Abstract
Bile acids are a group of chemically different steroids generated at the host/microbial interface. Indeed, while primary bile acids are the end-product of cholesterol breakdown in the host liver, secondary bile acids are the products of microbial metabolism. Primary and secondary bile acids along with their oxo derivatives have been identified as signaling molecules acting on a family of cell membrane and nuclear receptors collectively known as “bile acid-activated receptors.” Members of this group of receptors are highly expressed throughout the gastrointestinal tract and mediate the bilateral communications of the intestinal microbiota with the host immune system. The expression and function of bile acid-activated receptors FXR, GPBAR1, PXR, VDR, and RORγt are highly dependent on the structure of the intestinal microbiota and negatively regulated by intestinal inflammation. Studies from gene ablated mice have demonstrated that FXR and GPBAR1 are essential to maintain a tolerogenic phenotype in the intestine, and their ablation promotes the polarization of intestinal T cells and macrophages toward a pro-inflammatory phenotype. RORγt inhibition by oxo-bile acids is essential to constrain Th17 polarization of intestinal lymphocytes. Gene-wide association studies and functional characterizations suggest a potential role for impaired bile acid signaling in development inflammatory bowel diseases (IBD). In this review, we will focus on how bile acids and their receptors mediate communications of intestinal microbiota with the intestinal immune system, describing dynamic changes of bile acid metabolism in IBD and the potential therapeutic application of targeting bile acid signaling in these disorders.
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Introduction
The inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD), ulcerative colitis (UC), are chronic relapsing disorders caused by a dysregulated intestinal immune response to luminal antigens in genetically predisposed subjects that have emerged as a public health challenge worldwide. Traditionally regarded as a disease of westernized nations, the prevalence of IBD is rising rapidly worldwide among ethnicities and nationalities in whom IBD were previously uncommon [1]. While changes in the composition of the intestinal microbiota are recognized as the main drivers of dysregulated intestinal immunity seen in IBD, the chemical mediators that support this altered communication are still incompletely defined. Bile acids are steroidal molecules generated at the interface of the host and the intestinal microbiota [2]. Together, they represent one of the largest family of biologically active mediators found in mammalians acting on family of G-protein and nuclear receptors (Fig. 1 and Table 1). In this article, we will review the role of these steroids as signaling molecules placed at the interface between the intestinal microbiota and host immune system and how dysregulation of bile acid signaling might have mechanistic relevance in the development of IBD.
Bile Acid Metabolism
Bile acids are the end-product of cholesterol metabolism generated in the liver by a chain of enzymatic reactions that involve the products of 17 genes organized in two main metabolic pathways, known as “classic” and “alternative” [2]. These liver pathways generate mainly two primary bile acids, i.e., cholic acid and chenodeoxycholic acid (CA and CDCA). In the classic pathway, the first and rate limiting step is the cholesterol-7α-hydroxylase (CYP7A1), an enzyme that converts cholesterol in 7α-OH-cholesterol. In the alternative pathway, the first step is represented by the C27 hydroxylation of cholesterol by the sterol 27-hydroxylase (CYP27A1) [2]. The classical pathway, in humans, accounts for ≈80% of total bile acid pool in physiological settings [2, 3]. The alternative pathway or “acidic,” because the C27 hydroxylation generates a COOH group, mainly converts cholesterol to CDCA [2, 3]. The main final products of the two pathways in the liver are 3α-7α di-hydroxylated cholesterol derivatives, i.e., CDCA, and 3α-7α-12α-tri-hydroxylated derivatives, i.e., CA. In hepatocytes, these primary bile acids are amidated (i.e., conjugated) with glycine (G) or taurine (T), giving rise to the bile salts (GCDCA and