Abstract
Application of the latest approaches and protocols in probiotic research has resulted in significant advances over the last decade. These refer almost exclusively to the design of probiotic dairy products, mainly through the design of the probiotic culture incorporated. Several protocols have been developed for the assessment of probiotic potential through omic approaches, and many more are currently under development. In addition, through the improvement of our knowledge regarding the mechanisms that lead to infections and disorders, the genetic engineering of probiotic strains aiming at the delivery of bioactive molecules to specific cites was made possible. All these indicate that we are entering an exciting new era with great expectations.
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Introduction
The probiotic concept is one of the favorites among the researchers due to the width of the topic and the importance for health and well-being. Dairy products are the main vehicle for probiotic delivery worldwide, with several other products considered for this scope including fermented meat products, fruits, and vegetables (Montoro et al. 2016; Park and Jeong 2016; Neffe-Skocinska et al. 2017). A large number of these are already available in the market.
Recent advances, especially in the field of molecular biology , have allowed several improvements to take place. From a production point of view, innovations have occurred in the field of design of a probiotic product. Manufacture of a probiotic product essentially involves three steps: (a) selection of the starter culture, which is based on the ability to reach a specific niche within the gastrointestinal track of the host, colonize it, and confer the probiotic action; (b) technological evaluation of the starter culture, which is based on the ability of the starter culture to propagate at industrial level and retain viability and functionality after a series of processing steps; and (c) incorporation into the product, a probiotic culture may be incorporated as a starter or an adjunct culture.
Research in recent years has focused on the design of starter cultures . This can take place either by evaluating the potential of wild isolates or by engineering heavily studied strains. In the first case, the genetic background of many desired properties has been identified allowing the evaluation of the probiotic potential to take place through genetic determinants. On the other hand, improvements in the understanding of the mechanisms leading to infections and disorders have allowed the genetic engineering of probiotic strains for the delivery of specific bioactive molecules with prophylactic and/or therapeutic function. In the succeeding sections, recent advances in the field of probiotic product design are presented and critically discussed.
Probiotic Culture Selection
Culture selection involves the assessment of a culture’s safety, efficiency to reach the colonization site, and probiotic potential, considering the possible health benefits exerted to the consumer. These functions are currently predicted almost exclusively through in vitro tests. Recent advances in the field of molecular biology have allowed the prediction of these properties through the application of omic approaches.
Safety was traditionally assessed through hemolytic activity, antibiotic resistance, as well as production of enzymes (e.g., hyaluronidase, gelatinase), toxins (e.g., cytolysin), and biogenic amines. In the latter years, safety assessment is usually performed through the detection of the respective genes (e.g., cylA/B encoding cytolysins, hyl encoding hyaluronidase, gelE encoding gelatinase, tet(M), tet(K), and tet(W) responsible for tetracycline resistance, etc.) along with several virulence-associated ones. Especially regarding the latter, detection of agg (aggregation protein), esp (enterococcal surface protein), asa1 (aggregation substance), ace (collagen protein adhesin), and efaA fs (cell wall adhesin) is more often (Perumal and Venkatesan 2017; Hwanhlem et al. 2017; Motahari et al. 2017; Ojekunle et al. 2017; Guo et al. 2017; Rzepkowska et al. in press).
Efficiency to reach the colonization site is predicted through the ability to survive the stresses faced within the host and colonization potential. In the case of the former, ability to maintain high populations after exposure to pH values ranging from one to three in the presence of pepsin (simulating gastric juice conditions) and alkaline pH values in the presence of bile salts and pancreatin (simulating intestinal juice conditions) is the criterion applied more often. Colonization potential is predicted mostly through the assessment of cell surface hydrophobicity, cellular autoaggregation ability, binding to solubilized collagen, human or animal mucus, and adhesion to various cell lines, mostly Caco-2 and HT29. The disadvantages of in vitro testing were addressed with the use of animal models. However, in that case, other restrictions are introduced, including ethical ones, depending on the type of animal model (Yadav et al. 2017). Although the genome of several lactic acid bacteria species has been described, markers of probiotic features have been detected (Abriouel et al. 2017), and survival mechanisms and strategies to adhere to surfaces have been described (Bove et al. 2012; Arena et al. 2017), no omic approach has been utilized yet as an indicator. However, prediction through in silico models has been performed (Lee et al. 2000).
