The Farnesoid X Receptor: Good for BAD

Abstract

Diarrhea is a feature of several chronic intestinal disorders that are associated with increased delivery of bile acids into the colon. Although the prevalence of bile acid diarrhea is high, affecting approximately 1% of the adult population, current therapies often are unsatisfactory. By virtue of its capacity to inhibit colonic epithelial fluid secretion and to down-regulate hepatic bile acid synthesis through induction of the ileal fibroblast growth factor 19 release, the nuclear bile acid receptor, farnesoid X receptor, represents a promising target for the development of new therapeutic approaches. Here, we review our current understanding of the pathophysiology of bile acid diarrhea and the current evidence supporting a role for farnesoid X receptor agonists in treatment of the disease.

Keywords: ASBT, apical sodium-linked bile acid transporter; BAD, bile acid diarrhea; Bile Acid Diarrhea; C4, 7α-hydroxy-4-cholesten-3-one; CA, cholic acid; CDCA, chenodeoxycholic acid; Chloride Secretion; DCA, deoxycholic acid; EHC, enterohepatic circulation; Enterohepatic Circulation; Epithelium; FGF-19; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; LCA, lithocholic acid; OCA, obeticholic acid.

Figure 1

The FXR in regulation of the enterohepatic circulation. Bile acids (BAs) are synthesized in the hepatocyte by CYP7A1 and secreted into the enterohepatic circulation (orange arrows) by the bile salt export pump (BSEP). In ileal enterocytes, BAs are absorbed through the ASBT, bind to the ileal bile acid binding protein (IBABP), and are pumped into the portal circulation by the basolateral organic solute transporter (OST)α-OSTβ dimer. BAs are taken back up into hepatocytes by the Na⁺-taurocholate co-transporting polypeptide (NTCP). Treatment with FXR agonists (blue lines) induces expression of short heterodimeric partner (SHP) in the liver and of FGF19, IBABP, OSTα-OSTβ, and SHP in ileal enterocytes. FGF19 enters the portal circulation and acts on FGF receptor 4–Klothoβ receptors in hepatocytes (purple arrows) to inhibit CYP7A1 expression. SHP also down-regulates CYP7A1 expression in hepatocytes, further dampening BA synthesis. With each cycle of the EHC, a small proportion of the bile acid pool enters the colon where it is metabolized by the resident microbiota into deconjugated secondary bile acids. In primary BAD, impaired FGF19 production results in increased CYP7A1 expression and enhanced hepatic synthesis of bile acids. In turn, this results in a larger bile acid pool with increased colonic delivery.

Figure 2

The FXR in regulation of bile acid (BA)-induced colonic fluid secretion. Increased colonic delivery of dihydroxy BAs, such as DCA and CDCA, increases epithelial levels of the intracellular second messengers, Ca²⁺ and adenosine 3′,5′-cyclic monophosphate (cAMP), either by direct (solid black lines) or indirect actions, involving the enteric nervous system (ENS) and the mucosal immune system (MIS) (dashed black lines). These second messengers interact with specific transport proteins to promote transepithelial Cl^- secretion, thereby creating an osmotic driving force for fluid secretion, ultimately leading to the onset of diarrhea. Treatment with FXR agonists (blue lines) dampens epithelial fluid secretion by down-regulating the activity and expression of basolateral Na⁺/K⁺ adenosine triphosphatase (ATPase) pumps and apical cystic fibrosis transmembrane conductance regulator (CFTR) channels, key transport proteins of the Cl^- secretory pathway.