New insights into the bioactivity of peptides from probiotics
Probiotics are unique bacteria that offer several therapeutic benefits to human beings when administered in optimum amounts. Probiotics are able to produce antimicrobial substances, which stimulate the body’s immune responses. Here, we review in detail the anti-infective peptides derived from probiotics and their potential immunomodulatory and anti-inflammatory activities, including a major role in cross-talk between probiotics and gut microbiota under adverse conditions. Insights from the engineered cell surface of probiotics may provide novel anti-infective therapy by heterologous expression of receptor peptides of bacterial toxins. It may be possible to use antigenic peptides from viral pathogens as live vaccines. Another possibility is to generate antiviral peptides that bind directly to virus particles, while some peptides exert anti-inflammatory and anticancer effects. Some extracellular polymeric substances might serve as anti-infective peptides. These avenues of treatment have remained largely unexplored to date, despite their potential in generating powerful anti-inflammatory and anti-infective products.
Probiotics, Anti-Infective Peptides, Heterologous Expression, Bacterial Surface Engineered, Review
It is universally accepted that some antimicrobial peptides, such as bacteriocins, which are derived from lactic acid bacteria (LAB), may be a potential food preservative as they inhibit target organisms. The application of bacteriocins and their effectiveness has been described in detail in several review articles, and their synthesis and mode of action are also well described (1-4). The application of antimicrobial/anti-infective peptides depends upon the chemical composition of peptides and types of host (5).
Dynamic applications of probiotics has been extensively explored in conferring several health benefits, such as maintaining gut homeostasis, reducing inflammation, improving immunity, as well as antibacterial, antiviral and anticancer properties. Indeed, it has been noted that extracellular peptides produced by probiotics are important in controlling a number of acute or chronic infections.
The perception of peptide promiscuity, where multiple functions are associated with a single peptide, is currently gaining ground (6). For example, endogenous anti-infective peptides, derived from potential probiotics, have also been reported to serve as immunomodulators of the cellular immune response. Strategies like re-engineering of the probiotic cell surface with heterologous expression of new sugars and proteins are necessary to increase the viability and stability of anti-infective peptides derived from probiotics in the gut.
Furthermore, self-assembling strategies are important phenomena that may stabilize the peptide molecules in harsh conditions like high salt and acidic environment. In the self-assembling strategy, several weak interactions between molecules or atoms forming a complex supramolecular architecture may play a fundamental role (7). This binding has a strong dependency on balancing the forces of attraction and repulsion between the molecular building blocks that form supramolecular structures (8,9). These non-covalent bonds, including Van der Waals, electrostatic and hydrophobic interactions, as well as hydrogen and coordinate bonds, are formed between the assembled molecules and the substrate surface, and also between the molecules in the adjacent layers.
With the advances in peptide research, novel strategies may thus evolve to make them stable for longer periods. Attempts have also been made to design and develop potential receptors for bacterial exotoxin(s), such as cholera toxin and shigella toxin, among many others (10). Instead of binding to the target region of epithelial cells, exotoxin(s) with the respective receptor peptide(s) may be captured. Thus, probiotics are very promising in therapeutic applications with re-engineered anti-infective peptides.
3. Gut homeostasis
The human gastro-intestinal tract (GIT)consists of a complex community of microorganisms with highest density of natural bacterial population among other body parts. Bacterial density in the colon ranges from 1011 ml-1 to 1012 ml-1 content (11). The predominant gut bacterial phylotypes belong to two divisions — the Bacteroidetes (48%) and the Firmicutes (51%). The residual phylotypes are distributed among the Proteobacteria, Verrucomicrobia, Fusobacteria, Cyanobacteria, and Spirochaetes (12). Interestingly, the balance between the two major phylotypes, Bacteroidetes and Firmicutes, in the gut bacterial community, influences host health. Shifts or imbalance in the composition of the two are associated with multiple pathogeneses, including diabetes, obesity, bowel diseases, chronic inflammation and gastrointestinal cancer, as well as stress and autism. Such imbalances are often brought about by diet or usage of antimicrobials.
