Receptor 4 (FGFR4), which also results in inhibition of CYP7A1. Just before recirculation back towards the liver, BAs stimulate intestinal FXR, which induces FGF19 synthesis in ileocytes [54]. FGF19 is transported to the liver, where it binds FGFR4 and activates the c-jun N-terminal kinase (JNK) 1/2 signaling cascade, major to downregulation of CYP7A1 [33,55]. Pregnane X receptor (PXR) and vitamin D receptor (VDR) are each nuclear receptors activated by microbial-derived BAs that also bring about the binding of CYP7A1 promoter and repression of CYP7A1 [8,568]. Takeda G-protein receptor 5 (TGR5) is really a G-protein-coupled receptor for BAs that’s expressed in intestinal and biliary epithelial cells among other cell kinds [59,60]. TGR5 has widespread effects throughout the body, such as regulation of intestinal motility [61]. Taurine-PAK3 medchemexpress conjugated BAs activate TGR5 far more effectively than unconjugated or glycine-conjugated BAs [62]. TGR5 signaling can activate epidermal growth aspect receptor (EGFR) [63]. EGFR is also a BA receptor that, as soon as bound, initiates a signaling pathway ending in inhibition of CYP7A1 [43,64]. In the gut, principal bile salts can be microbially biotransformed to dozens of metabolites whose concentrations and affinities can effect host physiological response inside the intestine. 3.2. Microbial Bile Acid Metabolism Bile acids that enter the colon are metabolized by gut microbiota by means of a combination of de(re)conjugation, 7/-dehydroxylation, and epimerization (Figure 2). The very first step of microbial BA metabolism, called deconjugation, mainly occurs in the small intestine and requires the hydrolysis with the C-24 N-acyl bond linking the conjugated amino acid for the BA. This reaction is catalyzed by bile salt hydrolase (BSH) encoded by diverse microbiota, which includes Clostridium [65,66], Bacteroides [67,68], Lactobacillaceae [69], Bifidobacterium [70,71], Enterococcus [72], and archaea [73]. BSHs have differing substrate specificity and subunit size, but normally have conserved active internet site Cys, Arg, Asp, Asn, and a further Arg [74]. BSHs have a pH optimum of five and are usually intracellular [65,70], even though activity has been reported extracellularly in some cases [66]. Interestingly, re-conjugation of BAs by gut microbiota has lately been observed with special amino acids: Phe, Tyr, and Leu [75]. There are actually a number of hypotheses around the evolutionary part of BSH in microbial fitness: interspecies competitors, detoxification, and release of an energy source. DeconjugatedMicroorganisms 2021, 9,6 ofBAs are additional toxic than conjugated bile salts to some bacterial species; as a result, deconjugation may serve a competitive function to inhibit other bacteria [4]. Nonetheless, the reverse may also be correct. Some bacteria are extra sensitive to conjugated BAs and, hence, BSH may well help them detoxify their environment [76]. Amino acids Adenosine A2B receptor (A2BR) Inhibitor Accession released from deconjugation could be a crucial power supply for particular microbiota, for example Clostridium that will utilize amino acids via Stickland fermentation [77]. Deconjugated key BAs could be 7-dehydroxylated by a select couple of species inside the gut, which includes Clostridium scindens, C. hylemonae, and C. hiranonis (now reclassified as Peptacetobacter hiranonis) [4,780]. Via this course of action, the major BAs CA and CDCA are converted to “secondary” deoxycholic acid (DCA; 3,12-hydroxy) and lithocholic acid (LCA; 3-hydroxy), respectively. Despite the fact that so handful of species encode the 7-dehydroxylation pathway, secondary BAs make up the majority of.