Applications of Lactic Acid Bacteria: Comparison
Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Assad Moon.

Lactic acid bacteria (LAB) especially Lactobacillus are the vital microbiota of the gut, which is observed as having valuable effects on animals’ and human health. LAB produce lactic acid as the major by-product of carbohydrate degradation and play a significant role in innate immunity enhancement. LAB have significant characteristics to mimic pathogen infections and intrinsically possess adjuvant properties to enhance mucosal immunity. Increasing demand and deliberations are being substantially focused on probiotic organisms that can enhance mucosal immunity against viral diseases. LAB can also strengthen their host’s antiviral defense system by producing antiviral peptides, and releasing metabolites that prevent viral infections and adhesion to mucosal surfaces.

  • lactic acid bacteria
  • exo-polysaccharides
  • mucosal immunity
  • antivirals

1. Introduction

The animal and human body carry a variety of microorganisms, which are collectively referred as microbiota. The term ‘gut microbiota’ describes the collection of microorganisms colonizing the gastrointestinal tract (GIT). All of the microbes of the enteric microbiota often have a symbiotic correlation with their host, providing nutrients and protection from invading pathogenic organisms. However, opportunistic enteric pathogens can also be present in the enteric microbiota. These microorganisms cause infections when the host is immunocompromised [1]. Probiotics, which are living microorganisms, have a positive impact on the host by re-establishing the gut microbiota when taken orally in appropriate amounts; meanwhile, synergistic combinations of probiotics and prebiotics are called synbiotics [2]. The animal and human mucosal surfaces are exposed to various pathogens that cause diseases. So, prevention of the pathogen’s entry onto the mucosal surfaces is critical for disease prevention. Probiotics such as lactic acid bacteria (LAB) prohibit the entry of viruses and other pathogens and significantly benefit animal and human health [3].
Depending on the characteristics of bacteria, LAB are Gram-positive, non-motile, non-spore-forming, generally rods or cocci, and have a strong tolerance to low pH, are facultative anaerobic except Bifidobacteria, which are obligatory anaerobes, and catalase-negative organisms that produce lactic acid by the degradative metabolism of carbohydrates [4]. LAB have been classified into more than 60 genera, most of which are used as probiotics, including Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Streptococcus, Enterococcus, and Weissella, and phylogenetic classes such as Bacillus, Clostridia, Enterococcus, Streptococcus, and Mollicutes [2,5,6][2][5][6]. As probiotics are essential for a good and healthy life, LAB may have many beneficial effects by improving the intestinal microbiota balance [7,8,9,10][7][8][9][10].
Many LAB strains have been identified as possessing multifunctional characteristics such as high fermentation capability and can modulate the immune system against invading pathogens [11]. Most of the LAB species are considered probiotics; however, some of the LAB species, such as Streptococcus mutans, are serious pathogens of periodontal-associated diseases such as dental caries. It is also responsible for infective endocarditis (IE), which primarily occurs in cases with underlying heart disease [12,13][12][13]. The immunomodulatory effects and escalation of mucosal immunity by LAB may be accomplished by generating more mucin in the mucosa, developing a biofilm to mask the receptors for the attachment of viruses, and the activation of dendritic cells (DCs) [14]. Along with these events, the production of cytokines such as interleukin (IL)-6, IL-12, and gamma interferon (IFN-γ) and the activation of natural killer (NK) cells are responsible for the clearance of pathogens [14].