The desired functional properties of a probiotic culture are constantly updated; they include antagonistic activity against potentially pathogenic microorganisms, particularly invasive Gram-negative pathogens, as well as a series of assets that are beneficial to the host. The latter may either have prophylactic or therapeutic character (Varankovich et al. 2015). A wealth of literature is currently available on that subject and includes both tentative and demonstrated positive effects. In general, the health benefits that have been claimed include modulation of immune responses, protection of the function of the mucosal barrier, reduction of cholesterol levels, anticancer activity, as well as activity against gastrointestinal diseases.
The modulation of immune responses by probiotic cultures refers to the ability of the host to distinguish between the beneficial and pathogenic microorganisms through immune tolerance/hyporesponsiveness and humoral and cell-mediated immune mechanisms, respectively. The mechanisms through which the selective response is activated have been critically presented and discussed by Hardy et al. (2013). The term intestinal or mucosal barrier refers to the physical and immunological barrier that separates the luminal contents and the interstitial tissue and prevents the diffusion of factors that may affect negatively the host (Hardy et al. 2013; Rao and Samak 2013). The epithelial monolayer constitutes the physical barrier, while mucus, protease-resistant IgA, and antimicrobial peptides constitute the immunological. Both barriers are positively affected by the function of probiotics. More accurately, probiotics have been reported to upregulate the expression of the epithelial growth factor (EGF-R) and the pattern recognition receptor (TLR-2) (Resta-Lenert and Barrett 2003; Cario et al. 2004) along with the production of MUC2 and MUC3 intestinal mucins, TGFβ, IL-6 and IL-10 (Rodrigues et al. 2000; Rautava et al. 2006; He et al. 2007; Shang et al. 2008). These functions may be assessed through a variety of phenotypic assays that have been recently reviewed by Papadimitriou et al. (2015).
Interestingly, the interaction with the host may take place even in a probiotic culture viability-independent manner through the activation of responses upon recognition of specific bacterial components or metabolites (Adams 2010). Indeed, inactivated whole cells of Lactobacillus casei strain Shirota upregulated IL-12, IL-10, and IL-2 and inhibited the production of IgE, IgG1, IL-4, IL-5, IL-6, and IL-13, while TNFα and TNFγ provided with a mixed response (Matsuzaki and Chin 2000; Cross et al. 2004; Lim et al. 2009). There is currently a wealth of literature on the effect of inactivated whole cells, cell wall components, lipoteichoic acids, and even genomic DNA of a wide range of probiotic and potential probiotic cultures on the immune response of mouse and human cells, cell lines, and macrophages as measured by indicators such as interleukins (such as IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13), factors (such as TGF-β andTNF-α), and immunoglobulins (such as IgA, IgE, and IgG1) (Lammers et al. 2003; Matsuguchi et al. 2003; Shida et al. 2006; Mastrangeli et al. 2009; Kaji et al. 2010; Jensen et al. 2010; van Hoffen et al. 2010). These studies and many more along with a discussion on the possible mode of action have been comprehensively reviewed by Taverniti and Guglielmetti (2011). These functions indicate the efficacy of ghost probiotics and highlight the need for reassessment of the whole probiotic concept, including nomenclature.
Anticancer activity has been attributed to a series of actions including decomposition of carcinogenic compounds, production of compounds with anticarcinogenic activity, inhibition of cancer cell proliferation, and induction of apoptosis as well as modification of the composition and metabolic activity of intestinal microbiota.
Prevention of colorectal cancer (CRC) through probiotics has been extensively studied (dos Reis et al. 2017). Each of the aforementioned parameters plays its own role in the decrease of the colorectal cancer risk. Maintenance of a healthy intestinal microbiota reduces the risk of CRC both directly and through immumodulation. Moreover, reduction of β-glucuronidase and nitrate reductase activities by the intestinal biota has been proposed as a possible mechanism for the reduction of the production of metabolites that have been associated with the development of CRC (Hatakka et al. 2008; Mohania et al. 2013; Verma and Shukla 2013; Zhu et al. 2013). Increase in the production of anti-inflammatory cytokines, with a parallel decrease in the production of pro-inflammatory ones (Koboziev et al. 2013; Zhu et al. 2013) along with the production of short-chain fatty acids and conjugated linoleic acid, as well as compounds with established carcinogenic activity from probiotics or potential probiotic bacteria have been shown to reduce colorectal cancer risk (Ewaschuk et al. 2006; Hosseini et al. 2011; Bassaganya-Riera et al. 2012; Kumar et al. 2012; Vipperla and O’Keefe 2012; Serban 2014).
