics are unclear. The purpose of this paper is to review the current knowledge on the effects of probiotics on respiratory virus infections and to provide insights on the possible antiviral mechanisms of probiotics. A PubMed and Scopus database search was performed up to January 2014 using appropriate search terms on probiotic and respiratory virus infections in cell models, in animal models, and in humans, and reviewed for their relevance. Altogether, thirty-three clinical trials were reviewed. The studies varied highly in study design, outcome measures, probiotics, dose, and matrices used. Twenty-eight trials reported that probiotics had beneficial effects in the outcome of respiratory tract infections (RTIs) and five showed no clear benefit. Only eight studies reported investigating viral etiology from the respiratory tract, and one of these reported a significant decrease in viral load. Based on experimental studies, probiotics may exert antiviral effects directly in probiotic–virus interaction or via stimulation of the immune system. Although probiotics seem to be beneficial in respiratory illnesses, the role of probiotics on specific viruses has not been investigated sufficiently. Due to the lack of confirmatory studies and varied data available, more randomized, double-blind, and placebo-controlled trials in different age populations investigating probiotic dose response, comparing probiotic strains/genera, and elucidating the antiviral effect mechanisms are necessary.

Respiratory tract infections (RTIs) are a major cause of morbidity and mortality worldwide. Viral pathogens are the most common etiological agents of acute respiratory disease. The social and economic impact of viral respiratory disease is substantial, due to hospitalizations, medical costs, missed work, and school and day care absences. For instance, estimates show that viral respiratory tract illnesses (mostly common colds) cost US$40 billion annually in the United States alone [1] .

There are over 200 different types of viruses which cause RTIs in humans. Human rhinoviruses (HRV) are the largest group of respiratory viruses, comprising over 150 serotypes [2] . In humans, the predominant illness caused by HRV is the acute upper RTI, also known as the common cold. The second most common viruses infecting humans are the human enteroviruses (HEV), which are associated with clinical manifestations ranging from mild respiratory symptoms to serious conditions [2] . Influenza viruses, respiratory syncytial virus (RSV), and adenoviruses are also major causative agents of both upper and lower RTIs [3] [4] [5] . In addition, many other viruses or virus groups cause RTIs, e.g., parainfluenza viruses and coronaviruses can cause a broad spectrum of respiratory diseases, ranging from mild upper RTIs to pneumonia [6] . In recent years, with the rapid development of high-throughput molecular techniques, several new viruses associated with respiratory diseases, such as human bocavirus, human metapneumovirus, and the new coronaviruses HKU1 and NL63, have been identified as well [7] .

The prevention of viral respiratory infections is an important challenge to public health. Currently, the only effective antivirals and vaccines for the prevention and treatment of respiratory virus infections are available against influenza viruses and adenoviruses. For the viruses causing common cold (HRV, HEV), no effective therapies are available. Large varieties of etiologic agents and increasing antibiotic and antiviral resistance challenge the development of efficient therapies. Consequently, it is of importance to find alternative and safe ways to reduce the risk of these infections. Even partially effective therapy in the treatment and prevention of viral RTIs such as the common cold could have an impact on reducing morbidity and economic losses due to this illness.

Probiotics are defined as live microorganisms that confer a health benefit on the host [8] . The most common types of microbes used as probiotics are lactobacilli and bifidobacteria, which are generally consumed as part of fermented foods, such as yoghurts or dietary supplements. Criteria for probiotic bacteria include that the bacterial strain: (1) must be able to survive in the gastrointestinal tract and to proliferate in the gut; (2) should exert benefits to the host through growth and/or activity in the human body; (3) should be non-pathogenic and non-toxic; (4) provide protection against pathogenic microorganisms by means of multiple mechanisms; and (5) should be lacking transferable antibiotic resistance [9] . Different bacterial strains of the same genus and species, verified also by genomic information, may exert completely different effects on the host.

