br Experimental Procedures Information on the materials

Experimental Procedures Information on the materials used in this study and the details of how the in vivo and in vitro assays were performed are provided in Supplemental Information.
Acknowledgments This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT [MSIP]; NRF-2015R1A2A1A10052663) for S.G.K. and the Basic Science Research Program through NRF funded by the Ministry of Education (2017R1D1A1B03028272) for C.Y.H. The authors thank Dr. Bart Staels (Institut Pasteur de Lille, Lille, France) for providing FXRE luciferase reporter.
Introduction Bile acids (BAs) derive from cholesterol and all share a sterol-ring structure. They are principal end products secreted from the liver upon a multistep conversion of the hydrophobic and insoluble cholesterol, and key regulators of a network of metabolic pathways [1]. Owing to their amphipathic nature, BAs solubilise dietary lipids and improve their NVP-LCQ195 in the gastrointestinal (GI) tract. In addition, they influence the intestinal microflora and affect intestinal cell integrity [2]. In healthy humans the level of BAs secreted daily in the liver depends on cycles of fasting and refeeding and fluctuates between 200 and 600 mg per day [3]. The variations in the BA pool are controlled by the farnesoid X receptor (FXR)-dependent pathways. FXR is expressed predominantly in the liver, kidney and intestine and regulates the activation of several genes involved in maintaining BA homeostasis [4]. An increasing body of evidence suggests that modulation of FXR activity both in the liver and in the intestine reduces inflammation and epithelial permeability by decreasing the level of proinflammatory mediators in the gut. Furthermore, intestinal FXR activation induces the transcription of genes participating in enteroprotection as well as prevents bacterial invasion and epithelial injury in the intestine [4]. Therefore, targeting FXR both in the liver and in the intestine is a tempting approach in the development of potential therapeutics for patients with functional GI disorders (FGIDs), such as irritable bowel syndrome (IBS) or chronic constipation (CC) [5].
FXR and its role in BA turnover Any imbalance in BAs homeostasis, especially an increase in BA levels can have a deleterious toxic effect not only to the liver, a major organ involved in the synthesis and conjugation of BAs, but also to the colon, where further BA modifications take place [5], [6]. The conversion of cholesterol into BA is complex and requires the action of at least 17 liver enzymes, in which cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1) are the key regulators belonging to the cytochrome P450 family [1]. Two pathways, classic and alternative, serve as dominant regulators of BA synthesis. CYP7A1 is the main enzyme that catalyzes the first and rate-limiting step in the classic BA biosynthetic pathway, whereas CYP27A1, an essential catalyst of the alternative pathway, utilizes the side-chain of oxysterols followed by 7α-hydroxylation. The primary products of hydroxylation of cholesterol by CYP7A1 in the human liver are cholic acid (CA) and chenodeoxycholic acid (CDCA), which ratio is predominantly controlled by CYP8B1. To increase the solubility and decrease toxicity of acids both CA and CDCA undergo conjugation with glycine or taurine in the hepatocytes (predominant in humans and mice, respectively). Conjugated forms of CA and CDCA are then secreted into the biliary tract and transported either to the gall bladder and stored there until released into the duodenum upon ingestion of a meal, or to the intestines [1]. It is important to emphasize that the primary products obtained through cholesterol metabolism differ between species (Table 1[8], [9], [10], [11]). For example, in mice an additional step is compulsory to convert CDCA into muricholic acid (α- and β-MCA), which along with other hydrophilic BA, omega-muricholic acid (ω-MCA) and CA, are main components of murine BA pool [7].