Molecular physiology of bile acid signaling in health, disease, and aging

Several diseases and conditions have been associated with an uncontrolled rise in bile acid (BA) concentrations. This is often the case when the tight feedback regulation of BA synthesis is compromised to the point that BAs become detrimental. BAs and their cognate receptors, farnesoid X receptor (FXR) and Takeda G-protein receptor 5 (TGR5), however, exert many beneficial roles as they enable tissues to adapt to environmental, nutritional, and physiological cues. Over the last two decades, BA mimetics targeting FXR, TGR5, or both, have been proven to be efficacious in alleviating chronic metabolic and inflammatory disorders, such as obesity, Type 2 diabetes (T2D), atherosclerosis and non-alcoholic steatohepatitis (NASH). While several aspects of BA signaling are still poorly understood, the first therapeutics targeting FXR are making their way into the clinic to treat liver diseases, such as primary biliary cholangitis (PBC) and NASH. Drugs targeting BA signaling may, hence, have a bright future and the continuing efforts on studying the impact of changing BA signaling pathways in humans will be beneficial to translate our emerging knowledge on BA physiology in model organisms into clinical benefits.