Bile-acid receptor signaling axis

The bile-acid receptor signaling axis is a complex physiological network that coordinates bile acid homeostasis, nutrient metabolism, and inflammatory signaling across the enterohepatic system (Trauner & Jansen, ResearchGate, 2013). It primarily involves the nuclear farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1/TGR5), which serve as sensors for various bile acid species (Physiology.org, 2024). Activation of these receptors regulates the synthesis, transport, and detoxification of bile acids, notably through the induction of fibroblast growth factor 19 (FGF19) in the ileum and its subsequent signaling through FGFR4 in the liver (NIH.gov, 2021). Beyond bile acid regulation, the axis influences glucose and lipid metabolism, energy expenditure, and immune cell function (NIH.gov, 2022). This axis is a major therapeutic target for cholestatic liver diseases like primary biliary cholangitis and metabolic disorders such as non-alcoholic steatohepatitis (NASH) (NIH.gov, 2022). Pharmacological modulation of the axis, including FXR agonists and TGR5 modulators, aims to alleviate hepatic stress and metabolic dysfunction, though clinical use is often limited by side effects like pruritus and dyslipidemia (MDPI.com, 2024). Emerging research also explores the role of this axis in the gut-microbiome-liver crosstalk and its implications for cancer and neurodegenerative diseases (Frontiersin.org, 2024).

Other names

Bile acid signaling pathwayFXR-TGR5 signaling axisBile acid-activated receptor signalingGut-liver bile acid axis

Drugs targeting this axis primarily act as agonists of the farnesoid X receptor (FXR) or the G protein-coupled bile acid receptor 1 (TGR5) to modulate bile acid synthesis and metabolic pathways. FXR agonists induce the expression of small heterodimer partner (SHP) and fibroblast growth factor 19 (FGF19), which inhibit the rate-limiting enzyme CYP7A1 to reduce bile acid production. TGR5 agonists stimulate the release of glucagon-like peptide-1 (GLP-1) and increase energy expenditure. Additionally, inhibitors of the apical sodium-dependent bile acid transporter (ASBT/IBAT) modulate the axis by reducing bile acid reabsorption, thereby lowering the systemic bile acid pool and indirectly influencing receptor signaling.