GCA, and TCDCA and TCA) [2, 3]. In addition, bile acids can be conjugated with the glucuronic acid by the uridine 5’ diphospho-glucoronosyltransferases (UGT1A1, 2B4 and 2B7), or sulfated by the sulfotransferases (SULT2A1 and SULT2A8) at positions C3 and C7 [2, 3]. In humans, the conjugation with G is prevalent and accounts for ≈ 90% of the bile acid pool. Conjugated bile acids are secreted in the intestine, becoming the substrate of an array of bacterial enzymes. These bio-transformations give rise to two secondary bile acids, i.e., lithocholic acid and deoxycholic acid (LCA and DCA). The “gateway reaction” of bile acid metabolism by intestinal bacteria is the enzymatic hydrolysis of the C-24N-acylamide bond operated by bile salt hydrolases (BSHs) which are found in all major bacterial phyla of the intestinal microbiota and some human gut archaea (Table 2 [4,5,6,7,8,9,10,11,12,13,14]). This first step is followed by the 7α-dehydroxylation of the OH in the C7 position, a reaction mediated by 7α-dehydroxylase expressing bacteria such as Clostridium and Eubacterium (Fig. 1). These reactions give rise to two main secondary bile acid, i.e., the 3α-mono-hydroxylated bile acids (i.e., LCA from CDCA), and 3α-12α-di-hydroxylated bile acids (i.e., DCA from CA) [2, 3, 5]. Additionally, the C7 β-epimerization of CDCA by Bacteroides, Clostridium, Escherichia, Eubacerium (and others) originates the 7β epimer of CDCA, i.e., the 3α,7β-dihydroxy-5β-cholanoic acid, known as ursodeoxycholic acid (UDCA) (Fig. 1 and Table 1 and 2) [15]. In addition to secondary bile acids, the intestinal microbiota generates 3, 7, and 12 oxo-bile acid analogues which contribute for a significant fraction (20–30%) of the bile acid metabolites produced by gut microbiota in the colon (Table 1). The bacterial genes involved in generation of oxo-bile acids are the 3α, 7α and 12α-hydroxysteroid dehydrogenases (HSDHs), which are mainly found in Clostridium clusters XIVa (i.e., C. scindens, C. hiranonis, and C. hylemonae), IV, and XI (Table 2) [5]. These oxo-bile acids are gaining growing attention because the ability of some 3-oxo-bile acids to bind to the retinoid-related orphan receptor (ROR)ɣt [16, 17]. In humans, the bile acid pool consists of CA (≈40%), CDCA (≈ 40%), DCA (≈ 20%), with a glycine over taurine conjugation ratio of 3–1 [18].
In rodents, there are additional bile acids, the α- and β-muricholic acids (MCA), generated in the liver from CDCA [19, 20]. These bile acids represent the product of specific murine gene, Cyp2c70, which is absent in human, and as such Cyp2c70−/− mice present a bile “humanized” bile acid profile [20,21,22]. Accordingly, the T conjugated of α- and β-MCA are primary bile acids in mice, while ω-MCA, generated from the two MCAs in the intestine, is a secondary bile acid. As such, there is almost no CDCA in mice, and while >90% of bile acids are T conjugated, the bile acid pool is made up by TCA (≈ 60%) and Tα-MCA and Tβ-MCA (≈ 40).
The large majority of bile acid species that reach the terminal ileum is reabsorbed by the intestinal epithelial cells (IEC) and transported back to the liver through the portal vein, completing a cycle in the so-called “entero-hepatic circulation” [2, 3]. A number of transporters and transcription factors are involved in the regulation of bile acid synthesis and metabolism in the liver and intestine and are described in Figs. 1 and 2 [2, 3, 15].
Bile Acid-Activated Receptors and Intestinal Immune Cells
Bile acids function as ligands for various receptors collectively known as “bile acid-activated receptors (BAR),” a family of cell membrane and nuclear receptors (Table 3) mainly expressed in the entero-hepatic system [15]. The best characterized of these receptors are the farnesoid-x-receptor (FXR, NR1H4), a nuclear transcription factor activated by primary bile acids, originally described in 1995 and deorphanized in 1999 [23,24,25], and the G-Protein Bile Acid-activated Receptor (GPBAR)-1, also known as TGR5, a seven-transmembrane G-protein-coupled receptor discovered in 2002 [26, 27] (Table 3). In addition, primary and secondary bile acids activate other nuclear receptors including the pregnane-x-receptor (PXR) [28], the constitutive androstane receptor (CAR) [29] and the vitamin D receptor (VDR) [111, 112] (Tables 8 and 9).
