# Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds
## 5 Probiotic Derived Bioactive Compounds and Immunity
### SCFAs
#### 5.2.2 SCFAs as Immunomodulatory Molecules
Accumulating evidence underlines the role of SCFAs in regulating the maturation and stimulation of DCs, which primarily express GPR41 and GPR109 receptors on their surface [140]. Butyrate activates GPR109A in colonic DCs, which, in turn, induces IL-10-producing Tregs, as well as the secretion of IL-18 in the intestinal epithelium of mice, providing protection against inflammation and tumorigenesis [151]. Additionally, butyrate promotes naive T-cell differentiation to Tregs or Th1 and Th17 cells, ensuring their balance, which is a significant prerequisite to the elimination of gut inflammation [152; 153]. Both butyrate and propionate were found to exert immunomoddulatory properties via modulation of gene expression in DCs [154]. Supplementation with SCFAs has been proved to enhance the cytotoxic capacity of NK cells in rats while boosting the secretion of IFN-\(\gamma\), the predominant cytokine produced in response to inflammatory signals [155]. Gut-associated NK cells detect invading pathogens, as well as cancer cells, and induce the recruitment of various immune cells to elicit the innate and/or adaptive immunity [140]. SCFAs are implicated in the differentiation of naive CD4+ T cells into Tregs expressing the forkhead box protein (Foxp3) through the activation of GPR43 or GPR41 in vivo [130]. A similar increase in Tregs has been observed following oral administration of SCFAs, individually or in combination, to GF mice [156]. In vitro studies have also confirmed that butyrate and propionate favor the polarization of naive CD4+ T cells toward IL-10+ Tregs, thus promoting resilience in the gut microbiota [140]. Upon interaction with GPR43, SCFAs activate Th1 cells and induce the mTOR and STAT3 pathways, resulting in upregulation of B lymphocyte-induced maturation protein 1 (Blimp-1) expression and IL-10 secretion in vivo [157]. Butyrate and propionate promote IFN-\(\gamma\) secretion, thus enhancing the cytotoxic activity of CD8+ T cells, the preponderant effector cells found in the tumor microenvironment [1; 158]. Interestingly, the administration of butyrate, both in vitro and in vivo, enhanced the efficacy of the chemotherapeutic oxaliplatin via amplification of CD8+ T cell responses [159]. Moreover, the presence of SCFAs is associated with increased levels of intestinal IgA in mice. It has been confirmed that acetate activates GPR43 in intestinal DCs, thus triggering IgA secretion by B cells [1]. Alternatively, SCFA attachment to GPRs activates DCs to produce class 1A acetaldehyde dehydrogenase (ALDH1a). ALDH1a catalyzes the conversion of vitamin A into retinoid acid, thereby causing the IgA isotype switching towards secretory IgA production [1; 3]. The increased energy requirements of B cells due to their multifaceted cellular processes are met by enhancement of oxidative phosphorylation and fatty acid synthesis induced by SCFAs [1; 160]. Furthermore, differentiation of B cells into plasma cells in Peyer's patches is enhanced by SCFAs, which activate the mTOR pathway [160]. SCFAs employ multiple mechanisms in order to boost B cell differentiation into plasma cells and antibody production, including epigenetic regulation of specific genes such as _Aicda_, _Xbp1_, and _lrf4_, production of IL-6, and activation of Tfh cells [160; 161].