The most promising health effects of probiotics in human intervention studies include the amelioration of acute diarrhea in children, relief of children's milk allergy/atopic dermatitis, and relief of irritable bowel syndrome [10, 11] . Probiotics are likely to have an impact through gut mucosa by balancing the local microbiota by inhibiting the growth of pathogenic microorganisms [12] , and by enhancing local and systemic immune responses [13] . They may also influence the composition and activity of microbiota in the intestinal contents. Considering the beneficial effects of probiotics in virus infections, specific probiotics have been suggested to be effective in alleviating the duration and severity of acute rotavirus gastroenteritis [14] . In addition, increasing evidence shows that probiotics are beneficial in RTIs [15] , which, in most cases, are of viral origin. However, the mechanisms behind these effects are largely unknown.

The aim of this review is to present the current knowledge of the health effects of probiotics on RTIs in humans, with a focus on viral respiratory infections. In addition, possible antiviral mechanisms of probiotics are discussed in context with studies conducted in vitro and in animal models.

A PubMed and Scopus database search was performed up to January 2014 to review the relevant literature investigating the effects of probiotics on respiratory virus infections in cell culture, animal models, and clinical trials. The following search terms were used individually and in combination: ' probiotic' , ' Lactobacillus' , ' Bif idobacterium' , 'Lactococcus', 'respiratory infection', 'respiratory virus', and 'influenza virus'.

Animal experiments provide insight on the clinical effects of probiotics against respiratory virus infections ( 

Children Altogether, five clinical trials have been conducted in children using L. rhamnosus GG as a probiotic [42] [43] [44] [45] [46] . In healthy children attending day care, L. rhamnosus GG reduced the number of children experiencing RTIs [42, 43] , the number of upper and lower RTIs [43] , and the number of antibiotic treatments or absences from day care [42] . In another study, no differences were reported between the L. rhamnosus GG and the control groups in the number of antibiotic treatments or respiratory symptom episodes [47] . However, in a subgroup with L. rhamnosus GG identification in feces, L. rhamnosus GG usage reduced the duration of RTIs. In hospitalized children, L. rhamnosus GG reduced the risk of RTIs and duration of RTI episodes [42] . In preterm infants, L. rhamnosus GG reduced the incidence of RTIs [46] . In addition, a meta-analysis of four randomized controlled trials investigating the role of L. rhamnosus GG in the prevention of respiratory infections in children showed that L. rhamnosus GG has the potential to reduce the risk of upper RTIs, incidence of acute otitis media, and antibiotic use. There were no significant differences between the L. rhamnosus GG and the control groups in the incidence of lower RTIs [48] .

There are seven studies conducted with probiotic bacteria other than L. rhamnosus GG. L. casei rhamnosus in children reduced the number of RTIs [49] . Also, L. casei DN114001 reduced the incidence rate for upper RTIs43 and decreased the duration (days) and incidence of only lower RTIs, but not upper RTIs [50] . L. fermentum CECT5716 with prebiotics in infants, however, reduced the incidence of both upper and lower RTIs [51] . The use of B. animalis ssp. lactis Bb12 in healthy newborns was able to reduce the number of RTIs as well, but was ineffective in reducing the occurrence of acute otitis media (AOM) or symptoms of otitis media [52] . In healthy infants, treatment with L. reuteri SD112, but not with B. animalis ssp. lactis Bb12, resulted in fewer days of absence from day care due to illness, lower number of days with fever, and clinical visits. Both strains were ineffective in reducing the incidence or duration of RTIs [53, 54] . In healthy children, L. casei CRL431 or L. reuteri DSM17938 did not reduce the incidence, number, or duration of acute RTIs or RTI episodes [55] .

The effectiveness of several combinations of probiotics on RTIs has been investigated in four clinical trials. A combination of L. rhamnosus GG, L. rhamnosus Lc705, B. breve Bb99, and P. freudenreichii ssp. shermanii JS in otitis-prone children [56] or a combination of L. rhamnosus GG and B. animalis ssp. lactis Bb12 in healthy newborns [57] both reduced the occurrence of recurrent RTIs, but not the incidence of AOM. A combination of L. acidophilus and B. bifidum in healthy children reduced the duration of acute RTI symptoms, school absence, and the risk of upper RTI symptoms as well [58] . However, a combination of 12 bacteria including species of Lactobacillus, Bifidobacterium, Streptococcus, and Enterococcus was not able to reduce the number of RTIs [49] .