RORγt and IBD
RORγt is selectively expressed by Th17 lymphocytes and innate lymphoid cell group 3 (ILC3), acting as a critical transcription factor for Th17 cell differentiation in chronic inflammation and autoimmune diseases [113]. On the other hand, ROR-γt-dependent ILC3 provide a protective immunity [114,115,116,117]. Recently, S. Hang et al. [16] and X. Song et al. [17] have shown that oxo-bile acid derivatives, specifically the 3-oxo-LCA, can bind RORγt by acting as an inverse agonist. Both groups have shown that in a mouse models of colitis, the binding of RORγt decreases IL-17 production and Th17 cell number and attenuates intestinal inflammation. These data are consistent with finding that pharmacologic inhibition of ROR-γt provides therapeutic benefits in mouse models of intestinal inflammation and reduces the frequencies of Th17 cells but not ILC3s [118]. Studies in patients with IBD have shown that Th17 lymphocytes are involved in the pathogenesis of both CD and UC [119,120,121,122,123]. IL-17 expression in the mucosa and serum is increased in IBD patients and correlates with an increase in the expression of RORγt and the number of Th17 cells [124,125,126]. Despite that these data might suggest that transient inhibition of RORγt could be an effective in IBD and secukinumab a IL-17A blocking mAB has been shown beneficial in rheumatoid arthritis, a phase 2 clinical trial in active CD patients was interrupted for lack of efficacy and higher rate of adverse events in comparison with placebo [127]. Small molecules inverse agonist of RORγt may be, therefore, an alternative and effective approach to control Th17 immunity in IBD while boosting ILC3 function [128].
Vitamin D Receptor (VDR) and IBD
The VDR is a nuclear receptor activated by 1,25-dihydroxyvitamin D. The receptor is involved in the regulation of human metabolism, immunity, and cancer [129,130,131]. VDR is also activated by the secondary bile acid LCA and its metabolites (3-oxoLCA and iso-alloLCA) [17, 30]. VDR is mainly expressed in bone and intestine [132], but also in immune cells [133], and modulates both the innate and adaptative immune responses [129]. VDR activation blocks B cell proliferation and differentiation [134, 135], inhibits T cell proliferation [136], promotes a shift from a Th1 to a Th2 phenotype [137, 138], and drives T cell maturation facilitating the induction of T regulatory cells [139,140,141,142] and reducing the Th17 cell formation [143, 144]. In addition, it inhibits the production of inflammatory cytokines by monocytes such as IL-1, IL-6, IL-8, IL-12, and TNFα [145], and the differentiation and maturation of dendritic cells [146,147,148]. Results from preclinical models in mice have widely shown that vitamin D reduces the severity of colitis [149,150,151]. Vitamin D dietary deficiency exacerbates the symptoms in IL-10−/− mice in a model of enterocolitis, whereas dietary vitamin D supplementation improves diarrhea and prevents weight loss [152]. In addition to immune cell modulation, the VDR seems to be involved in regulating IEC homeostasis. Transgenic expression of human VDR in murine IEC is reported to protect mice from colitis by reducing IEC apoptosis and promoting the maintenance of intestinal mucosal barrier [153]. Accordingly, IEC-specific VDR KO mice show a more severe colitis and higher expression of TNF-α, IL-1β, and MCP-1 than wild-type mice [154, 155].
