Targeting microbial biofilms by probiotics. Probiotics employ different mechanisms by which interfere with the activity of pathogenic bacteria. They produce antagonistic substances such as, surfactants, bacteriocins, EPS, organic acids, lactic acid, fatty acids, enzymes (lipase, amylase) and hydrogen peroxide that can hinder the activity of pathogenic bacteria and their adhesion to surfaces. Moreover, they prevent QS, biofilm formation and the survival of pathogens as well as interfere with biofilm integrity/quality, finally, lead to biofilm eradication. Furthermore, probiotics generate unfavorable environmental conditions for pathogens (e.g., pH alteration as well as competition for surface and nutrients). Their competitive adhesion to human tissues or medical devices (catheters, prostheses, or other medical devices), prevent the colonization of harmful bacteria. Additionally, by modulating host immune responses and formation of non-pathogenic biofilms, they target pathogenic biofilms that prevent the biofilms formation by certain pathogenic bacteria.
Abbreviations: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; EPS, extracellular polymeric substance; QS, quorum sensing; UTI, urinary tract infection.
The probiotic strains can be isolated from numerous sources such as human, animal, plant, environment and foods.18,19 Then, they can be identified and characterized by microbiological, biochemical and molecular-based techniques. Streptococcus salivarius, S. oralis, L. rhamnosus, L. fermentum, L. plantarum L. casei, L. acidophilus, L. brevis, L. sporogenes, L. salivarius, L. delbrueckii, L. pentosus, Bifidobacterium lactis and B. longum are the most reported probiotic strains that exert anti-biofilm activity (Tables 1 and and22).
Several in vitro biofilm models have been developed by attaching bacteria on adhesive surfaces.20 All of these models lack features of the host immune competence and environment. So, animal models take into account since it is practically impossible to study the development of infectious diseases in humans (reviewed comprehensively in Ref ). MRSA mouse model22 and rabbit model of ischaemic and infected wounds were developed. Moreover, a removable in vivo abutments was developed that mimicked dental implants. To address in vitro and in vivo problems, a novel human plasma biofilm model was developed for studding the impact of probiotics on pathogens that mimicked a biofilm-challenged human wound milieu.
Probiotic Products Against the Different Pathogenic Biofilms
Lactobacillus species produce different exometabolites such as EPSs, bacteriocins, oxygen reactive species (ROS) and biosurfactants with anti-biofilm activity. The polysaccharides produced by LAB possess anti-biofilm, immune system stimulatory and antioxidant effects. The EPS of Lactobacillus spp. was effective in both Gram-positive (e.g., Listeria monocytogenes and S. aureus) and Gram-negative (e.g., P. aeruginosa and Salmonella typhymurium) bacteria. The results displayed that the biofilm removal ability is related to EPS concentration.
The anti-biofilm activity of bacteriocins has been demonstrated in different reports. L. brevis DF01 bacteriocin prevents biofilm formation but does not eradicate the established Escherichia coli and S. typhimurium biofilms.32 The mechanisms of biofilm inhibitory effects of bacteriocin are not well understood. Some of the bacteriocins eradicate biofilm by the induction of pore-formation on the bacterial cell surface, leading to ATP efflux, while some others have biological activity by proteolytic enzymes.33 Subtilosin A, a cyclic bacteriocin (lantibiotic protein) synthesized by Bacillus subtilis, is another derivative of probiotics. It has a net cationic charge that generally targets the surface receptors rather than binding to bacterial cells electrostatically. Beside the antimicrobial activity of subtilosin against Gardnerella vaginalis and L. monocytogenes, its anti-biofilm effect was reported against G. vaginalis alone and with natural antimicrobial agents. Given the wide-ranging activities of subtilosin, Chikindas et al observed its anti-QS effect in E. coli O157:H7, L. monocytogenes ScottA and G. vaginalis ATCC 14018. Subtilosin led to the inhibition of 60% of E. coli, 80% of L. monocytogenes and 90% of G. vaginalis biofilms.37 Likewise, sonorensin, a bacteriocin produced by Bacillus sonorensis MT, was able to decrease S. aureus biofilms cell viability, inhibit biofilm attachment and formation, and cause the thinning of mature biofilms.