The viral etiologies of RTIs were investigated in only five studies. In preterm infants, L. rhamnosus GG decreased the incidence of rhinovirus-induced episodes, but not rhinovirus load [46] . In otitis-prone children, a combination of L. rhamnosus GG, L. rhamnosus Lc705, B. breve Bb99, and P. freudenreichii ssp. shermanii JS reduced human bocavirus load in the nasopharynx [59] , but not picornaviruses [60] . In healthy children attending day care, L. rhamnosus GG was not able to decrease significantly respiratory viruses (HRV, HEV, influenza viruses, parainfluenza viruses, RSV, adenovirus, and human bocavirus) in the upper respiratory tract [47] . Healthy children receiving L. casei rhamnosus had significantly lower odds of viral infection diagnosed by a doctor and a significant difference in doctor-diagnosed RTI. However, specific viruses were not reported in that study [49] .

Probiotics' effectiveness in RTIs has been addressed in 13 studies in healthy adults, in athletes, and in individuals under stressful conditions. In healthy adults, L. fermentum CETC5716 reduced the number of RTIs and increased antigen-specific IgA formation after influenza virus vaccination [61] . In addition, a combination of L. gasseri PA16/8, B. longum SP07/3, and B. bifidum MF20/5 reduced the duration of RTI symptoms [62] , duration of RTI episodes [63, 64] , but not the severity of RTI symptoms [63, 64] . None of these trials reported the effects of combinations on respiratory virus load, although their viral etiology was studied. B. animalis ssp. lactis Bl-04 reduced the risk of an upper RTI episode [65] . A combination of L. rhamnosus GG and B. animalis ssp. lactis Bb12 reduced both the duration of upper RTI and the severity of RTI symptoms [66] .

Altogether, seven trials have been conducted among athletes or stressed individuals, but they did not report studying the viral etiology. In male elite distance runners, L. fermentum VRI003 reduced the duration of RTI symptoms, but not the incidence of RTIs or the severity of symptoms [67] . In competitive cyclists, L. fermentum (PCC) had some decreasing effects on the symptoms of upper RTI in males, but not in females [68] . In rugby union players [69] , a combination of L. gasseri, B. bifidum, and B. longum reduced the incidence of upper RTIs, but not the severity of symptoms. However, in marathon runners, L. rhamnosus GG did not decrease the number of RTI episodes or the severity or the duration of RTI symptoms [70] . In addition, in commando trainers, L. casei DN114001 was ineffective in reducing the incidence of RTIs or RTI symptoms [62] [63] [64] 71] . Similarly, L. salivarius did not lower the number of RTI episodes or reduce the severity or the duration of RTI symptoms in trainers [72] . However, in shift workers, L. casei DN114001 reduced the number of RTIs and increased the function of immune cell activity [73] .

Only five studies have investigated the effects of probiotics on RTIs, but not on the occurrence of specific viruses, in the elderly. L. casei DN114001 decreased the duration of RTIs [74, 75] , but had no effect on the incidence of RTIs [74] . L. casei Shirota did not have an effect on the number of upper RTIs or the severity of upper RTI symptoms, but probiotics decreased the duration of upper RTIs [76] . However, in another study, L. casei Shirota had no effect on the duration of RTI symptoms [77] . A combination of L. rhamnosus GG, L. rhamnosus Lc705, B. breve Bb99, and P. freudenreichii ssp. shermanii JS was ineffective in lowering the number of RTIs and reducing the duration of RTI symptoms. However, the combination reduced the duration of RTI episodes [60] .