The use of probiotics has been proved beneficial against a series of gastrointestinal tract (GIT) disorders including infectious, antibiotic-associated, and travelers’diarrhea (Sullivan and Nord 2005; McFarland 2007; Preidis et al. 2011; Girardin and Seidman 2011; Maziade et al. 2013; Patro-Golab et al. 2015; Szajewska and Kolodziej 2015a, b; Lau and Chamberlain 2016), irritable bowel syndrome (O’Mahony et al. 2005; Whorwell et al. 2006; Lorenzo-Zuniga et al. 2014; Yoon et al. 2014), pouchitis (Turroni et al. 2010; Shen et al. 2014; Tomasz et al. 2014), and H. pylori infection (Mukai et al. 2002; Tong et al. 2007; Dore et al. 2015; Holz et al. 2015; Szajewska et al. 2015). Specific effects on each of the aforementioned along with the respective mode of action have been recently presented by Domingo (2017).
Cholesterol-reducing capacity of probiotics has been repeatedly exhibited and recently reviewed by Ishimwe et al. (2015). A series of mechanisms have been proposed including enzymatic deconjugation of bile, coprecipitation of cholesterol with deconjugated bile, binding to probiotic cell surface, and conversion to coprostanolin that is excreted in feces (Daliri and Lee 2015).
The above mentioned functions have been studied in depth and known to influence the choice of probiotic cultures. Despite the fact that several mechanisms of action have been described, no omic approach has been yet applied for their prediction.
Technological Evaluation of Probiotic Cultures
Evaluation of a strain’s capacity from a technological point of view is very often neglected. However, the ability to reach high population during industrial production scale, capacity to withstand processing such as drying or freezing, and the ability to remain viable and retain functionality during food processing and storage are crucial and strain-dependent properties.
Industrial-scale biomass production takes place in bioreactors whose capacity may reach several hundred liters. Specific attention should be paid to the nutrient content, pH value, dissolved oxygen, and temperature that very often compromise scale-up of biomass production.
Preservation of Probiotic Cultures
Freezing or drying is the processes most commonly applied for the preservation of probiotic cultures. Regarding the former, the rate of temperature decrease is the most crucial factor. High rate creates small ice crystals evenly distributed that minimizes the damage caused by mechanical or osmotic stresses during both freezing and thawing. However, drying is the most commonly process of choice for culture preservation because it may facilitate stability and shelf-life of the culture and on the other hand reduce the logistics costs. Among the drying techniques, spray-drying is most commonly applied in the case of dairy products (Huang et al. 2017). The factors that affect culture viability include the inlet temperature that may be as high as 200 °C (Silva et al. 2002, 2005), the dehydration itself, and the subsequent storage conditions. The strategy most commonly applied to improve viability is the use of appropriate growth conditions before drying and the addition of protective molecules, such as skim milk, polydextrose, inulin, etc. These factors along with many more have been critically discussed by Silva et al. (2011). In general, resistance to the stresses inflicted by spray-drying, namely, heat and osmotic, seems to be a strain-dependent property. However, there are reports stating that Propionibacterium spp. are usually more resistant than Bifidobacterium spp., Lactobacillus spp., and Lactococcus spp. (Schuck et al. 2013; Huang et al. 2016), Streptococcus spp. than Lactobacillus spp. (Bielecka and Majkowska 2000; Kumar and Mishra 2004; Wang et al. 2004), and Bifidobacterium longum than B. infantis (Lian et al. 2002). Omic approaches for the prediction of tolerance are possible to occur in the near future since a series of genes involved in the adaptation to these conditions, such as the clp and opu genes, have been described, and their effect on survival is already known (Zotta et al. 2017).
Survival of Probiotic Cultures During Storage
Another aspect that has been extensively studied is the survival of the probiotic cultures during storage of the product in which they have been incorporated as a starter or an adjunct culture. It has been reported that factors such as pH value, concentration of organic acids, type and concentration of other ingredients, and storage temperatures may significantly affect the viability of the probiotic cultures (Donkor et al. 2007). Viability during storage of dairy products has been given much consideration. Enrichment of yoghurt with whey proteins (Marafon et al. 2011), flavoring agents (Vinderola et al. 2002), fruit pulps (Kailasapathy et al. 2008; El-Nagga and Abd El–tawab 2012), cereals (Coda et al. 2012; Zare et al. 2012), lactulose (Oliveira et al. 2011), or inulin (Bozanic et al. 2001; Donkor et al. 2007) either had no negative effect or resulted in the enhancement of the survival of the respective probiotic culture that has been incorporated. However, there are also several reports in the literature that claim the exact opposite, i.e., the decrease of the viability (Ranadheera et al. 2012; Bedani et al. 2014) leading to the conclusion that this property is strain-dependent. The viability during production and storage of a variety of cheeses including Feta (Mazinani et al. 2016), soft goat (Radulovic et al. in press), Italico (Blaiotta et al. 2017), Pecorino Siciliano (Pino et al. 2017), white brined (Liu et al. 2017), Minas (Buriti et al. 2007), and Cheddar (Phillips et al. 2006) has also been assessed confirming that cheese is the best product for probiotic delivery and leading to the basic conclusion that this property is strain-dependent. However, due to the complexity of the microecosystem, and the number of genes involved, an omic approach to predict such a virtue is not expected to occur soon.