Due to exometabolites formation, Lactobacillus species also inhibit Candida albicans biofilm by inhibiting the initial stage of colonization and hypha formation.39 Lactobacilli that produce biosurfactant had antimicrobial, anti-adhesive properties and aggregation ability against pathogenic biofilm formation.40 L. rhamnosus producing biosurfactants could disrupt the physical membrane structure or protein conformations; resulting in cell lysis.41 Furthermore, biosurfactants significantly decrease the adhesion and biofilm generation of bacteria in a dose-dependent manner.28
Probiotics Influence Gene Expression of Pathogenic Biofilms
The mechanism by which probiotics prevent the biofilms formation is fairly unclear. Several in vitro studies have shown that the expression of genes involved in cell adhesion, QS, virulence factors and biofilm formation can be influenced by probiotics. Wasfi and coworkers assessed the Lactobacillus spp. effect on the gene expression of S. mutans in a co-cultured condition. They focused on genes involved in EPSs formation (gtfB, sacB (ftf), gtfC and gtfD), signal transduction systems (vicR, comC, vicK and comD) and stress survival (atpD and aguD). Results revealed that there was an overall significant decrease in the expression of these genes among different groups, in both biofilm-forming and planktonic cells. Additionally, by producing organic acid and peroxide, probiotics led to a decline in cell adherence and preformed biofilm. Moreover, EPS produced by L. acidophilus A4 considerably could inhibit biofilm formation of E. coli O157: H7 by reducing the expression of genes related to chemotaxis (cheY) and curli formation (csgA, csgB and crl).29 Burton et al clarified a mechanism of biofilm inhibition of C. albicans using the combination of L. plantarum SD5870, Streptococcus salivarius DSM 14685 and L. helveticus CBS N116411. The expression of some C. albicans genes such as ALS3 (adhesin/invasin), HWP1 (a critical hyphal wall protein for biofilm formation), EFG1 (hyphae-specific gene activator) and SAP5 (secreted protease) are affected by these probiotics. The results showed that these probiotics are effective in inhibiting the biofilm formation and also removing of the preformed biofilms of C. albicans. Therefore, it is rational to claim that probiotics and their derivatives can be used as both prophylactic and treatment biodrugs.
Some probiotics have also inhibitory effects on QS systems that inhibit the QS-dependent physiologic behaviors of bacteria.44 Lactic acid produced by probiotics had shown an inhibitory effect on QS by suppressing short-chain AHL production and biofilm formation of P. aeruginosa that is regulated by QS.44 Probiotics also secret organic acid as QS antagonists that interfere with AHLs production at the gene expression level and prevent biofilm formation.45
Biosurfactants isolated from L. plantarum and Pediococcus acidilactici could inhibit the adhesion and biofilm formation of S.aureus CMCC 26003 in a dose-dependent manner in vitro. The molecular mechanism of biosurfactants is mediated by affecting the expression of biofilm-related (cidA, sarA, icaA, dltB, sortaseA, and agrA) genes and interfering with the release of signaling molecules (AI-2) in QS systems.28 Similarly, S. mutans produce extracellular glucans by glucosyltransferases (gtfs) that are vital for the initiation and progression of dental caries. Biosurfactant produced by L. fermentum could decrease the S. mutans gtfB/C gene expression, the process of attachment and biofilm formation.
Probiotics Modulate the Host Immune Responses to the Biofilms
The host immune responses against biofilms are mediated by various cellular receptors, chemokine and cytokine expression, that can be different based on the stage of biofilm. Probiotics and their secreted soluble factors are speculated to be recognized by the toll-like receptors (TLRs) on epithelial cells; and thereafter exert their immunomodulatory effects on intestinal and systemic immunities.48 Moreover, probiotics can modify innate immune functionality in different ways, some of which include the secretion of immunomodulatory metabolites, lipids and proteins, receptor expression, micro-RNAs induction and production of negative regulatory signaling molecules. Therefore, by modulating the immune responses, probiotics can impact biofilms indirectly. Streptococcus thermophilus strains (ST1342, ST1275, and ST285) can activate monocyte cells to secret IL-1β, TNFα, IL-6 and IFN-γ that activate the innate immune responses in order to eliminate pathogens. Strain ST1342 could induce high levels of IL-1β secretion that has both anti–viral and anti-bacterial activities.50 Likewise, it was mentioned that the probiotic L. paracasei DG utilized generally in commercial probiotic products, possess immune-stimulatory activities by enhancing of TNFα, IL-6 and CCL20 expression in the human monocyte leukemia cell line.51 Lactobacillus sp. could induce IFN‐γ production and inhibit IL‐10 production and exert immunomodulatory effect on S. mutans in human-cultured cells. Detailed knowledge of the immune mechanisms, the cytokine and receptor expression profiles and bacterial defense mechanisms under biofilm formation is needed for demonstrating the effects of probiotics on the immune system to fight against microbial biofilm.
Probiotic Biofilms Against Pathogenic Biofilm
The formation of biofilm by probiotics is considered to be a beneficial strategy against pathogenic biofilms since they compete with pathogens for nutrients and space with different mechanisms of action. Moreover, probiotic biofilms can stimulate the colonization and longer stability of probiotics in the host mucosa that prohibit colonization of pathogenic bacteria. Only some of Lactobacillus strains such as L. reuteri, L. rhamnosus, L. fermentum and L. plantarum can form biofilm on abiotic surfaces (glass or polystyrene). The EPS production by some biofilm-former probiotics can prevent the biofilms formation of certain pathogenic bacteria.