The clinical trials in children, adults, and the elderly presented in this review are summarized in Table 2 . A variety of probiotic strains have been used in these clinical trials, most of them belonging to the genus Lactobacillus. In addition, various combinations of probiotics have been used. Of 33 studies, altogether, 28 studies reported that probiotics had beneficial effects in the outcome of RTIs and five showed no clear benefit. Only eight studies, however, reported investigating the viral etiology. Of these, only one study showed a statistically significant reduction in the virus load in the probiotic group. A Cochrane systematic review by Hao et al. concluded that probiotics were better than placebo in terms of reducing the number of upper RTI episodes, the incidence of acute upper RTI episodes, and antibiotics used [15] . Although clinical trials show that the use of specific probiotics and probiotic combinations are beneficial in RTIs, there are also studies that report no clear advantage. In addition, several viruses can cause respiratory illnesses, but only a few studies have investigated probiotics' effectiveness on viral agents. The lack of consistent evidence between probiotic strains/genera and even within strains may be due to variation in study designs and reported outcome measures, the length of intervention, study populations used (children vs. adults) or bacterial doses (10 6 -10 10 cfu), and matrices (milk, yoghurt, capsule) used. In addition, in the elderly, decreased immunity due to aging may partly explain the conflicting results [79] .

Clinical and animal studies have demonstrated that specific probiotics have antiviral effects, but the underlying mechanisms are unclear. Additionally, the strain-to-strain variation may be relatively large concerning strain properties and efficacy. Possible antiviral mechanisms of probiotics include: (1) hindering the adsorption and (2) cell internalization of the virus; (3) production of metabolites and substances with a direct antiviral effect; and 4) crosstalk (immunomodulation) with the cells in establishing the antiviral protection. The possible mechanisms of probiotics against respiratory viruses are presented in Fig. 1 .

The respiratory tract is covered by mucosal epithelial surfaces, which are constantly exposed to numerous microorganisms and serve as primary ports of entry for respiratory viruses. Virus attachment to a host cell is the first essential step in the disease process, and, therefore, interruption of this attachment could be beneficial to the host. Probiotic bacteria may bind directly to the virus and inhibit virus attachment to the host cell receptor. For instance, there is evidence that specific strains of lactobacilli are able to bind and inactivate vesicular stomatitis virus (flu-like virus) in vitro [81] . Probiotics may also show direct antimicrobial activity against pathogens by producing antimicrobial substances such as organic acids, hydrogen peroxide, biosurfactants, and bacteriocins [12] . In experimental studies in epithelial cells and macrophages, metabolic products of specific lactobacilli and bifidobacteria prevented vesicular stomatitis virus infection in a strain-specific manner [81] . In addition, metabolites of bacteria in yoghurts showed antiviral activity, inhibiting influenza virus replication [82] . The induction of low-level synthesis of nitric oxide may also be involved in the protective actions of probiotics against viruses in the respiratory cells, as shown in alveolar macrophages in vitro [27, 83, 84] . However, it should be noted that respiratory viruses infect cells with different mechanisms by using various receptors and, also, the antiviral effects of probiotics are strain-specific.

The induction of antiviral cytokines such as interferons (IFNs), as well as proinflammatory cytokines and chemokines, upon antigen recognition in epithelial cells or underlying effector cells [macrophages, dendritic cells (DCs), neutrophils] play a key role in virus infections by initiating cell-mediated viral elimination and adaptive immune responses. Probiotics may mediate their antiviral effects against respiratory viruses possibly by eliciting systemic immune responses via gut or enhancing cellular immunity in the airways with increased activity of natural killer cells and macrophages. In the gut epithelial cells and/or antigen-presenting cells, probiotics are recognized by toll-like receptors (TLRs) [85] [86] [87] [88] . Probiotics may, therefore, modulate cytokine expression patterns through epithelial cells [89] and through underlying professional antigen-presenting cells, such as macrophages and dendritic cells [90] [91] [92] [93] [94] [95] .

