The Battle of Probiotics and Their Derivatives Against Biofilms

The Battle of Probiotics and Their Derivatives Against Biofilms

Authors: Abolfazl Barzegari, Keyvan Kheyrolahzadeh, Seyed Mahdi Hosseiniyan Khatibi, Simin Sharifi, Mohammad Yousef Memar, and Sepideh Zununi Vahed
Published: 2020 Feb 26

Abstract
Biofilm-related infections have been a major clinical problem and include chronic infections, device-related infections and malfunction of medical devices. Since biofilms are not fully available for the human immune system and antibiotics, they are difficult to eradicate and control; therefore, imposing a global threat to human health. There have been avenues to tackle biofilms largely based on the disruption of their adhesion and maturation. Nowadays, the use of probiotics and their derivatives has gained a growing interest in battling against pathogenic biofilms. In the present review, we have a close look at probiotics with the ultimate objective of inhibiting biofilm formation and maturation. Overall, insights into the mechanisms by which probiotics and their derivatives can be used in the management of biofilm infections would be warranted.
Keywords: antibiotic resistance, biofilm, probiotics, lactobacillus, sepsis, infection

Introduction
Biofilms are the aggregates of micro-organisms that are embedded in a self-produced polymeric matrix in a sessile state.1 In the history of microbiology, biofilms have been detected earlier; however, only recently has their clinical burden been fully recognized. According to the National Institutes of Health (NIH), biofilms are involved in approximately 65% and 80% of all microbial and chronic infections, respectively. In the clinic, microbial biofilms through colonization on implants (prosthetic heart valves, catheters and joint replacement) and medical devices, account for hospital-acquired infections that make the patients easily infected by certain pathogens. Moreover, biofilm infections lead to different disorders, for instance, diabetes mellitus, dental caries, medical implants and wound infections that significantly affect the quality of life, cancer development, and subsequently, increase the global morbidity rate.1

Hardly are biofilms detectable with routine diagnostic tests; therefore, the management of their infections are challenging in the clinic.2 Methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus mutans, Pseudomonas aeruginosa, S. epidermidis and Gardnerella vaginalis are the most common biofilm formers in the clinic.3 Different strategies like new generations of antibiotics and the inhibition of biofilm formation by quorum sensing (QS) inhibitors have been developed. Due to the challenges of these therapeutic agents in the clinic, there is a demand for developing new strategies. Recent evidence indicates that one of the strongest options for fighting pathogenic biofilms would be probiotics.

Probiotics are living bacteria that confer a health-related profit to the host when administered in acceptable doses. This action of probiotics is mediated by interacting with host gut microbiota. High-throughput approaches including transcriptomics, metabolomics, proteomics and metagenomics have revealed that probiotics present beneficial for the host and they can modify host mucosal and systemic immune responses and protect the host against pathogens.4 Lactobacillus (lactic Acid Bacteria, LAB) and Bifidobacterium are the most important microbial genera that are generally used in the preparations of probiotics. These strains support a balanced immune function, healthy gut microbiome and improved nutrient absorption and lead to a healthy host.5 They are also capable to potentially modulate the microbial ecology of biofilms by pathogens’ growth inhibition, adhesion and co-aggregation. Furthermore, probiotics exert antimicrobial activities against the gastrointestinal (GI) tract pathogens via declining luminal pH, competing for adhesion sites and nutrients and producing antimicrobial agents such as bacteriocins, hydrogen peroxide and organic acids (Tables 1 and ​and2).2). Based on these properties, probiotics present effectiveness in managing biofilms.

In this review, first, we have an overview on the mechanisms of biofilms formation and approaches for combating biofilms. Then, we highlight the novel probiotic-based progressive strategy to manage the pathogenic biofilms with emphasizing on probiotics’ molecular mechanisms of actions.