Genetic Engineering of Probiotic Strains
An alternative approach to the selection procedure is to provide the probiotic culture with the desired properties through bioengineering. These properties may extend from enhanced tolerance to the GIT or technologically relevant conditions to the improvement of the functionality within the host. The rationale behind the use of bioengineering is to address the limitations of the cultures currently characterized as probiotics or potential probiotics. However, there are certain concerns regarding the use of genetically modified organisms in general that are discussed at the end of this paragraph. In the succeeding paragraphs, the most characteristic studies involving genetic engineering of probiotics or potential probiotics are presented aiming to depict the possibilities offered by genetic engineering.
otsB, the gene encoding for trehalose-6-phosphate phosphatase originating from Propionibacterium freudenreichii strain B365, was expressed in Lactococcus lactis strain MG1363 in order to provide with trehalose synthesis capacity (Carvalho et al. 2011). Then, strains with the ability to produce trehalose exhibited improved tolerance to acid, cold and heat shocks. On the contrary, no improvement in the viability upon exposure to freeze-drying was observed. However, a nearly 100% viability after freeze-drying was reported for the same strain containing atsBA genes originating from E. coli DH5a (Termont et al. 2006). In addition, improved tolerance to gastric juice as well as resistance to bile was reported. This enhanced tolerance did not interfere with IL-10 secretion by the same strain (Steidler et al. 2000). Lc. lactis strain MG1363 was also used by Bermudez-Humaran et al. (2015) to construct recombinant strains able to secrete cytokines (IL-10 or TGF-β1) and serine protease inhibitors (Elafin or Secretory Leukocyte Protease Inhibitor , SLPI). Then, a DSS-induced murine colitis model (C57BL/6 mice) was used to evaluate the effect after oral administration of the recombinant strains. Significant reduction of the inflammation was observed as an effect of the serine protease inhibitors. On the contrary, only moderate anti-inflammatory effect was recorded when IL-10 or TGF-β1 expressing recombinant strains were administered. In addition, overproduction of Elafin obtained by inactivation of HtrA resulted in enhanced reduction of the inflammation indicating dose dependence.
A recombinant strain based on a Lb. paracasei strain able to produce Listeria adhesion protein was constructed by Koo et al. (2012) in order to outcompete Listeria monocytogenes in adhesion, transepithelial translocation, and cytotoxicity in Caco-2 cells. In addition, several wild-type bacteria with probiotic potential were also examined for the same capacity. The latter failed to prevent L. monocytogenes infection. On the contrary , the recombinant strain managed to reduce L. monocytogenes translocation by 46% after 24 h and cytotoxicity by 99.8% after 1 h.
Focareta et al. (2006) engineered E. coli strain DH5a to express glycosyltransferase genes from Neisseria gonorrhoeae and Campylobacter jejuni . The aim was to produce a mimic of the ganglioside GM1 receptor and inactivate in situ the cholera toxin. Indeed, administration of the construct significantly protected 3-day-old Swiss mice against fatal challenge with Vibrio cholerae . Another approach was employed by Duan and March (2008, 2010). They constructed a strain based on E. coli Nissle 1917 able to express cholera autoinducer 1 and studied the effect on V. cholerae colonization and virulence gene expression. Regarding the latter, downregulation of virulence gene expression in Caco-2 cells was reported. Furthermore, pretreatment of 2–3-day-old CD-1 mice with the recombinant strain resulted in 69% reduction of the V. cholerae intestinal population after 40 h and 80% reduction of the cholera toxin intestinal binding after 8 h.
