**3. Modulation of adaptive immunity by probiotics**

Adaptive immunity is responsible for identifying and destroying individual invading microbes in mammalian hosts. The cells that carry out the adaptive immune response are B and T cells, which produce a cascade of immune responses upon recognition of foreign antigens interacting with their specific toll-like receptors (TLRs) [16]. Unlike the innate immune system, which is preprogrammed to react to common broad categories of pathogens, the development of adaptive immune responses to new pathogens is slower. Due to its highly specific antigen receptors, specifically the B cell receptor (BCR) and T cell receptor (TCR), to the pathogen, the body has encountered. Adaptive immunity creates immunological memory after an initial response to a specific pathogen and leads to a robust response to encounter with pathogens

in the future. B cells act *via* humoral immunity by secreting antibodies while T cells work *via* T helper cells (CD4+) and cytotoxic T cells (CD8+) to either expand or suppress downstream immune activation [17]. CD4 T cells can be broken down into 5 major subsets: Th1, Th2, Th17, T regulatory (Treg), and follicular T helper (Tfh). This categorization is determined based on the expression of specific cytokines and lineage-specific transcription factors. Th1 cells activate macrophages to help protect against intracellular pathogens such as bacteria and viruses. Th2 cells recruit eosinophils, basophils, and mast cells to sites of infections caused by parasites. Th17 cells aid in the clearance of extracellular bacteria by stimulating continuous neutrophil recruitment and the creation of antimicrobial peptides by epithelial cells. Treg cells contribute to the maintenance of immune tolerance and the prevention of autoimmune diseases. Tfh cells support B cells in the production of antibody formation by aiding in germinal center formation and immunoglobulin class switching [18]. The gastrointestinal tract is the largest immune organ in the human body and comprises the epithelial layer, lamina propria, and mucosal-associated lymphoid tissue (MALT). Adaptive immunity plays a vital role in the development and maintenance of the mucosal immune system (MIS) [16, 19]. Peyer's patches are aggregates of lymphoid follicles found throughout the intestinal mucosal cells [20]. They are the main site for B cell activation and class-switch recombination from IgM to IgA. These cells also aid the immune system in discriminating between pathogenic and commensal bacteria. Their function is imperative to maintaining the integrity of the gut mucosal barrier, protecting the host from infections, and maintaining homeostasis with the native microbiota [21]. At the mucosal level, antigen-presenting cells (APCs) present in Peyer's patches will retrieve immunoglobulin A antigen from mucosal folds and communicate with T cells resulting in different T cell activation, which then ensures mucosal barrier integrity [16, 22].

Numerous studies have demonstrated a variety of molecular pathways where probiotics appear to have influence, such as the production of cytokines, IgA secretion, formation of antibacterial compounds, mucosal cellular integrity, and competition with opportunistic pathogens for enterocyte adherence. A proposed probiotic immunomodulation works by antigenic proteins native to the probiotic microorganism crossing epithelial cells and interacting with the innate and adaptive immune system that resides in Peyer's patches [23]. In turn, this interaction produces a cascading effect resulting in the release of cytokines, such as tumor necrosis factor (TNF), interferons (IFN), interleukins (IL), and chemokines. This interaction between probiotics and the host suggests probiotics play an important role in the production and deployment of a more robust immune response by the host when faced with pathogenic organisms. Cellular wall compounds, such as lipoteichoic acid, which is found in *Bifidobacteria* and *Lactobacilli*, are known to stimulate nitric oxide (NO) synthase. The production of NO is a critical component in the cell death mechanism carried out by macrophages when dealing with pathogen-infected cells [24]. *B. longum* is considered one of the first immune-priming probiotics. Known as the "maternal probiotic", most of the inoculation comes *via* the mode of vaginal birth. Studies have demonstrated that *B*. *longum* plays a crucial role in immune system priming, Peyer's patch development, and IgA production [25]. Lactic acid bacteria such as *L. casei*, *Lactobacillus acidophilus*, *L*. *rhamnosus*, *Lactococcus lactis*, and *Streptococcus thermophilus* have been shown to play a role in maintaining the intestinal barrier by stimulating B cells to produce IgA. Lai, Hung-Hsiang, et al. administered *L*. *casei* and *L*. *rhamnosus* to children with acute diarrheal illness. When compared to the control group, the children who received the probiotics had higher

### *Translation of Immunomodulatory Effects of Probiotics into Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.109864*

total fecal IgA levels and significantly lower concentrations of fecal lactoferrin and calprotectin. This study suggests that the probiotics *L*. *casei* and *L*. *rhamnosus* may be useful supplements during acute diarrhea to reduce clinical severity and intestinal inflammatory reaction [26].

Additionally, probiotics have been observed to modulate pro−/or anti-inflammatory responses by the adaptive immune system *via* interaction with dendritic, Th1, Th2, and Treg cells at the intestinal mucosal surface [24]. In Celiac disease (CD) patients, dysbiosis is thought to play a primary role in its pathogenesis [27]. Numerous studies have demonstrated a significant difference between intestinal microbial populations in healthy children and children with CD [28]. With a gluten-free diet, many of these microbial differences dissipate, except for persistently reduced levels of *Bifidobacterium* in the CD subjects [29]. This finding is particularly important as *Bifidobacteria* has been shown to protect human intestinal cells from the noxious effects of gliadin peptides by altering their molecular structure. Unmodified gliadin peptides result in an adaptive immune response leading to the development of anti-tissue transglutaminase antibodies (anti-tTG), which cause a local inflammation destroying microvilli responsible for nutrient absorption and disrupting the intestinal mucosal barrier [30]. Current murine model studies suggest that the immunomodulatory effects of probiotics are strain specific. Borruel et al. studied ileal mucosal samples from patients with active Crohn's disease and cultured them with either *Escherichia coli*, *Lactobacillus casei*, *Lactobacillus bulgaricus* or *Lactobacillus crispatus*. The probiotic *Lactobacillus bulgaricus* and *Lactobacillus casei* cultured samples demonstrated a significant reduction in TNF-α, a known proinflammatory cytokine. The most robust effect on the downregulation of TNF-α came from viable bacteria, while heat-killed bacteria did not produce a statistically significant change. This finding suggests that cellular products manufactured by viable bacteria play an important role in the suppression of TNF-α production in inflamed tissue [31]. Livingston et al. explored the immunoregulatory response of bone marrow-derived dendritic cells to *Lactobacillus reuteri* 100–23, as previous studies suggested that this bacterial strain had modulatory effects on proinflammatory cytokines in murine models. They found that exposure to *L*. *reuteri* increased the production of IL-10 suggesting an induction of a regulatory dendritic cell phenotype. This resulted in lower IL-2 production while increasing TGF- output [32]. This is important as IL-10 and TGF- are immunoregulatory cytokines and the overall suppression of the murine immune response directed at *L. reuteri* allows the bacteria to colonize and have a commensalistic relationship with the host. Moreover, various probiotic strains have demonstrated the ability to stimulate immunoglobulin receptors in intestinal epithelial cells [33].
