New approach methodologies (NAMs) to understand and predict drug-induced effects on bile acid homeostasis and cholestasis

Abstract

General introduction1.1 Bile acids as signaling molecules Bile acids are the major functional components of bile, and have been known to serve as emulsifiers of dietary lipids and lipid-soluble vitamins for a long time (Hofmann, 1961). Bile acids are found throughout the whole body, but mainly in the liver, gall bladder and intestine (Jantti et al., 2014; Monteiro-Cardoso et al., 2021). Besides their role as emulsifiers in the intestinal lumen, bile acids are increasingly recognized as important hormone-like signaling molecules regulating lipid, glucose and energy metabolism and innate and adaptive immune functions in the whole body (Jia et al., 2023;Hylemon et al., 2009). Bile acids exert these signaling functions via binding to numerous nuclear receptors, such as the farnesoid X receptor (FXR, NR1H4), the G protein-coupled bile acid receptor (TGR5, GPBAR1), vitamin D receptor (VDR, NR1I1) and pregnane X receptor (PXR, NR1I2) (Guo et al., 2003; Makishima et al., 2002; Anstee et al., 2013). Two major pathways include those regulated via FXR and TGR5 (Fiorucci et al., 2009). FXR is highly expressed in the gastrointestinal tract . FXR tightly controls bile acid homeostasis by regulation the expression of genes related to bile acid synthesis, secretion and absorption. FXR also acts as a metabolic sensor in glucose metabolism, lipid and energy metabolism (Chiang, 2017), and regulates cell proliferation and inflammation (Fiorucci et al., 2011). Furthermore, FXR-deficient mice were shown to have increased colon cell proliferation rates and subsequent tumorigenesis compared to wildtype mice, indicating that FXR has anti-tumorigenic properties (Maran et al., 2009). TGR5 is not only expressed throughout the intestinal epithelium, but also in monocytes and macrophages, liver sinusoidal endothelial cells and Kupffer cells, but not in hepatocytes . TGR5 regulates amongst others energy homeostasis, intestinal integrity, insulin secretion, cell proliferation and inflammation (Ticho et al., 2019; Guo et al., 2016).Bile acids are involved in the crosstalk between the host and the gut microbiome in the intestinal lumen. The gut microbiome is a dynamic ecosystem that plays a pivotal role in shaping various aspects of human physiology and heath (Visconti et al., 2019). Comprising more than 100 trillion microorganisms, the microbiome forms a symbiotic relationship with the host, influencing essential functions ranging from digestion to immune response modulation (Comess and Abad-Jorge, 2023). Several microbial species in the microbiome possess the ability to modify bile acid structures. These modifications result in different bile acid species with different kinetic and signaling properties.For example, the first bacterial modification step is deconjugation of bile acids. Deconjugation improves membrane-permeability and thereby intestinal reuptake of bile acids . Furthermore, the affinity for the nuclear receptors depends on the type of bile acid formed, since some types of bile acids are more potent ligands for nuclear recept...