Gut bacteria may also afford an efficient protective barrier against different pathogens, through a phenomenon known as colonization resistance (13). Fulfillment of very important physiological functions like the development of the digestive system, immune system maturation and antigen tolerance are dependent on the interactions between commensal bacterial species and the host (14). Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis (15). In the GIT, certain antimicrobial peptides (AMPs) have been identified as essential molecules for the maintenance of intestinal barrier and immune homeostasis. Most of the human defensin peptides (including cathelicidin, LL-37) are expressed in gut mucosa, such peptides are also known to be expressed in the paneth cells in the small intestine or epithelia of gastrointestinal tissues, stomach, small intestine and colon (16). Some defensin molecules are also released upon proteolytic degradation by enzymes like trypsin, chymotrypsin etc. (18). In addition to these AMPs of human origin found in the GIT, another class of AMPs has been identified as derived from gut microflora. The molecular mechanisms by which the inhabitant microbial community inhibits the development of invading microbes remain obscure, but there is increasing evidence that direct microbe-microbe interactions could play a critical role in this specific process (19).
Gut microbiota have several beneficial aspects to health in different ways but the imbalances in this community, dysbiosis can poses a threat to host health. In this context, probiotics can restore the balance once again. They are produced by bacteria for the fulfillment of the defense mechanism. The common beneficial features of antibacterial peptides include being nontoxic to humans and the possession of specific antibacterial activity. These peptides have recently been extensively used as food preservatives, especially those produced by LABs (18). However, LABs are not the only species of probiotics that produce antimicrobial peptides. There are some other species of Bacillus and Bifidobacteria that are endowed with the same ability to produce AMPs, but two genera, Lactobacillus and Bifidobacteria, constitute the majority of the probiotics (20). Antimicrobial peptides are produced exclusively by probiotics, and so their impact on gut homeostasis is essential in restricting pathogen numbers in the GIT.
4. Evidence of effectiveness
Antibacterial peptides, probiotic characteristics and biopreservative efficacy of Bacillus species have been studied for several years. The antibacterial compounds from B. subtilis and B. licheniformis strains exhibited the highest inhibitory activity against M. luteus ATCC 9341. Peptides whose isolation or synthesis is pH dependent but stable in a wide pH range (4.0.–10.0.) have found applicability in controlling spoilage of diverse acidic or alkaline fermented foods. An example of the commercial use of such peptides is nisin, a bacteriocin that acts in acidic conditions and is practically insoluble at pH 8.0. Since there have been claims that many Bacillus species are probiotic in nature, it is vital to characterize these organisms for their gastrointestinal persistence before they are prescribed as probiotic. To be finally prescribed as a potential probiotic, the bacterial culture must pass the test of tolerance to both acid and bile, which would permit survival and growth in the adverse conditions encountered in the gut, before conferring a beneficial health effect (21). A few Bacillus strains have shown tolerance to a high acidic condition at pH 3.0. Among the strains capable of producing bacteriocins that would have application as a bio-preservative, there are some B. subtilis strains and the Ec1 and lactic acid bacterial (LAB) strains (22).
The majority of bacteriocins have been discovered so far and summarized in the Bactibase database, a few of the representative structures are shown in Figure 1. The antimicrobial activities of bacteriocins E 50–52 and B 602 against antibiotic-resistant strains involved in nosocomial infections were studied in detail (23). The bacteriocin-producing strain, Enterococcus faecium, was isolated from the cecum of a Russian broiler chicken. Synthesis of the matching bacteriocin E 50–52 was accomplished by growing the isolate in Brucella broth at pH 6.8.–7.2. The other bacteriocin, B 602, produced by Paenibacillus polymyxa B 602, was also isolated from a Russian broiler chicken’s cecum. Based on multiple sequence alignment analyses, these peptides were assigned as pediocin-like bacteriocins or class IIa bacteriocins.
