# Immunomodulatory Properties of Probiotics and Their Derived Bioactive Compounds
## 5 Probiotic Derived Bioactive Compounds and Immunity
### SCFAs  
#### 5.2.1 Overview of SCFAs  
Specific commensal anaerobic bacteria residing in the intestinal lumen are major contributors in the fermentation of non-digestible complex carbohydrates, thus producing a great amount of SCFAs [116]. SCFAs are saturated fatty acids containing six or fewer carbon atoms, including: formate (C1), acetate (C2), propionate (C3), butyrate (C4), valerate (C5), and caproate (C6) [117]. The most abundant SCFAs found in colon are acetate, propionate, and butyrate. SCFAs are released longitudinally in the intestine in different concentrations, with a maximum level in the proximal colon (100 mM) [1; 118]. The fatty acids acetate, propionate, butyrate, isobutyrate, 2-methylbutyrate, isovalerate, and valerate have been detected in human feces, in decreasing order of abundance [119]. The branched SCFAs isovalerate and isobutyrate are produced in lower amounts in the gut and have been associated with aging [120]. Members of the Firmicutes phylum mostly synthesize butyrate, while members of the Bacteroidetes phylum mainly synthesize acetate and propionate [121]. Upon production in colon, SCFAs are disseminated into the bloodstream with the aim of being delivered to distant tissues, thereby exerting their beneficial effects [122].  
SCFAs exhibit distinct anti-inflammatory and immunomodulatory properties and play a fundamental role in gut homeostasis, serving as the interface between gut microbiota and immunity [123]. IECs metabolize SCFAs into acetyl coenzyme A (acetyl-CoA) via the tricarboxylic acid (TCA) cycle, thus promoting cell metabolism and acquiring the essential energy for multiple cellular functions, including proliferation and activation of immune cells [124]. Butyrate serves as the primary substrate for energy production and corresponds to approximately 60-70% of total energy consumption in IECs [125; 126]. Moreover, SCFAs promote the differentiation of the goblet cells involved in the secretion of mucus, thus having a well-appreciated role in maintaining mucosal barrier integrity [3]. Collectively, SCFAs perform a great variety of functions, which include protection and restoration of the intestinal epithelial barrier [125; 127], prevention of gut dysbiosis via inhibition of harmful pathogens [124; 128], regulation of intestinal immunity [129; 130], maintenance of a balanced crosstalk between gut microbiota and extraintestinal tissues [18], and inhibition of gut inflammation through reduction in the levels of pro-inflammatory cytokines produced by immune cells [131].  
In addition to the common SCFAs produced upon microbial fermentation, the presence of lactate in the intestinal lumen is considered to be a critical indicator for the preservation of gut integrity [132]. Lactate, a short chain hydroxy-carboxylic acid examined separately from SCFAs [133; 134], serves as an energy substrate for a subgroup of lactate-utilizing bacterial species [132]. Under normal conditions, it is metabolized to acetate, propionate, and butyrate via distinct biochemical pathways employed by gut microbes. Therefore, the colonic concentrations of lactate are relatively low, ranging from 5 to 10 mM, in comparison to the major SCFAs [134]. On the other hand, lactate accumulation in the gut has been associated with inflammatory gastrointestinal disorders [132; 134]. Lactate is not only considered as an important intermediate in cell metabolism [135; 136; 137], but also a multifunctional signaling molecule [138] with profound immunomodulatory properties both in physiological and pathological states [139].