VDR signaling plays a beneficial role in clinical IBD [156, 157]. First of all, VDR polymorphisms (TaqI, BsmI, FokI, and ApaI) are associated with susceptibility to CD and UC [158]. In general, the distribution of VDR in intestinal tissue in patients with IBD correlates with mucosal inflammation. Low vitamin D levels in the plasma are associated with a poor prognosis, such as higher risk of surgery or increased risk of clinical relapse, in patients with UC [159]. In another study, Zator et al. proposed that low vitamin D levels may lead to earlier cessation of TNF-α therapy [160]. Furthermore, in a randomized double-blind placebo-controlled study, Jorgensen et al. showed that daily oral supplementation with 1200 IE vitamin D3 increased serum vitamin D levels and reduced the risk of relapse in CD patients from 29% to 13% (p = 0.06) [161]. However, the obtained result was not statistically significant; thus, further studies with larger populations are needed. In another clinical study, vitamin D (300,000 IU administered intramuscular) decreased the serum erythrocyte sedimentation rate and high-sensitivity C-reactive protein levels, in UC patients in remission after 90 days [162]. The beneficial effects of VDR signaling may be attributed to alterations in the resident microbiota. In two recent studies, the microbiota of CD and UC patients changed after early vitamin D administration [163, 164]. Other groups reported that vitamin D deficiency might worsen colitis through multiple effects including alterations of the gut microbiome [153, 165,166,167,168]. To date, however, we have only few available randomized double-blind, placebo-controlled studies investigating therapeutic effects of vitamin D in IBD.
PXR
PXR is a promiscuous receptor that, in addition to many endo- and xeno-compounds, accomodates LCA, thus functioning as LCA sensor [28].The human PXR is activated by the intestinal restricted antibiotic rifaximin, and its activation represses the intestinal immune response in a NF-KB-dependent manner [169, 170]. Additionally, probiotic metabolites activate intestinal PXR [171]. Several studies have investigated the genetic associations of the PXR gene polymorphism with IBD. Although a meta-analysis that included 6 studies suggested that 3 PXR SNPs (rs1523127, rs2276707, and rs6785049) had no obvious influence on the risk of IBD in Caucasians patients, further studies are needed to confirm the results [172]. PXR is expressed in human CD4+ and CD8+ T lymphocytes, CD19+ B lymphocytes, and CD14+ monocytes, and its activation in both mouse and human T cells inhibits T cell proliferation and CD25 and IFN-γ expression in vitro. In vivo PXR activation by pregnenolone 16α-carbonitrile (PCN a human PXR agonist) is protective against DSS-induced colitis due to the activation of phase II enzymes and cellular efflux transporters, such as GSTa1, MDR1a, and MRP2, which alleviates the expression of the pro-inflammatory cytokines IL-6, TNF-α, ΜCP-1, and IL-1β [169]. The protective effects are abrogated by PXR gene ablation. Mechanistically, PXR activation inhibits the activating effects of TNF-α on NF-κB. Rifaximin is an agonist for human, but not rodent, PXR. Using primary fetal human colon epithelial cells, Mencarelli et al. in this laboratory were able to show that rifaximin represses the expression of IL-6, TNF-α, and IL-8 mRNAs and promotes the expression of TGF-β by repressing lipopolysaccharide-induced NF-κB DNA-binding activity. These protective effects were abrogated PXR gene silencing in human macrophages [170]. As an antibiotic, rifaximin inhibits bacterial translocation, adhesion, and internalization [173]. Consistent with this view a randomized, double-blind placebo-controlled study has demonstrated that treating CD patients with a high dose formulation of rifaximin results in a higher 12-week clinical remission rate than placebo [174]. Rifaximin also effectively maintains remission in CD patients who had achieved remission with a standard therapy (100% of rifaximin-treated versus 87% of placebo-treated patients) [174].
Sphingosin1-Phosphate Receptor 2 (S1PR2)
The sphingosine1-phosphate (S1P) receptor 2 (S1PR2) is expressed in the ileum and colon and is activated by conjugated primary bile acids (GCA and TCA and GCDCA and TCDCA) [109]. Preliminary data suggest that S1PR2 deletion exacerbates intestinal inflammation caused by DSS in mice and that a S1P/S1PR2 pathway modulates MHC-II expression and regulates CD4+T-cell proliferation via the extracellular signal-regulated kinase (ERK) pathway [175, 176]. Zonulin-1 expression is increased by S1P analogue and decreased by S1PR2 antagonist. Several S1P modulators with differing selectivity toward S1P receptors have been advanced for clinical development for IBD. The S1PR1 antagonist ozanimod (RPC1063) has provided encouraging results in the Phase 2 TOUCHSTONE trial, and a Phase 3 trial in patients with moderate-to-severe UC is ongoing [177]. Etrasimod, a S1Pr1, S1pR3, and S1Pr5 antagonist, has also been investigated in patients with moderately to severely active UC. At the dose of 2 mg etrasimod was found more effective than placebo in producing clinical and endoscopic improvement, suggesting that further investigations are warranted [178]. Both ozanimod and etrasimod inhibit various S1PRs but not S1PR2; therefore, the role of S1PR2 in IBD remains to be proven.