Volzing et al. (2013) constructed a recombinant Lc. lactis strain able to produce Alyteserin-1a and A3APO, two peptides with antimicrobial activity against both Gram-positive and Gram-negative species. The recombinant strains effectively inhibited growth of E. coli and Salmonella strains in vitro providing with promising results, necessitating further in situ study. Lc. lactis was also used to create a recombinant strain expressing Tcd-AC and Tcd-BC, two fragments of the cytotoxins A (TdcA) and B (TcdB) produced by Clostridium difficile (Guo et al. 2015). Purified fragments or the recombinant strain was orally administered to 5–6-week-old pathogen-free C57BL6 mice that were subsequently challenged with Cl. difficile. The vaccinated mice exhibited significantly lower mortalities due to the higher IgG and IgA titers.
The construction of a recombinant Lb. acidophilus strain able to produce K99 fimbrial protein was reported by Chu et al. (2005). The strain effectively inhibited binding of enterotoxigenic E. coli to intestinal epithelium of pigs exhibiting dose-dependence. Similarly, a recombinant Lc. lactis strain able to produce a surface-associated flagellin after induction with nisin for 6 h was reported by Sanchez et al. (2011). The recombinant strain was able to outcompete E. coli and Salmonella enterica strains to adhesion to mucin-coated polystyrene plates.
Apart from the above mentioned approaches, probiotics have been extensively studied as a vehicle for the targeted delivery of bioactive molecules for prevention and/or treatment of various diseases. Among the most characteristic studies performed so far are the following. Ma et al. (2014) reported the construction of a recombinant Lc. lactis strain expressing HSP65 with tandem repeats of P277 that was able to combat the onset of diabetes mellitus type 1. Oral administration of the recombinant strain in non obese diabetic mice resulted in reduced insulitis, improved glucose tolerance, and ultimately prevented hyperglycemia.
Antitumor activity of probiotic bacteria has also been considered to some extend with promising results. The study of Wei et al. (2016) is characteristic of the potential applications. In that study, a B. longum strain was engineered to produce tumstatin, an effective angiostatin that inhibits proliferation and induces apoptosis of tumorous endothelial cells. The in situ effectiveness of this approach was examined after intragastric administration of the recombinant strain to tumor-bearing mice. The antitumor effects recorded were significant and very promising for further study.
Finally, Chamcha et al. (2015) reported the construction of a Lc. lactis-based strain able to produce HIV-1 Gag-p24 antigen. The aim was to induce HIV-specific immune responses in BALB/c mice and achieve immunity. Indeed, a strong humoral and cellular immunity against HIV was obtained through oral administration of the recombinant strain in which the antigen was expressed on the tip of Group A Streptococcus pilus.
The aforementioned approach, although promising, still requires the use of genetically modified organisms (GMOs) for which there are certain concerns. These concerns may result from predicted (Stemke 2004) or unpredicted functions (Hill Jr. et al. 1993). However, there are approaches that may lead to the improvement of the potential probiotic cultures without the need of genetic modification. Such an improvement may occur mainly through directed evolution and dominant selection (Derkx et al. 2014). These approaches may not lead to the development of strains with the improved or targeted health benefits described above, but may result in enhanced resistance to certain stresses and out-competition of pathogens. Such phenotypes may be obtained through adaptation to specific adverse conditions. However, adaptation is only temporary and is still under debate whether it is possible to inflict permanent changes without any change in the genetic material. Epigenetics may provide with a solution, but further study is still necessary to detect and understand the mechanisms involved. Moreover, such an approach requires high level of expertise, time, and effort with safety assessment being still a prerequisite for industrial use.
Conclusions and Future Perspectives
A series of exciting advances in the design of probiotic products have taken place over the last decade. The majority of them refer to the selection of the most appropriate strains, regarding the desired properties or the approach used for their assessment. In parallel, strains with probiotic properties, referring at least to their ability to reach the colonization niche within the host, have been used in genetic engineering studies for targeted delivery of bioactive molecules aiming at the treatment and/or prevention of infections and diseases. The number of such studies is expected to increase within the next few years enriching the selection criteria for the characterization of potential probiotic strains. Moreover, it is very likely that meta-transcriptomic approaches will find their way into the in situ assessment of the GIT microecology and the effect of the probiotic strains.
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Paramithiotis, S., Drosinos, E.H. (2018). Probiotic Dairy Products: Inventions Toward Ultramodern Production. In: Panda, S., Shetty, P. (eds) Innovations in Technologies for Fermented Food and Beverage Industries. Food Microbiology and Food Safety. Springer, Cham. https://doi.org/10.1007/978-3-319-74820-7_8
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