2. LAB as Immunomodulators and Mucosal Immunity Enhancers

The immune system, which consists of the acquired and innate immune systems, works to neutralize invading viruses and other pathogens. Researchers reported that DCs play an important role in bridging innate and adaptive antiviral immunity. Numerous viruses are continually attacking the body. Epithelial surfaces, such as the skin and the mucosal linings of the digestive, respiratory, and urogenital tracts, which are home to DCs, are the first line of defense against pathogens, especially viruses [15]. When these barriers are breached, pathogens are captured by DCs, which are activated and attach to lymphoid organs where the proper specialized immune responses are initiated [15]. Mucosal immunity is the capacity to induce the protective immune response within mucosae where pathogens enter and initiate infections [16,17][16][17]. Animals and humans could initiate both systemic and mucosal immunity by recognizing pathogens as foreign objects for their neutralization. The difference between mucosal immunity and systemic immunity is the production of secretory immunoglobulin IgA (sIgA) which is more resistant to protease enzymes [18,19][18][19]. For protective mucosal immunity, participation of all kinds of mucosal immune cells are necessary for producing protective IgA antibodies. This process can be divided into entrance sites, where the pathogens adhere to the mucosal surface, and effector sites, where the plasma cells make antibodies that trigger a local immune response, as shown in Figure 1 [16,20][16][20].
Figure 1. Effect of orally administered LAB on activation of gut-induced mucosal immunity.
The LAB strains significantly impact on the process of DCs’ activation and the subsequent immunological responses. It has been demonstrated that murine DCs can respond differently depending on the strain of LAB, and this is exacerbated further by the fact that these responses can vary even amongst DC subtypes [21,22,23][21][22][23]. It has been reported that Lactobacillus modulates the maturation and function of DCs, macrophages, and CD4+FoxP3+ regulatory T cells (Tregs) as well as the differentiation of CD4+CD8+ and CD4+FoxP3+ T cells in Peyer’s patches (PPs) [24,25][24][25]. The counterattack of pathogens is carried out by specialized DCs of mucosa in the mesenteric lymph nodes also called membrane-associated lymphoid tissues (MALTs). These lymphoid tissues are located beneath the mucosal epithelium of the intestine. These MALTs are similar to peripheral lymph nodes with an abundant supply of B cells and M cells for capturing the invading pathogens [26]. LAB could also initiate the cellular response by differentiation of DCs, and production of cytokines, that could favor the differentiation of näive T cells into Tregs, which are a specialized T cell subpopulation with specific regulatory mechanisms that inhibit the core components of adaptive and innate immune responses [27]. Tregs can drive the depression of an excessive response of effector T cells either by Th1, Th2, or Th17 and maintain mucosal immune homeostasis [10]. Differentiated DCs perform a significant role in the triggering of the immune system against challenging viruses by attaching to them. These DCs are mainly located in the MALTs of the mucosal membrane of the intestine along with some draining lymphoid nodes in the mucosal membrane of the gastrointestinal tract. Plasmacytoid DCs (pDCs) and conventional DCs (cDCs) are the types of DCs presenting at the mucosal membrane. The pDCs are less commonly found in the blood circulation, the mucosal membrane of GIT, and the lymphoid tissue that produces IFN-α [28]. The DCs in the mucosal membrane are classified into CX3CR1+CD103+ DCs with fractalkine (FKN) receptors and CX3CR1+ DCs. Among these DCs, CX3CR1+ DCs have long stellate extensions which elongate from epithelial cells to the antigen found in the lumen of the gut and they usually do not migrate to another place. The mucosal immunity is thought to be organized within the MALTs, thus the antigen must be transported from the lumen to the MALTs by DCs for Tregs to initiate the immune response [29]. As a result of priming, a cascade of cytokines such as TGF-β, IL-6, IL-10, IL-12, IL-23, and other molecules are produced. These cytokines started a cascade of other interleukins’ production and priming of T-helper cells to produce Th1, Th2, Th17, and other T regulatory cells for the neutralization of invading pathogens [30]. Gut microbiota dysbiosis increases the susceptibility of an individual to various diseases. Emerging evidence suggests that LAB are beneficial for the control of RV and SARS-CoV-2 infections. Probiotics are known for restoring stable gut microbiota through the interactions and coordination of the intestinal innate and adaptive immunity [31]. The researchers have reported on the effective protection of LAB against gastrointestinal viruses that originated from clinical cases in humans [32]. The activation of antiviral peptides and the production of mucin by intestinal epithelial cells, and the activation of the local innate immune system lead to an increase in sIgA antibodies for neutralization of the challenge [32]. RV infection deteriorates the mucosal barrier of the GIT [33]. In the clinical cases of RV infection, when Lacticaseibacillus rhamnosus GG (LGG) is administered orally, it could prohibit diarrhea caused by RV infection by mucosal immunity enhancement [33]. The treated cases of LGG reduced the adverse effects of RV on the barrier function in the GIT of piglets, improved relatively the intestinal microbiota, lowered autophagy, increased apoptosis of epithelial cells in the ileum, and retarded the viral multiplication in the intestinal epithelial cells (IECs) [33,34][33][34]. It has also been shown that combinations of probiotics and immunization work together to effectively change the gut microbiota. An oral RV vaccine’s immunogenicity is increased by Lactobacillus acidophilus, which also improves the production of IgG and IgA antibodies. Probiotics such as Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 also modulate dendritic cell responses via distinct Toll-like receptor (TLR) signaling, and function as immunostimulants for the RV vaccine [31]. LAB given orally travel down into the intestinal tract surviving through the stomach and are entrapped in the mucus layer secreted in the villi of the small intestine. Lactobacilli from enteric cells could come into contact with the mucosal epithelium. IgA that is secreted by sensed plasma cells in the epithelial membrane is secreted via the IgA receptor into the gut lumen and could be a superintended factor in bacterial presence. Pathogens that come in contact with the apical surface of the mucosal membrane might be sensed by DCs that can capture the viruses by entailment through their protrusions between enterocytes without breaching the integrity of the epithelial layer. The PPs found in the enteric wall are major contact sites where pathogens and antigens are prone to attach to enteric cells. M-cells in the epithelium transport pathogens present inside the lumen to the membrane-associated lymphoid tissue (MALTs) where pathogens are neutralized. DCs that are present in the area of the PPs can uptake and phagocytose viruses and transport them to the MALTs, where they can directly modulate immune responses that are activated by the potential pathogens.

