# Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds
## 5 Probiotic Derived Bioactive Compounds and Immunity
### Bacteriocins
#### 5.1.3 Bacteriocins as Immunomodulatory Molecules  
Although the immunomodulatory properties of bacteriocins have not been completely elucidated, their role as signaling peptides [99] affecting host immunity has been reported [91] (Table 1). A recent study has shown that bacteriocins, including nisin A, plantaricin 423, and bacST4 SA, can migrate across endothelial and epithelial cells in vitro without causing toxicity, and they display stability in blood plasma [100]. The above observations provide strong evidence which supports the ability of bacteriocins to cross the gut-blood barrier, thereby affecting local and systemic immunity [101]. It is also suggested that bacteriocins may contribute to the stimulation of IECs which, in turn, produce antimicrobial substances to eradicate the colonization of intruding pathogens [90]. Researchers have mainly focused their interest on how nisin, a lantibiotic used in food preservation (E234), commercially available as Nisaplin [87], may affect immune responses [20]. Nisin was found to promote the production of anti-inflammatory cytokines at the expense of pro-inflammatory cytokines to inhibit inflammation in vivo [102]. Additionally, investigations on the effect of nisin on the immune system of mice showed that short-term nisin consumption induces an increase in the number of CD4+ and CD8+ T cells, as well as a significant reduction in the percentage of B cells. Following long-term nisin-consumption, T cells and B cells return to normal levels, and the population of macrophages/monocytes isolated from peripheral blood increases [103]. Similarly, a recent study which evaluated the effect of various nisin concentrations on porcine peripheral blood mononuclear cells (PBMC) in vitro, found that a high dose of nisin induces the proliferation of CD4+ and CD8+ T cells and the secretion of IL-1B and IL-6 in PBMCs, thus indicating the  
Figure 2: Classification of LAB bacteriocins. enhancement of immune response against potential infections [104]. Moreover, the nisin Z variant can promote the secretion of the chemokines monocyte chemoattractant protein-1 (MCP-1), IL-8, and growth regulated oncogene-alpha (Gro-\(\alpha\)), as well as suppress the production of tumor necrosis factor-alpha (TNF-\(\alpha\)) in human LPS-stimulated PBMCs [105]. Nisin can also enhance the function of phagocytes that comprise an important part of innate immunity, including neutrophils and macrophages. Nisin activates the formation of neutrophil extracellular traps (NETs) by neutrophils in vitro [106], a process probably attributed to the increased production of IL-8 [107], and therefore inhibits pathogen infiltration in host cells. Treating macrophage cells with a synthesized nanoparticle containing nisin was shown to increase the levels of IL-12 without causing any effects on IL-10 and TNF-\(\alpha\) levels [108]. Generally, bacteriocins have the ability to modulate the cytokine levels via controlling various signaling cascades (e.g., TLR, NF-\(\kappa\)B, MAPK) in order to exert their immunomodulatory properties in case of inflammation [90]. It is reported that bacteriocins can elicit innate immune response upon viral infection via the inflammasome activation [109]. Sublancin, an antimicrobial peptide originated from _Bacillus subtilis_, was found to stimulate innate immune response via IL-1\(\beta\), IL-6, TNF-\(\alpha\), and nitric oxide (NO) production in both RAW264.7 cells and mouse peritoneal macrophages [110]. The enhanced phagocytic capacity of macrophages was correlated with the TLR4 and the NF-\(\kappa\)B [111] and MAPK signaling pathways, while the oral administration of sublancin increased the number of CD4+ and CD8+ T cells in MLNs in vivo [110]. Treatment of human PBMCs with acidocin A, a pediocin-like bacteriocin, resulted in increased production of multiple cytokines and chemokines, including MIG, MCP-1, MCP-3, macrophage inflammatory protein (MIP)-1\(\alpha\), MIP-1\(\beta\), IL-6, and TNF-\(\alpha\)[112].