Review article: therapeutic aspects of bile acid signalling in the gut-liver axis

Abstract

Background: Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues.

Aim: This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies.

Methods: We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease.

Results: Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target.

Conclusions: Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.

FIGURE 1

Regulatory pathways of bile acid synthesis. Primary bile acids (BA) are synthesised from cholesterol in hepatocytes, following either the “classical” or the “alternative” pathway. In the classical pathway, cholesterol is first modified by CYP7A1 and subsequently by CYP8B1 to produce cholic acid (CA) or, alternatively by CYP27A1 to produce chenodeoxycholic acid (CDCA). In the alternative pathway, CYP27A1 initiates cholesterol modification, followed by CYP7B1‐dependent biotransformation, resulting in formation of CDCA. Expression of CYP7A1 is the rate‐limiting enzymatic step for BA synthesis, while CYP8B1 defines the BA pool as it is critical for production of CA. Metabolisation of BAs by gut bacteria leads to the formation of the secondary BAs deoxycholic acid (DCA) and lithocholic acid (LCA). BA synthesis is mainly regulated by two mechanisms: First, intrahepatic farnesoid X receptor (FXR) activation induces the expression of small heterodimer partner (SHP), which suppresses the expression of CYP8B1 and (to a lesser extent) CYP7A1. Second, activation of FXR in the intestines induces the release of fibroblast growth factor‐19 (FGF19) into the portal venous system. FGF19 binds to the FGF receptor 4 (FGFR4) and its co‐receptor beta‐Klotho (KLB) on hepatocytes, thereby strongly suppressing CYP7A1 expression. Abbreviations: BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FGF19, fibroblast growth factor‐19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; KLB, beta‐Klotho; LCA, lithocholic acid; SHP, small heterodimer partner

FIGURE 2

Enterohepatic circulation of bile acids: anatomical overview. Primary bile acids (BA; indicated as green dots) are released into bile canaliculi and secreted into the duodenum, where they mediate absorption of nutrients, for example emulsification of lipids and fat‐soluble vitamins, and regulate signalling pathways in the gut‐liver axis. Metabolisation of BA by gut bacteria leads to the formation of secondary BAs. Most BAs undergo enterohepatic circulation: the highest proportion of BAs is reabsorbed in the ileum, transported into the portal circulation, and delivered back to the liver via the portal vein. After reuptake in hepatocytes, BAs are recycled and secreted into the bile, and again reach the gut, thus completing the enterohepatic cycle. Abbreviation: BA, bile acid

FIGURE 3

Bile acid gut‐liver axis signalling modulates the enterohepatic circulation, bile acid synthesis and glucose homeostasis. (i) Enterohepatic circulation of bile acids (BA) is contingent on four important transporters in the gut‐liver axis: ASBT, OST‐α/‐β, NTCP and BSEP. ASBT mediates BA uptake from the intestinal lumen (primarily ileum), whereas OST‐α/‐β releases BAs into the portal circulation. Ileal bile acid binding protein (IBABP) binds intracellular BAs and protects enterocytes from BA toxicity. NTCP facilitates BA uptake from sinusoidal blood into hepatocytes, and BSEP mediates BA secretion into bile canaliculi. Activation of FXR downregulates ASBT and NTCP and upregulates OST‐α/‐β, BSEP and IBABP (indicated in red and green color). (ii) Bile acid synthesis is regulated by the enterohepatic FXR‐FGF19 pathway, and the intrahepatic FXR‐SHP pathway. Activation of FXR in the intestines (primarily in the ileum) leads to release of FGF19 into the portal circulation, which represses BA synthesis (CYP7A1 gene) by binding to FGFR4/KLB (‘enterohepatic’ feedback signalling). Activation of FXR in hepatocytes induces expression of SHP, which acts as a transrepressor of genes for BA synthesis (“intrahepatic” feedback signalling). (iii) Activation of TGR5 on intestinal L‐cells induces release of GLP‐1, which induces insulin secretion and enhances glucose tolerance. Abbreviations: (ASBT) apical sodium dependent bile acid transporter; (BA) bile acids; (BSEP) bile salt export pump; (FXR) farnesoid X receptor; (FGF19) fibroblast growth factor 19; (FGFR4) FGF receptor 4; (GLP‐1) glucagon‐like peptide‐1; (IBABP) ileal bile acid binding protein; (KLB) beta‐klotho; (NTCP) sodium/taurocholate cotransporting polypeptide; (OST‐α/‐β) organic solute transporter alpha and beta; (SHP) small heterodimer partner; (TGR5) transmembrane G protein‐coupled receptor‐5

FIGURE 4

Bacterial translocation in cirrhosis: Pathophysiological aspects and therapeutic implications of bile acid signalling in the gut‐liver axis. Left upper panel: Advanced chronic liver disease (or cirrhosis) is associated with increased bacterial translocation, which is characterised by (i) dysbiosis and small intestinal bacterial overgrowth, (ii) reduced excretion of antibacterial peptides and mucus thickness, (iii) disruption of epithelial integrity associated with reduced expression of tight junction (TJ) proteins, and (iv) an impaired gut‐vascular barrier, which enables the translocation of gut bacteria and danger/pathogen associated molecular patterns (PAMPs/DAMPs) into the portal circulation. Right upper panel: Bacterial translocation induces—directly or indirectly—an intrahepatic inflammatory response, which comprises (i) activation of Kupffer cells (KC) and other immune cells associated with increased shedding of cytokines and systemic inflammation, (ii) activation of hepatic stellate cells (HSC) and induction of fibrogenesis and (iii) endothelial dysfunction of liver sinusoidal epithelial cells (LSEC) which aggravates portal hypertension. Left lower panel: Bile acid signaling may ameliorate intestinal barrier integrity and bacterial translocation via FXR‐ and TGR5‐mediated upregulation of antibacterial defense, TJ proteins, epithelial regeneration, which ultimately leads to amelioration of fibrogenesis, endothelial dysfunction and systemic inflammation in cirrhosis (data based on experimental studies in animals). Right lower panel: The clinical relevance of bacterial translocation in cirrhosis is underlined by the association of portal hypertension and systemic inflammation with the incidence of clinical complications that are associated with increased mortality. Abbreviations: DAMPs/PAMPs, danger/pathogen associated molecular patterns; EC, enterocyte; FXR, farnesoid X receptor; GC, goblet cell; HSC, hepatic stellate cell; KC, Kupffer cell; LSEC, liver sinusoidal epithelial cell; TGR5, transmembrane G protein‐coupled receptor‐5; TJ, tight junction