Introduction
Bile Acid Metabolism
Bacterial enzymes | Distribution of enzymes among microbial species microbiota |
---|---|
Bile Salt Hydrolase (BSH) | Gram positive: Lactobacillus (i.e., L. salivarius, Lactobacillus acidophilus, Lactobacillus johnsonii, Lactobacillus plantarum) Bifidobacterium (i.e., Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium adolescentis, and Bifidobacterium animalis) Enterococcus (i.e., Enterococcus faecium) Clostridium spp. (i.e., Clostridium perfringens, Clostridium innocuum, Clostridium Sordellii) Gram negative: Bacteroides spp. (i.e., Bacteroides vulgatus, Bacteroides fragilis subsp. fragilis) |
3α Hydroxysteroid Dehydrogenase (HSDH) | Most prevalent intestinal bacteria: Clostridium perfringens, Peptostreptococcus productus, Egghertella lenta; Intestinal bacteria present in lower numbers (≤ 105 /g wet weight feces): Clostridium scindens, Clostridium hylemonae, Clostridium hiranonis |
3β Hydroxysteroid Dehydrogenase (HSDH) | Several species of Clostridium and Rumminococcus. |
7α/β Hydroxysteroid Dehydrogenase (HSDH) | Bacteroides thetaiotaomicron, Bacteroides Fragilis, Clostridium sp. 25.11.C, Clostridium absonum, Clostridium sordellii, Clostridium scindens, Clostridium hylemonae, Clostridium hiranonis, Clostridium bifermentans, Clostridium limosum, Escherichia coli, and Ruminococcus sp. |
12α/β Hydroxysteroid Dehydrogenase (HSDH) | 12α/β-HSDH have been detected among members of the genus Clostridium: 12α-HSDH have been detected in Clostridium leptum, Clostridium group P, Eggerthella lenta, Clostridium perfringens, Clostridium scindens, Clostridium hylemonae, Clostridium hiranonis; 12β-HSDH have been detected in Clostridium tertium, Clostridium difficile, Clostridium paraputrificum |
7α/β Dehydroxylase | Clostridium (i.e., Clostridium scindens, Clostridium hylemonae, Clostridium hiranonis, Clostridium sordellii, Clostridium Leptum, Clostridium Bifermentas), Eubacterium sp. |
Bile Acid-Activated Receptors and Intestinal Immune Cells
Receptor | Natural bile acid agonists | Synthetic ligands | Main tissue distribution |
---|---|---|---|
Farnesoid-X-Receptor (FXR) (NR1H4) | CDCA > CA > LCA > DCA CDCA Antagonists Αβ-muricholic acids | GW4064, 6-ECDCA (OCA) BAR501, Fexaramine, Px-104, Tropifexor, Cilofexor, Nidufexor, EYP001, TERN-101, and MET409 | Hepatocytes, ileal epithelial cells |
Liver-X-Receptor (LXR) (NR1H3) | Hyo-DCA | Hepatocytes, macrophages | |
Costitutive Androstane Receptor (CAR) (NR1I3) | LCA, CDCA | Hepatocytes | |
Vitamin D receptor (NR1I1) | LCA | Intetsinal epithelial cells | |
Pregnane-X-Receptor (NR1H2) | CDCA-LCA | Hepatocytes Intestinal epithelial cells | |
Rtinoid Related Orphan Receptor (ROR)γt ((NR1F3) | 3oxo-LCA | Th17, type 3 innate lymphoid cells (ILC3) | |
G-protein bile acid receptor 1 (GPBAR1) also known as TGR5 | LCA > DCA > CDCA > UDCA > CA. Oleanolic acid, Betulinc acid, and Ursolic acid | BAR501 BAR502, INT-767, and INT-777 | Intestinal epithelial cells ileum and colon, ileal endocrine L cells, biliary epithelial cells, gallbladder, adipose tissue |
Sphingosine-1-phosphate receptor 2 (S1PR2) | LCA | Hepatocytes | |
Muscarinic receptor M3 | DCA-LCA | CNS, smooth muscle cells |
Cell type | Receptor | Bile acid ligands | Function |
---|---|---|---|
Monocyte/Macrophages cells | GPBAR1 | LCA > DCA > CDCA > UDCA > CA | Anti-inflammatory effect (↓IL-6, IFN-g, TNF-a and ↑IL-10), Differentiation from M1 to M2 phenotype |
