The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that arises due to complex interactions between host genetic risk factors, environmental factors, and a dysbiotic gut microbiota. Although metagenomic approaches have attempted to characterise the dysbiosis occurring in IBD, the precise mechanistic pathways interlinking the gut microbiota and the intestinal mucosa are still yet to be unravelled. To deconvolute these complex interactions, a more reductionist approach involving microbial metabolites has been suggested. Bile acids have emerged as a key class of microbiota-associated metabolites that are perturbed in IBD patients. In recent years, metabolomics studies have revealed a consistent defect in bile acid metabolism with an increase in primary bile acids and a reduction in secondary bile acids in IBD patients. This review explores the evolving evidence that specific bile acid metabolites interact with intestinal epithelial and immune cells to contribute to the inflammatory milieu seen in IBD. Furthermore, we summarise evidence linking bile acids with intracellular pathways that are known to be relevant in IBD including autophagy, apoptosis, and the inflammasome pathway. Finally, we discuss how novel experimental and bioinformatics approaches could further advance our understanding of the role of bile acids and inform novel therapeutic strategies in IBD.

Keywords: Crohn’s disease; bile acids; gut metabolites; gut microbiome; immunology and inflammation; inflammatory bowel disease; ulcerative colitis.

Figure 1

Bile acid synthesis, recirculation and microbial modifications in the gut. Bile acids are synthesised in the liver from cholesterol. In the classical pathway, cholesterol 7α-hydroxylase (CYP7A1) converts cholesterol to 7α-hydroxycholesterol which can then form either of the PBAs, CA and CDCA, through multistep pathways involving cytochrome P450 enzymes. In the alternative pathway, sterol-27-hydroxylase (CYP27A1) initiates the conversion of cholesterol to 27-hydroxycholesterol which mainly forms CDCA. These PBAs are then conjugated with either taurine (T) or glycine (G) to make them water soluble, before being released into bile where they form mixed micelles. As bile enters the duodenum via the ampulla of Vater, absorptive micelles are formed which facilitates the absorption of fatty acids, monoglycerides, fat soluble vitamins, and cholesterol in the small intestine. In the terminal ileum, 95% of conjugated BAs are reabsorbed through the enterohepatic circulation, whilst the remaining 5% enter the colon. Here, BAs undergo a number of chemical modifications by gut bacteria including deconjugation, desulphation, dehydrogenation, dehydroxylation, and epimerisation reactions to form the SBAs, LCA and DCA, and their oxo, iso, and epi-derivatives. PBAs, primary bile acids; SBAs, secondary bile acids; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; T, taurine; G, glycine; CYP7A1, 7α-hydroxylase; CYP27A1, sterol-27-hydroxylase.

Figure 2

Regulation of BA synthesis by FXR and FGF19 in humans. Cholesterol 7α-hydroxylase (CYP7A1) initiates the conversion of cholesterol to PBAs through the classical pathway in hepatocytes. BAs are transported from hepatocytes into the bile canaliculus through the bile salt export pump (BSEP). BAs then enter the small intestine via the common bile duct. In the terminal ileum, enterocytes absorb BAs through the apical sodium-dependent bile salt transporter (ASBT). Here, BAs can activate the nuclear BA receptor, farnesoid X receptor (FXR), which results in the upregulation of fibroblast growth factor 19 (FGF19) and subsequent release of FGF19 into the portal circulation. BAs also enter the portal circulation via the organic solute transporter α/β (OST α/β) located in the basolateral membrane of enterocytes. BAs from the portal circulation are reabsorbed back into the liver via the Na⁺-taurocholate cotransporting polypeptide (NTCP). FGF19 also binds to fibroblast growth factor receptor 4 (FGFR4). Both these actions result in the inhibition of CYP7A1, thus resulting in the downregulation of BA synthesis. BA, bile acid; CYP7A1, cholesterol 7α-hydroxylase; BSEP, bile salt export pump; ASBT, apical sodium-dependent bile salt transporter; FXR, farnesoid X receptor; FGF19, fibroblast growth factor 19; NTCP, Na⁺-taurocholate cotransporting polypeptide; FGFR4, fibroblast growth factor receptor 4.

Figure 3

Cell type-specific effects of BAs on immune cell populations relevant to IBD. Mixtures of PBAs (CA/UDCA, CDCA/UDCA or CA/CDA/UDCA) or SBAs (DCA/LCA/3-oxoCA/3-oxoLCA/7-oxoCA/7-oxoCDCA/12-oxoCA/12-oxoDCA or LCA/3-oxo-LCA) have been found to stimulate RORγt⁺ FOXP3⁺ Treg cells by acting on the VDR in mice (N.B. In mice, UDCA is considered to be a PBA). IsoalloLCA can stimulate the differentiation of FOXP3⁺ Treg cells through an epigenetic pathway. 3-oxoLCA and isoLCA inhibit the differentiation of Th17 T cells by acting on the RORγt receptor, whilst LCA inhibits Th1 T cell differentiation through a VDR-dependent mechanism. IsoDCA induces an anti-inflammatory profile in DCs by acting on the FXR, which leads to the promotion of RORγt⁺ FOXP3⁺ Treg cells. Similarly, LCA induces an anti-inflammatory phenotype in macrophages by activating TGR5. Purple text - SBAs, Green text - PBAs, Blue arrows - stimulatory interactions, Red arrow - inhibitory interaction, Black arrow - anti-inflammatory effect. PBAs, primary bile acids; SBAs, secondary bile acids; DCA, deoxycholic acid; LCA, lithocholic acid; RORγt, Retinoic acid-related orphan receptor gamma t; VDR, vitamin D receptor; FXR, farnesoid X receptor; TGR5, Takeda G protein-coupled receptor 5.

Figure 4

Cell type-specific effects of BAs on the intestinal epithelium. The SBAs, LCA and DCA, inhibit the production of pro-inflammatory cytokines IL1β and IL8 in Caco-2 cells that resemble enterocytes. They also promote stem cell growth in the intestinal crypts by acting on TGR5. CDCA acts on goblet cells to promote MUC2 expression and antimicrobial peptide (AMP) release. Key: Blue arrows - stimulatory interactions, Red arrow - inhibitory interaction. DCA, deoxycholic acid; LCA, lithocholic acid; CDCA, chenodeoxycholic acid; MUC2, mucin 2; AMP, antimicrobial peptides; TGR5, Takeda G protein-coupled receptor 5; IL1β, interleukin 1-beta; IL18, interleukin 18.