In line with this subject, Gómez and coworkers tested the protective effect of biofilms with bacteriocinogenic (L. curvatus MBSa3, L. sakei MBSa1, L. lactis VB94 and L. lactis VB69) and non-bacteriocinogenic (Weissela viridescens 113, L. helveticus 354, L. lactis 368, and L. casei 40) lactic acid bacteria to fight against E. coli O157:H7, Salmonella typhimurium and L. monocytogenes. Results show a prevention in biofilm formation of these pathogenic bacteria in 24, 48 and 72h of exposure.60 Moreover, biofilms of probiotic E. coli Nissle 1917 on silicone substrates could decrease the colonization of the pathogenic E. faecalis 210.61 Likewise, L. kunkeei biofilm reduces the infection of P. aeruginosa by affecting biofilm formation and/or their stability.62 Furthermore, biofilms of probiotic formed by Bifidobacterium infantis and L. reuteri can be utilized as efficient bacteria to delay the L. monocytogenes growth.18
L. brevis 104/37, L. plantarum 118/37 and 6E could effectively eradicate staphylococcal biofilms. Yet, only L. rhamnosus ATCC 7469 and L. plantarum 2/37 could form their own biofilms to replace with the pathogenic ones. Additionally, the L. plantarum WCFS1 and NA7 biofilms produce extracellular molecules with immunomodulatory and growth inhibitory properties against food pathogens (S. aureus, E. coli O157:H7, L. monocytogenes, and Salmonella enterica). All the studied Lactobacillus strains had an anti–inflammatory effect in the in vitro, while just L. fermentum NA4 displayed a protective effect in vivo. Hence, Lactobacillus in biofilm status exerts beneficial probiotic properties in a strain-dependent manner.64 The progress of the new technologies for the encapsulation of biofilms that covers in the double coated capsules has developed a new generation of probiotics. L. rhamnosus GG microcapsules, as effective inhibitors of transcriptional activators of the luxS QS system, could prevent biofilm formation and disturb the mature biofilms.
Biofilm infection therapy has been a complex challenge for clinicians. Better understanding and hacking into bacterial biofilms help scientists develop robust strategies. Recently, the immune system and probiotics relationships have been reported in defending the host against the colonization of pathogenic species. In fact, probiotics yield different compounds, ranging from peroxides and fatty acids to highly specific bacteriocins, to kill or hinder pathogenic bacteria. Recently, clinical trials and in vitro studies have provided evidence on the impact of the probiotics on different medical fields (wound, oral, intestinal and vaginal infections) to fight against pathogenic biofilms via a counteraction, competition and gene silencing of pathogenic factors. All data together signify a great ability of probiotics to be used both in prevention and treatment of pathogenic biofilm infections.
In fact, in vitro studies on adhesion, the secretion of extracellular anti-biofilm factors, metabolic activity, the growth inhibition, co-aggregation, the prevention of biofilm formation and the eradication of mature biofilm have recommended possible roles for probiotic in modifying the biofilms microbial ecology. On the other hand, biofilm-forming probiotic strains can exchange resident biofilm pathogens with a non-pathogenic variant that produce bacteriocin;40 however, their molecular mechanisms have been poorly examined.
Challenges with the Management of Biofilms by Probiotics
Data demonstrate that probiotics and their derived-products can be hopeful strategy to manage biofilms. It should be noticed that data are still scarce and there is not enough evidence to consider probiotics as bio-drugs to inhibit pathogenic biofilm formation and/or disperse pre-formed biofilms. Confounding results may be related to the diversity in delivery vehicle, dose, assessment of efficacy and viability, and particularly to the variability in selection of strains. It has been revealed that the impacts of probiotics are strains-specific, different strains of even one probiotic species can present an altered impact on the host and pathogenic biofilm since the host molecular signaling reprogramming extremely tend to depend on the bacterial strain and cell context. No two probiotics look like each other and different strains may exert different effects. Additionally, under various circumstances, even the same strains may function differently. Therefore, an ideal strain of probiotic for interfering and competing with pathogenic biofilms should be screened and identified at the molecular level for specific pathophysiological states, particularly in the context of definite infection and microbial targets.
Additionally, characterization and evaluation of safety aspects (blood hemolytic activity and resistance to antibiotics) of strains should be performed before their clinical administration. The essential criteria for selection of potential probiotic strains are proposed to be their adhesion to epithelial cells and mucus along with their co-aggregation with pathogens.66 Furthermore, other criteria including potential antimicrobial activity against pathogens, survival in the human GI conditions and inhibition of colon cancer define a strain as a probiotic. Moreover, their viability and stability during production and storage processing are also important issues in the clinical application of probiotics. Resistance in probiotics has been a focus of researchers. A major concern in this area would be the increased risk of transferable drug resistance(s) genes from probiotics to other bacterial population.67 Therefore, it is essential to assess their non-transferable or transferable antibiotic resistance at the genome level. It seems that the use of cell-free supernatants of probiotics can address most of the aforementioned concerns.
Getting reliable enough in vivo and human study results are needed for transferring this treatment strategy in human subjects. In the near future, it would be quite possible to employ the probiotics or their products to develop an innovative safe therapy for biofilm-related infection.
This work was financially supported by the Kidney Research Center at Tabriz University of Medical Sciences, Tabriz, Iran (IR.TBZMED.REC.1398.080). The authors wish to express their gratitude to Fatemeh Zununi Vahed for her kind assistance. Keyvan Kheyrolahzadeh and Seyed Mahdi Hosseiniyan Khatibi should be considered first coauthors.
All of the authors declare that there are no personal, commercial, political, and any other potential conflicting interests related to the published paper.
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