FXR | CDCA > DCA > LCA > CA | Anti-inflammatory effect (↓IL-1b, TNF-a NLRP-3, Caspase-1) | |
VDR | 3-oxo-LCA, isoallo-LCA, LCA | Anti-inflammatory effect (↓IL-1, IL-6, IL-8, IL-12, and TNFα) | |
DC (Dendritic cells) | GPBAR1 | LCA > DCA > CDCA > UDCA > CA | Anti-inflammatory effect (↓TNF-a, IL-12) |
FXR | CDCA > DCA > LCA > CA | Anti-inflammatory effect (↓IL-6, IL-1b, TNF-a) | |
VDR | 3-oxo-LCA, isoallo-LCA, LCA | Inhibition of differentiation and maturation of dendritic cells | |
ILCs (Innate lymphoid cells) | RORγt | Inverse agonist) Isoallo-LCA 3-oxo-LCA | Increase differentiation and function of ILC3 |
NKt (Natural Killer T cells) | GPBAR1 | LCA > DCA > CDCA > UDCA > CA | Anti-inflammatory effect (↓IFN-g, TNF-a, and ↑IL-10), Polarization toward the NKt10 phenotype |
FXR | CDCA > DCA > LCA > CA | Anti-inflammatory effect (↓IFN-g, TNF-a), Less induction of apoptosis (↓Osteopontin) | |
T cells | VDR | 3-oxo-LCA, isoallo-LCA, LCA | Inhibits T cell proliferation Promotes a shift from a Th1 to a Th2 phenotype Inhibits differentiation of Th17 (↓RORγt), Increases differentiation of Treg (↑FoxP3) |
RORγt | (Inverse agonist) Isoallo-LCA 3-oxo-LCA | Increases differentiation of Th17 (↑RORγt), Inhibits differentiation of Treg (↓FoxP3) |
Bile Acids in IBD
Intestinal Microbiota: Dysbiosis and IBD
Crohn’s disease | Ulcerative colitis |
---|---|
↓ Bacterial diversity | ↓ Bacterial diversity |
↑ Proteobacteria | ↑ Proteobacteria |
Enterobacteriaceae ↑ E. coli ↑ K. Pneumoniae ↑ Pasteurellaceae ↑ Neisseriaceae | Enterobacteriaceae ↑ E. coli |
↑ Fusobacteria | ↑ Fusobacteria |
↑ Fusobacteriaceae | ↑ F. varium |
↓ Firmicutes | ↓ Firmicutes |
↓ Clostridiales ↓ F. prausnitzii ↓ E. rectale Ruminococcaceae ↑ R. gnavus | ↓ Clostridiales ↓ F. prausnitzii ↓ E. rectale Ruminococcaceae ↑ R. gnavus |
Fungal diversity | Fungal diversity |
↑ Candida | ↑ Candida |
Bile Acid Metabolism in IBD
Bile Acid-Activated Receptors in IBD
FXR in Rodent Models of Intestinal Inflammation and IBD Patients
Intestinal epithelial cells (IEC) | |
Higher expression on IEC in the terminal ileum. FXR regulates bile acid uptake by IEC and their secretion in portal circulation by modulating the expression/activity of the following transporters: ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) (inhibition), IBABT and organic solute transporters (OST)α/β (induction) and nuclear receptors (SHP) Induction of FGF15/19 secretion by IEC | |
Intestinal immune cells | |
FXR deficient mice develop a pro-inflammatory phenotype with age Activation of FXR promotes a tolerogenic phenotype by intestinal macrophages | |
FXR expression in the intestine is negatively regulated by TLR4 and positively regulated TLR 9 via Interferon regulated Factor (IRF)7 | [90] |
FXR exerts antibacterial effects | |
FXR represses NLRP3 inflammasome assembly | [94] |
FGF15/19 | |
FGF19-reduced bile acid synthesis and pool size, modulated its composition and protected mice from intestinal inflammation and preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response, and modulation of microbiota composition. Effect of FGF19-M52 were FXR dependent. Levels of FGF19 in CD patients were reduced | [88] |
FXR signaling in CD | |
A cross-sectional study in individuals with (n = 74) and without (n = 71) CD Finding: Decreases in glycochenodeoxycholic acid, taurocholic acid and lithocholic acid were seen in CD with increases in glycodeoxycholic acid and glycocholic acid relative to the total plasma bile acid profile Interpretation: specific changes in the plasma bile acid composition lead to reduced activation of FXR and PXR target genes in vitro and in vivo | [96] |
