# Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds
## 5 Probiotic Derived Bioactive Compounds and Immunity
### SCFAs
#### 5.2.2 SCFAs as Immunomodulatory Molecules  
SCFAs play a significant role in modulating innate and adaptive immune response (Table 2, Figure 3). They are mainly recognized by three distinct G-protein-coupled receptors (GPR41, GPR43, and GPR109A) found on the surface of host IECs. Following activation of GPRs, SCFAs can modulate various signaling cascades, including MAPK, the signal transducer and activator of transcription 3 (STAT3) and the mammalian target of rapamycin (mTOR) pathways [140]. Additionally, SCFAs are involved in cell proliferation and programmed cell death via the inhibition of the enzyme histone deacetylase (HDAC) [141], and they participate in inflammasome activation, a key element of innate immune response [140]. Butyrate or acetate-GPR43-mediated signaling facilitates the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomeome in IECs, thereby resulting in the production of IL-18, which has been linked to intestinal epithelial barrier maintenance [142]. A recent study indicated the importance of three SCFAs in restoring the reduced mucin levels in Caco-2 cells and mouse IECs previously treated with the chemotherapeutic 5-Fluorouracil (5-FU) [131]. It is speculated that SCFAs activate the NLRP6 inflammasome in order to enhance the secretion of mucin 2 by the intestinal goblet cells [1] in a similar way to other microbiota-associated metabolites [143]. Furthermore, it is reported that SCFAs inhibit the production of pro-inflammatory cytokines, including interferon-gamma (IFN-\(\gamma\)), TNF-\(\alpha\), IL-6, IL-1\(\beta\), and IL-8, and they favor the production of anti-inflammatory cytokines such as IL-10 and TGF-\(\beta\), via suppression of the NF-\(\kappa\)B pathway in IECs [127,144]. Butyrate induces the activation of nuclear peroxisome proliferator-activated receptor gamma (PPAR-\(\gamma\)) [145], thus enhancing the \(\beta\)-oxidation of SCFAs and oxidative phosphorylation, contributing to the maintenance of hypoxic conditions in the microenvironment of IECs [16,17]. Under  
Figure 3: SCFAs modulate innate and adaptive immune cells residing in the gut. SCFAs exert their immunomodulatory properties via activation of GPRs (namely GPR41, GPR43, and GPR101A) on the IECs surface. As a result, they induce: (1) naïve CD4+ T cells differentiation towards Th1, Th17, and IL-10 producing Tregs, (2) activation of DCs, which in turn trigger IL-10 producing Tregs, (3) secretion of mucin by intestinal goblet cells, (4) M2 macrophage polarization with subsequent production of IL-10, (5) secretion of IL-18 via activation of the NLRP3 inflammasomeome, (6) chemotaxis of neutrophils at inflammation sites, and (7) activation of DCs which produce ALDH1a causing IgA secretion by plasma cells. these conditions, commensal obligate anaerobic SCFA-producing bacteria thrive, while pathogenic facultative anaerobic bacteria are eliminated [1]. The development of augmented inflammation in GPR43-deficient mice confirmed that GPR43-mediated signaling pathway leading to the activation of p38 MAPK [3] is directly associated with neutrophils chemotaxis [146; 147]. Interestingly, upon exposure of LPS-stimulated neutrophils to SCFAs, the levels of NO, TNF-\(\alpha\), and cytokine-induced neutrophil chemoattractant-2 alpha beta (CINC-2\(\alpha\beta\)) decreased, resulting in inhibition of HDAC activity [148]. Treatment of LPS-induced THP-1 macrophages with SCFAs secreted by _E. coli_ KUB-36 resulted in reduction of pro-inflammatory cytokines, and anti-inflammatory cytokine IL-10 production was triggered [149]. A recent study has also highlighted the role of butyrate in promoting M2 macrophage polarization both in vitro and in vivo in mice with dextran sulfate sodium (DSS)-induced colitis. The reduced transcription of pro-inflammatory genes in bone-marrow-derived macrophages was attributed to butyrate-induced epigenetic modulations, thus indicating the significant impact of butyrate on immune tolerance enhancement [150].