Conclusions: Are Bile Acid-Based Therapies an Opportunity in IBD?
The data discussed so far illustrate that not only a dysregulation of bile acid signaling mediates the dysfunctional communication between the intestinal microbiota and immune system in IBD, but that bile acid-based therapies could by exploited for treating IBD. A number of the bile acid-activated receptors are altered in IBD patients, and restoring bile acid signaling might be beneficial in IBD as demonstrated for VDR and PXR. The two main bile acid receptors FXR and GPBAR1, however, have been poorly investigated for their therapeutic potential in this setting, despite the fact that a defective expression of FXR, gene and protein, increases the propensity to develop inflammation in mice and in humans. At the moment, there are no FXR agonists under development for IBD, but several non-selective and intestinal FXR selective agents are currently available. It could be anticipated, however, that there will be several drawbacks in using FXR ligands in treating IBD. First of all, FXR ligands cause side effects, the most common of which being itching. This side effect is dose dependent, and almost all currently available synthetic FXR ligands cause itching in a dose-dependent manner [179]. Additionally, FXR ligands exert profound effects on bile acid synthesis and cholesterol metabolism [109]. Because one of the main mechanisms involved in FXR-dependent inhibition of bile acid synthesis is the FGF15-/FGF-19-mediated repression of Cyp7A1, activation of intestinal FXR will result in liver repression of bile acid synthesis. The biological relevance of this effect in IBD patients remains unclear, but casts severe doubt that an FXR ligand could ever be developed for IBD.
In contrast, there is an increasing interest for GPBAR1 agonists. The expression of GPBAR1 is restricted to the intestine, and the receptor is not expressed by liver parenchymal cells. Data from preclinical models suggest that GPBAR1 ligand [102] exerts profound immune modulatory effects in rodent models of colitis. Potential side effects of a GPBAR1 ligand might include, again, itching since GPBAR1 (TGR5) activation has been associated with bile acid-induced pruritus in rodents, and its ablation attenuated pruritus caused by topical application of bile acid to the skin [103]. Because there are no GPBAR1 ligands currently under development, it is unclear whether or not the receptor mediates itching in humans. However, UDCA which we have shown to be a weak GPBAR1 ligand has been used to treat IBD and experimental data suggest a potential useful role for this agent in this setting [180,181,182,183,184,185]. Another potential complication of a GPBAR1 ligand could be diarrhea.
RORγt ligands hold potential in treating IBD, and works are in progress to identify RORγt reverse agonists (i.e., antagonists) to target intestinal inflammation.
Finally, there are several approaches that could be used for indirect modulation of intestinal FXR, GPBAR1, and RORγt by harnessing the intestinal microbiota by using probiotics or fecal microbial transplantation [6, 186,187,188,189,190,191]. Development of live bio-therapeutics engineered to produce ligands for beneficial receptors is another appealing possibility.
In conclusion, moving from the intestinal surface that promotes nutrient absorption, bile acids and their receptors have been revealed as an essential component of the chemical communications between the intestinal microbiota and the host. Altered bile acid signaling impacts on intestinal homeostasis and promotes the immune dysfunction seen in IBD, making bile acid receptors an interesting therapeutic target in IBD.
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Prof. Stefano Fiorucci, is listed as an inventor of some of the compounds mentioned in this paper: INT767 (Intercept Pharmaceuticals), BAR501 and BAR502 (Bar Pharmaceuticals) and has received research grants from BAR Pharamceuticals. The other authors do not have any conflict of interest to be disclosed.
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Fiorucci, S., Carino, A., Baldoni, M. et al. Bile Acid Signaling in Inflammatory Bowel Diseases. Dig Dis Sci 66, 674–693 (2021). https://doi.org/10.1007/s10620-020-06715-3
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DOI: https://doi.org/10.1007/s10620-020-06715-3