Gene/protein expression of FXR | |
Reduced expression of FXR in the ileum and colon of patients with Crohn disease and Ulcerative colitis FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with primary sclerosing cholangitis (PSC)-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients | |
Genetic variations | |
Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 CD and 1193 UC) and in 853 healthy controls None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD mRNA expression of villus marker Villin correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients | [98] |
To evaluate FXR-1G > T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients Conclusions: female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22–52.38, p < 0.0001) and early progression to surgery (OR = 6.28, 95% CI = 3.62–10.90, p < 0.0001) | |
Five FXR variants (rs3863377, rs7138843, rs56163822, rs35724, rs10860603) were genotyped in 1138 Swiss individuals (591 non-IBD, 203 UC, 344 CD). The FXR SNP rs3863377 is significantly less frequent in IBD cases than in non-IBD controls (allele frequencies: p = 0.004; wild-type vs. SNP carrier genotype frequencies: p = 0.008), whereas the variant rs56163822 is less prevalent in non-IBD controls (allele frequencies: p = 0.027; wild-type vs. Conclusions: The substitution − 1 G > T in rs56163822 lead to reduced FXR protein expression and activity | [99] |
GPBAR1 in Intestinal Inflammation and IBD Patients
GPBAR1 natural ligands: LCA > DCA > CDCA > UDCA > CA Selective GPBAR1 ligands: INT-777, BAR501, Dual FXR, and GPBAR1 ligands: BAR502 and INT-767 | |
Epithelial cells | |
GPBAR is expressed on IEC of ileum but the higher expression has been detected in the colon. GPBAR1 is essential for maintaining intestinal barrier integrity. GPBAR1 deficient mice develop an increased intestinal permeability destroyed architecture of intestinal epithelial tight junctions and abnormal distribution of zonulin-1 | [101] |
Intestinal immune cells | |
GPBAR1 is expressed by intestinal immune cells including DC, monocytes and macrophages and NKT cells (see Table 3). GPBAR1 ligands (BAR 501) exerts anti-inflammatory effect (↓IL-6, IFN-γ, TNF-a, and ↑IL-10) in murine models of colitis and promotes differentiation of from M1 to M2 phenotype | [102] |
Intestinal nerve system | |
GPBAR1 expressed on enteric neurons and mediates the effects of bile acids on colonic motility. GPBAR1 deficiency causes constipation in mice. Laxative properties of bile acids could be mediated by GPBAR1 GPBAR1 is expressed in a subset of colon-innervating sensory neurons with the Mas-gene-related GPCRs Mrgpra3 and Mrgprc11 and mediates perception of colonic-originating sensation | |
Intestinal endocrine cells | |
GPBAR1 is by L type intestinal endocrine cells and promotes GLP1 release |
GPBAR1 expression in IBD | |
GPBAR1 gene expression is increased in area of inflammation in Crohn’s disease patients | [101] |
GPBAR1 genetic in IBD | |
Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms of GPBAR1 (TGR5) were detected in 267 PSC patients and 274 healthy controls. Five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function Fine mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the GPBAR1 single-nucleotide polymorphism rs11554825 and PSC (p = 0.010) and UC (p = 8.5 × 10(−7) | [106] |