Bacteriocins E50–52 and B 602 were shown to possess a wider activity spectrum against both Gram-positive (S. aureus) and Gram-negative bacteria (Acinetobacter baumannii,Citrobacter freundii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus spp.), compared to the previously characterized class IIa bacteriocins. Additionally, the potency of these peptides was tested against 10 MRSA isolates with the MDR phenotype (resistant to several classes of antibiotics, such as beta-lactams (oxacillin), aminoglycosides (gentamicin), fluoroquinolones (ciprofloxacin), tetracyclines (doxycycline), erythromycin, clindamycin, chloramphenicol, and rifampicin). The MRSA isolates were found to be very sensitive to both B 602 (MIC<0.0.2.5. μg/ml) and E 50–52 (MIC ranged from 0.0.5. to 0.2. μg/ml) bacteriocins. The non-fermenting Gram-negative rods, A. baumannii and P. aeruginosa, were also found to be sensitive to B 602 (MIC: 0.0.2.5. µg/ml for A. baumannii; MIC range: 0.1. to 1.6. μg/ml for P. aeruginosa) bacteriocin. The said bacteriocins, B 602 and E 50-52, were also found to be effective against several members of Enterobacteriaceae (E. coli, K. pneumoniae, C. freundii, and Proteus spp.).
In another study, isolated peptides from L. rhamnosus were found capable of inhibiting the growth of a wide range of bacterial pathogens comprising E. coli, E. aerogenes, S. typhi, Shigella sp., P. vulgaris, P. aeruginosa, Serratia marcescens, S. aureus, K. pneumoniae, H. pylori, Campylobacter jejuni, Micrococcus luteus and Listeria monocytogenes (24). Growths of the clinical strains of Candida albicans and S. aureus were found to be inhibited by lectins produced by the probiotic strains of Lactobacillus and Bifidobacterium. It was reported that lectins were effective against nystatin-resistant C. albicans strains of clinical origin. It has been envisaged that the presence of probiotic bacterial lectins results not only in preventing fungal growth in the earlier stage of infection (primary anti-fungal effect) but also in the relatively late stages of biofilm formation and colony lysis phase (secondary or prolonged antifungal effects). Acidic Bifidobacterial lectins were also shown to have antifungal effect at sub-cyto-agglutinating concentrations (from 0.0.1.–0.0.8. μg mL-1) (25).
5. Strategies for re-engineering probiotic surface for anti-infective therapy
Re-engineering the bacterial cell surface via recombinant technology is an acceptable molecular method to re-make far more potent tools for biotechnological or biomedical applications (Figure 2). The plausible cell surface-expressed proteins may have potential application in biotech-based industry, such as immobilized enzyme(s), biocatalysts, biosensors, and biosorptive materials; and in the biomedical sector they can be a good candidate for vaccine development or anti-cancer agents (26). In the process of vaccine development, the pathogen-associated antigenic part is required to develop the adaptive immune response in the cell. Hence, the expression of a pathogen-associated antigen on the cell surface of probiotics, with the aid of recombinant DNA technology, is important to improve immunogenicity. It is known that surface expression of proteins produces a multivalent display of antigens and so can be easily cross-linked to B-cell receptors (27). Surface-engineered probiotic cells open up a novel opportunity for delivery along with inactivated bacterium in different food grades or as a live bacterial vector. Recombinant live probiotics expressing a pathogen-associated antigen may lead to the generation of antigens at the mucosal level, which will in turn greatly influence delivery to the APC (28).
Moreover, several probiotics are also capable of producing antiviral peptides. For example,the bacteriocin subtilosin, the antimicrobial peptide produced by Bacillus amyloliquefaciens, has shown remarkable activity against Herpes simplex virus type 1 (HSV-1) (29). There are several possibilities for probiotics to act as antiviral agents through different modes of action. Generally, probiotic bacteria inhibit virus attachment by directly binding to the host cell receptors. When probiotics adhere to the epithelial surface blocking the viral attachment, they may also induce intestinal production of mucins. Mucins in turn interfere with the viral adherence to epithelial cells by neutralizing the viruses. All these cellular phenomena may finally activate CD8+ T lymphocytes to destroy virus-infected cells. Thus, the use of probiotics in antiviral therapy would be of intense interest.