Biofilm Formation
A biofilm is an agglomeration of micro-organisms on biotic and abiotic substances.7 The formation of biofilm is not accidently, it is programmed with a complex mechanisms, whereby their lifecycle involves different distinct stages, from bacterial attachment and adherence to maturation and the release of cells from the matrix7,8 (Figure 1). Beyond guarding the bacterial cells, biofilms ease the distribution of antibiotic resistance via stimulating horizontal gene transfer.9 In the course of biofilm formation, various bacterial species display social behaviors and communicate with each other through a quorum sensing (QS) mechanism.10

QS is a bacterial cell-to-cell communication that regulates gene expression coordination and detection of cellular density that is mediated by hormone-like small organic compounds called auto-inducers (AIs). Using these signaling molecules, bacteria collectively regulate the expression of virulence factors, the production of secondary metabolite, biofilm development and communications with host and other microbes based on population density. During the process of QS, signaling molecules bind to new bacterial receptors and lead to the transcription of genes within a single bacterial species and between different bacterial species that enable intraspecies and interspecies communications.

Treatment Strategies for Combating Bacterial Biofilm Infections
Currently, biofilm infection therapy is a complex challenge for clinicians. Antibiotic treatment is insufficient in combating against biofilm-related infections; however, understanding the nature of biofilms helps us support our efforts to fight with biofilm infections. Biofilm treatment can include the elimination of infected foreign bodies, the choice of well-penetrating and sensitive antibiotics, early administration of high dosage antibiotics/combinations and the usage of biofilm dispersal and/or anti-QS agents.11 In the following sections, we have a brief view of the biofilm-battling strategies, then a close look at the impacts of probiotics and their derivatives on biofilms will be discussed.

Prescribing Antibiotics
Different antibiotics like lincosamides, rifamycins, tetracyclines, macrolides, etc. penetrate better than β-lactam, glycopeptides, aminoglycosides and polymyxin into the cells and tissues.11 The combination therapy of antibiotics also is better than antibiotic monotherapy against biofilm infection. Beyond the proper selection of antibiotics, appropriate duration of antibiotic treatment is essential. Despite a superior ability of fluoroquinolones for Gram-negative bacteria and rifampicin for Gram-positive bacteria to counteract biofilms, the entire eradication of biofilm infection is still challenging. Antimicrobial agents used for treatment of infections are not effective on biofilm forming bacteria, since they induce a selective pressure on the pathogens which triggers development of resistance to certain agents.

Suppressing of Quorum Sensing

Targeting the Quorum sensing mechanisms has been a striking strategy to control infection in which bacterial virulence is attenuating to be easily cleared by the host immune system and not to establish an effective infection. Quorum sensing inhibitory compounds are a new generation of antimicrobial agents; however, they have not been largely successful. Several strategies are available to disturb bacterial QS. One of these strategies is the inactivation of LuxR homologs using N-acyl homoserine lactone (AHL) antagonists that competes with the native AHL to bind to the LuxR-type receptor. By inhibiting AHL-binding, the LuxR homolog would not be activated and the expression of virulence factor gets switched off. The suppression of the AHL synthesis is yet another strategy.15 While QS suppression has been studied as novel anti–infective strategy, evidence shows the development of bacterial resistance against QS-suppressing agents.16 In addition, the toxicity of some QS- suppressing compounds, such as nanoparticles, limits their biomedical usage.

Probiotics Fight Against Biofilm Formation
Due to the insufficiency of well-known approaches, the development of novel biofilm-fighting strategies would be valuable in the clinic. Recent evidence indicates that probiotics have opened a new horizon to fight with infectious biofilms. Since probiotics cannot induce the strong selective pressure on resistant isolates than conventional antibiotics and also they are less cytotoxic than QS-suppressing agents, they can be considered as ideal option for new anti–virulence agents. Using different mechanisms, probiotics can hinder the activity of pathogenic bacteria and their adhesion to surfaces. Moreover, they prevent QS, biofilm formation and the survival of biofilm pathogens, interfere with biofilm integrity/quality and finally lead to biofilm eradication

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 [21]). 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.

Future Perspective
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.

Acknowledgments
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.

Disclosure
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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