Many experimental studies in vitro and in animals show that specific strains of probiotics are capable of providing protection against virus infections by stimulating antiviral, cytokine, and chemokine responses in the respiratory and gastrointestinal epithelial cells or immune cells. In murine DCs, L. acidophilus NCFM and L. acidophilus X37 induced the expression of viral defense genes (IFN-β, IL-12, IL-10) [96] . In human macrophages, L. rhamnosus Lc705 induced Table 1 summarizes the effects of probiotic bacteria on cell-mediated immunity upon respiratory virus challenge in animal models.

Data from animal studies indicate that strains of lactobacilli and bifidobacteria provide protection against respiratory virus infections also by inducing the synthesis of virus-specific immunoglobulins in the respiratory secretions and in serum [25, 30, 39, 41] . In addition, studies in healthy human subjects suggest that specific probiotics may enhance the immunogenicity of viral vaccines. L. rhamnosus GG was effective in inducing protective immune response against the H3N2 strain in influenza virus vaccine [99] . Moreover, L. fermentum CECT5716 ingestion in adults resulted in lower influenzalike illness, increased proportion of NK cells in blood, significantly higher TNF-α, and increased anti-influenza-specific IgA and IgM after influenza vaccination [61] . The consumption of B. animalis ssp. lactis Bb12 or L. paracasei ssp. paracasei L. casei 431431 also showed significantly greater increase in influenza virus vaccine-specific IgG antibodies in plasma and secretory IgA in saliva [100] . In the elderly, the consumption of fermented yoghurt with L. casei DN-114 001 increased significantly influenza-specific antibody titers after influenza vaccination, especially against influenza B virus [101] . These studies suggest that orally ingested lactobacilli and bifidobacteria have an adjuvant-like effect on the humoral responses.

Probiotics are frequently part of the normal gastrointestinal microbiota, and, therefore, probiotic therapy is generally considered as safe [102] . However, probiotic therapy has raised potential safety concerns, including systemic infections, toxic or metabolic effects on the gastrointestinal tract, and the transfer of antibiotic resistance in the gastrointestinal microbiota [103] . In rare cases, some studies have reported Lactobacillus septicemia in children [104] , in immunocompromised subjects [105] , and detrimental effects in subjects with hepatitis [106] . However, the European Food Safety Authority (EFSA) has concluded that there are no specific safety concerns regarding Lactobacillus, Bifidobacterium, or Propionibacterium strains, as they have a long history of safe use in food [107] . In addition, for instance in Finland, increased consumption of probiotic products containing L. rhamnosus GG has not resulted in a significant increase in Lactobacillus bacteremia [108] and L. rhamnosus GG consumption is regarded as safe in immunocompromised human immunodeficiency virus (HIV)-infected patients [108] . It should be taken into consideration that the safety of probiotics has not been as systematically investigated as in drugs, and the safety evaluation is partly based on long-term experience.

The aim of this review was to summarize the current literature investigating the effects of probiotics in respiratory virus infections in cell models, in animal models, and in humans.

In addition, possible antiviral mechanisms of probiotics in There are also contradictory data on probiotic use in the prevention of RTIs. The variability in the outcomes between clinical trials studying probiotics' role in RTIs may be explained by the use of different probiotic strains, bacterial dose, and matrices. In addition, it should be noted that the effects of probiotics are highly strain-specific and the adequate amount of bacteria transferred into the effector sites in the gut may be crucial. Due to the lack of confirmatory studies and varied data available, more randomized, double-blind, and placebocontrolled clinical trials in different age populations investigating probiotic dose response, comparing probiotic strains, and elucidating the mechanisms of effects are necessary.

As many animal studies show that probiotic administration through the nose is able to reduce viral titers and relieve clinical symptoms, nasal bacteriotherapy for viral RTIs in humans could be worthy approach for consideration in the future. Probiotics' ability to enhance local and systemic innate immunity during virus infection in animal experiments is a likely, yet unverified, effect mechanism behind beneficial effects, and an interesting area of future research. The inclusion of serological and immunological diagnostics, such as the identification of virus-specific immunoglobulins and cytokines, in clinical research would have clear benefits in providing valuable information on the effects of probiotics in respiratory virus infections. 

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