Probiotics are gaining high-priority status and importance due to their tremendous beneficial effects on health and disease management. The claims are substantiated by various scientific reports resulting from clinical trials since 1999 (30). Antimicrobial peptides derived from probiotics in the GIT can diffuse through the mucus layer that finally triggers the immune cells. It was found that Bifidobacterium in the colon has the properties to mitigate inflammatory bowel disease, rheumatoid arthritis or lupus, irritable bowel syndrome, and infections by enteropathogens (31,32). The molecular signals generated from probiotics have the ability to activate several genetic cascades which modulate the expression level and make necessary physiological changes. These signals are relayed to the nucleus receptor through different pathways by means of mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI-3K), and glycogen synthase kinase-3 (GSK-3) (33).
The mining of information with respect to cellular receptors, which are responsible for the recognition of antimicrobial peptides derived from probiotic bacteria, is still inadequate. It can be imagined that AMPs may be acquainted with the Toll-like receptors (34,35) because TLR-2 is responsible for recognizing different lipoproteins (36); presumably, peptides derived from probiotics would also follow a similar recognition process. This speculation has been strengthened by a recent report which mentioned the possibility of the C-type lectin receptor (CLR) of dendritic cells (DCs) and macrophages recognizing several compounds of probiotic bacteria (37). However, future studies are indispensable to shed more exact light on the correct pathway for the involvement of other receptors specific to AMP.
Probiotics have proved their successful use in the treatment of inflammatory bowel disease and acute diarrhea. GIT associated diseases, such as inflammatory bowel disease (IBD) and chronic relapsing inflammatory disorders occur from the convergence of several reasons, including genetic, immunological, microbial, and environmental factors. The definite role of the gut microbiome in the etiopathogenesis of such diseases has been elucidated from data emanating from a number of clinical and genetic experiments. While all humans host many species of microorganisms, each human host has a unique make-up of these microorganisms. As a result of this diversity, different humans may respond differently to diseases and treatments. Since every individual has his or her unique background, designing a treatment contingent with probiotics may require different permutations of strains of probiotics, nutrients and nutritional supplements or a combination of the above with other medications or treatments, such as antibiotics or chemotherapy.
Novel opportunities, leading to finding effector molecules capable of eliciting definite responses in the human intestine, have been provided in the post-genomic era. With such advances it would be possible in the near future to define causes of IBD conditions and improve therapy by personalized intervention to restore the proper gut microbiome. Bacteria from the infected gut of an individual can be cultured and enriched with bacteria constituting a healthy microbiome (38). Such an enriched culture used for therapy may be more effective than probiotics administered according to the one-size-fits-all concept. Hence, in the context of recent knowledge, management of the gut microbiome by probiotics or a mixed culture of useful bacteria is becoming a pragmatic strategy in therapeutics and prophylactics to counter many infectious and inflammatory diseases within the gut.