3. LAB as Antivirals

The animal and human mucosa are exposed to several viruses and pathogens. Mucosal surfaces are the path for the internalization of viruses and pathogens. Thus, preventing the virus’s adsorption onto the mucosal epithelial surfaces is crucial for reducing disease development. LAB when administered orally neutralize the invading viruses and pathogens by preventing the attachment to mucosal surfaces and by production of several metabolites such as EPSs, bacteriocins, and ROS [10].

4. LAB as Mucosal Vaccine Vectors

To maintain the good health of animals and humans, LAB have been introduced as a vector in animal feed and human food as beneficial organisms to prevent many lethal viral and bacterial diseases by modulating the immune system, as shown in Figure 32 [5]. Diseases caused by various gastrointestinal viruses remain a big challenge for farmed animals and for humans [107][35]. Vaccination is the most important option to prevent viral infections in farm animals, but differences between pandemics and vaccine strains make vaccination less effective. Moreover, vaccine development for novel viral strains is a difficult task. Lactobacilli have been used as vehicles for the delivery of vaccines to counter many viral diseases [108][36]. The choice of LAB as a vaccine vector is based on a variety of characteristics that render them very appealing as a possible means of vaccine delivery. Dietary LAB organisms have a very long history of safe administration through the oral route [109][37]. Additionally, LAB are able to colonize cavities such as the mouth, the urogenital, and GIT, where they play a critical role in maintaining a balanced normal microflora. In addition, LAB have an absence of lipopolysaccharides (LPS) in their cell wall that virtually eliminates the risk of endotoxic shock and survival inside the stomach due to acid resistance [109][37]. The commensal and dietary types of Lactobacillus strains are used as inherent vaccine vectors that give beneficial effects to animals and humans [110][38].
Figure 32. Direct and indirect effects of vectored lactic acid bacteria delivered orally in the enhancement of mucosal immunity. Lactic acid bacteria (LAB) when used as probiotics orally display direct and indirect effects on the health of animals and humans by preventing the attachment of potential pathogens to the mucosal surface of the intestine. LAB also modulate the innate immune system to produce antibodies and immune cells for the neutralization of viruses.
Many researchers have reported that Lactobacillus gasseri is the most advantageous species, and is considered the model organism to be used as a vaccine vector, because of the unchallenging manipulation of its genome. This has made L. gasseri more beneficial for biotechnological use, covering a range from the production of recombinant proteins to the expression and delivery of modified chimera and bioactive molecules to the mucosal surfaces [108,111][36][39]. Characteristics of LAB such as high resistance to the acidic environment of the stomach, the ability to remain in the GIT without colonizing, less immunogenicity, and the lack of lipopolysaccharides in its cell wall, which reduces the chances of endotoxin shock, making such organisms highly versatile to be used as vectors, including in immunization programs [109,112][37][40]. In pigs, the composition of the gut microbiota might change the host’s immune response against invading viruses and other pathogens. Similar patterns have been seen in various viral infections, including the African swine fever virus and enteric viruses [113,114][41][42]. The production of various kinds of anti-viral peptides by LAB has also been reported by many researchers against viral infections [113,115][41][43]. The mechanism of antigen delivery to targeted DCs has tremendous potential for new-age vaccine development. LAB such as L. lactis, L. acidophilus, L. gasseri, and L. casei have great potential as a vector for the delivery of molecules orally to induce a mucosal immune response and production of IgA for many viral and pathogenic diseases. This advancement has a great leap to the conventional process of attenuating pathogens for vaccine development. LAB have conserved pathogen-associated molecular patterns (PAMPs) such as peptidoglycans, cell wall polysaccharides, lipoteichoic acid (LTA), surface-associated adhesion molecules of Gram-positive bacteria, and lipoproteins which are anchored in the cell cytoplasm membrane [19,116][19][44]. It should be taken into account that various strains of LAB differ in their immune regulatory properties, which can have significant roles in intrinsic use as vectors. In particular, their ability to attach to the mucosal surfaces is a principal characteristic.

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