A Current Understanding of Bile Acids in Chronic Liver Disease

Abstract

Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years in many countries. A recent understanding of nuclear bile acid receptor pathways has increased focus on the impact of crosstalk between the gut, bile acids, and liver on liver pathology. While conventionally used in cholestatic disorders and to dissolve gallstones, the discovery of bile acids' influence on the gut microbiome and human metabolism offers a unique potential for their utility in early and advanced liver diseases because of diverse etiologies. Based on these findings, preclinical studies using bile acid-based molecules have shown encouraging results at addressing liver inflammation and fibrosis. Emerging data also suggest that bile acid profiles change distinctively across various causes of liver disease. We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases.

Keywords: AD, Acute decompensation; ALP, Alkaline phosphatase; AMACR, α-methylacyl-CoA racemase (AMACR); ASBT, Apical sodium dependent bile salt transporter; BA, Bile acid; BSEP, Bile salt export pump; BSH, Bile salt hydrolase; CA, Cholic acid; CDCA, Chenodeoxycholic acid; CLD; CLD, Chronic Liver Disease; CTP, Child-Turcotte-Pugh; CYP7A1, Cholesterol 7 α hydroxylase; DCA, Deoxycholic acid; DR5, Death receptor 5; ELF, Enhanced Liver Fibrosis; FGF-19, Fibroblast growth factor-19; FGFR4, FGF receptor 4; FXR, Farnesoid X receptor; GCA, Glycocholic acid; GDCA, Glycodeoxycholic acid; GLP-1, Glucagon-like peptide1; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HVPG, Hepatic Venous Pressure Gradient; LCA, Lithocholic acid; LPS, Lipopolysaccharide; MELD, Model for End-Stage Liver Disease (MELD); MRI-PDFF, Magnetic resonance imaging derived proton density fat fraction; NAFLD; NAFLD, Non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, Nonalcoholic steatohepatitis; NTCP, Sodium taurocholate cotransporting polypeptide; OCA, Obeticholic acid; OST, Organic solute transporter; PBC, Primary biliary cirrhosis; PFIC, Progressive familial intrahepatic cholestasis; PSC, Primary sclerosing cholangitis; PXR, Pregnane X receptor; SHP, Small heterodimer partner; TBA, Total bile acids; TGR5, Takeda G-protein coupled receptor 5; TRAIL, TNF-related apoptosis-inducing ligand; UDCA, Ursodeoxycholic acid; UPLC-MS, Ultra-performance liquid chromatography with tandem mass spectrometry; VDR, Vitamin D receptor; bile acids; cirrhosis; microbiome.

Figure 1

Enterohepatic cycle: Primary bile acids are synthesized predominantly via the classic pathway (80%) and secreted via bile salt export pump (BSEP) following conjugation with glycine and taurine. Following storage, in the gallbladder, they are released postprandially into the proximal small bowel. The secreted bile acids are actively absorbed via luminal apical sodium-dependent bile salt transporter (ASBT) in the distal small bowel from where they are transported to the portal circulation via organic solute transporter (OST). The reabsorbed bile acids are taken up by hepatocyte sinusoidal membrane protein sodium taurocholate cotransporting polypeptide (NTCP) and resecreted. The efficient enterohepatic cycling enables reabsorption of up to 95% of the bile acids and loss of around 5% of the pool which is resynthesized. CYP7A1: cytochrome P450 family 7 subfamily A member 1; FGF-19:fibroblast growth factor 19; FGFR4: fibroblast growth factor receptor 4; FXR: farnesoid X receptor.

Figure 2

Bile acid signaling via nuclear and surface receptors. CA: cholic acid; cAMP: cyclic adenosine monophosphate; CDCA: chenodeoxycholic acid; CYP7A1: cytochrome P450 family 7 subfamily A member 1; DCA: deoxycholic acid; FGF19: fibroblast growth factor 19; FGFR4: fibroblast growth factor receptor 4; FXR: farnesoid X receptor; GLP-1: glucagon-like peptide-1; LCA: lithocholic acid; PRK A: phosphoribulokinase A; SHP: small heterodimer partner; TGR-5: takeda-G-protein-receptor-5.

Figure 3

Effect of progression of cirrhosis on bile acids and microbiota.