|Lactobacillus sakei||Sakacin G||Anti-listerial||39|
|Lactobacillus rhamnosus||Lactocin 160||Gardnerella vaginalis||40|
|Streptococcus salivarius K 12||Salivaricin A and salivaricin B||Infections of the human oral cavity||41|
|Enterococcus faecium||Bacteriocin E 50–52 and bacteriocinB 602||Multi-drug resistant nosocomial infections||42|
|Lactobacillus johnsonii||Peptide extract||Helicobacter pylori||43|
|Lactobacillus casei||Peptide extract||Helicobacter pylori||44|
|Lactobacillus gasseri||Peptide extract||Helicobacter pylori||45|
|Lactobacillus acidophilus||Peptide extract||Helicobacter pylori||46|
|Lactobacillus amylovorus||Peptide extract||Helicobacter pylori||47|
|Bifidobacterium longumsubsp. longum||Serpin(AAN23973)||Inhibition of pancreatic and neutrophil elastases||48|
|B. longumsubsp. infantis||CHWPR peptide||Anti-inflammatory and decreases the colonic permeability in IL-10-deficient mice||49|
|B. breve||Unidentified proteins||Prolonged survival and maturation of DCs; increased IL-10 and IL-12 production by DCs||50|
|L. rhamnosusGG||NPSRQERR and PDENK||Antimicrobial activity||51|
|L. acidophilusPZ 1138,L. fermentumPZ 1162||Unidentified secreted proteins||Induction of hBD2 production in epithelial cells||49|
|L. plantarum,L. acidophilus,L. caseiand L.delbrueckiisubsp. bulgaricus||Unidentified secreted proteins||Induction of mucin secretion||47|
|L. rhamnosusGG||Unidentified secreted proteins||Increase of the production of HSP25 and HSP72 in YAMC cells||52|
|L. acidophilusand L. rhamnosus||Unidentified secreted proteins||Increase of the chloride/hydroxyl exchange activity in Caco-2 cells||53|
|L. rhamnosusGG||p40(homologous to gi|116493594)||Growth promotion||54|
|L. rhamnosusGG||p75(homologous to gi|116493849)||Reduction of the injuries caused by TNF-α; attenuation of the TER decrease induced by hydrogen peroxide||55|
|L. rhamnosusGG||Supernatant containing P40 and p75||Decrease of IL-8 production in epithelial cells||54|
|L. acidophilus NCFM||SlpA(YP_193101.1.)||Induction of IL-10 production in DCs; DCimmunomodulation||54|
|Lactococcus Lactis||Pediocin PA-1 and Lactococcin A||Antimicrobial/antifungal||55|
|Lactobacillus plantarum||Unknown||Rotaviral Infection/induces endotoxin tolerance capacity||56|
|L.acidophilus, B. adolescentis, B. bifidum||Acidic and basic lectins||Candida albicans and Staphylococcusaureus||57|
|Bifidobacterium sp.||Peptides||Helicobacter pylori||58|
|L. rhamnosus||Peptides||Escherichia coli, Enterobacter aerogenes, Salmonella typhi, Shigella sp., Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcusaureus, Klebsiella pneumoniae, Helicobacter pylori, Campylobacter jejuni, Micrococcus luteus and Listeria monocytogenes||54|
|Lactococcus lactis subsp. cremoris||Nisin||L. monocytogenes and S. aureus||59|
|Lactococcus lactis GI3||Lactocin GI3||L. monocytogenes and S. aureus||60|
|Lactococcus lactis BFE||Nisin-like bacteriocin||L. monocytogenes and S. aureus||59|
|Lactobacillus curvatus LTH||Pediocin A||L. monocytogenes and S. aureus||60|
|Lactobacillus acidophilus LF221||Curvacin A||L. monocytogenes and S. aureus||61|
|Lactobacillus bavaricus MN||Bavaricin MN||L. monocytogenes and S. aureus||62|
Owing to the colonizing nature of probiotics in the GIT, they can be an effective tool in biotechnological applications. Antimicrobial peptides originating from different sources have been well studied on the basis of their structure-function relationship. Probiotics are the most important flora in the human gut, and several beneficial aspects have been tested, ranging from in vitro studies to clinical trials. However, the enumeration of the total molecules of probiotics has not been presented yet, particularly for anti-infective peptides derived from probiotics with multifunctional activities (Figure 3). Molecular information from synthesis to heterologous expression is inadequate. The signaling mechanisms and physiological changes induced by antimicrobial peptides in host cells are not well described. In the light of this discussion, a combined and urgent drive is required from researchers in diverse disciplines to design protocols to use probiotics successfully for sustainable health. Moreover, chemically and genetically re-engineered probiotics will serve as a novel tool in modern biomedical technology.
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