FXR is mainly expressed in the ileum and liver, and regulates various genes encoding for bile Enzastaurin MM acid transport proteins, including apical sodium-dependent bile acid transporter (ASBT) and ileal bile acid binding protein (IBABP) [1], [2]. Expression of the enterokine fibroblast growth factor (FGF)15 (human orthologue FGF19), which induces gallbladder (GB) refilling in the mouse, is also controlled by FXR [3]. It has been hypothesized that FGF15 functions as an ��ileal brake�� by signaling the end of the postprandial and return to the interdigestive phase. More recent data indicate a role for FXR in the regulation of lipid and glucose metabolism [4], [5]. There is clear evidence that the ileum is a key location where prevention of excessive intestinal inflammation and maintenance of intestinal barrier (both at the level of the small intestine and the colon) are orchestrated.

Patients with Crohn’s colitis (CC) are known to have an impaired antibacterial defense and impaired intestinal barrier function. For example, endogenous antimicrobial peptides such as ��-defensins are produced in the ileum, and their levels are reduced in Crohn’s disease, thereby compromising mucosal host defence [6]. In addition, phospholipid concentration and composition in the colonic mucus layer (pivotal in intestinal barrier function) are dependent on bile acid-induced phospholipid secretion in the ileum with subsequent spread to the distal colon by propulsory motility, and these are deficient in patients with Inflammatory Bowel Disease (IBD) [7], [8].

Finally, FXR has been implicated in maintaining intestinal barrier integrity and in the prevention of intestinal bacterial overgrowth [9]. According to recent data, patients with CC have an altered FXR expression in areas of inflamed mucosa [10]. In two murine models for colitis, we recently showed that the administration of a semi-synthetic FXR agonist ameliorates intestinal inflammation, with improvement of colitis symptoms, preservation of intestinal barrier function, reduced goblet cell loss and inhibition of proinflammatory cytokine expression [11]. The underlying mechanism for these anti-inflammatory effects is thought to be inhibition of NF-��B [11], [12]. Furthermore, we recently found reduced FXR target gene expression in the ileum of patients with clinically quiescent CC [13]. The aim of this study was to investigate whether pharmacological activation of FXR with its endogenous ligand chenodeoxycholic acid (CDCA) is feasible in patients with Brefeldin_A CC. As a read-out for FXR activation as well as to obtain more insight in the regulation of gallbladder motility in the fasted state, we also measured serum FGF19 levels and determined GB volumes after CDCA ingestion.