Altered enterohepatic circulation of bile acids in Crohn's disease and their clinical significance: a new perspective

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Date: Jan. 2013
Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 6,401 words
Lexile Measure: 1440L

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Author(s): Jonathan D Nolan 1 , Ian M Johnston 1 , Julian RF Walters [*] 2

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bile acids; bile acid malabsorption; Crohn's disease; FGF19; FXR; FXR agonists

Bile acid homeostasis & the enterohepatic circulation of bile acids

Bile acids (BA) are the end product of cholesterol metabolism and their secretion is the main determinant of hepatic bile flow. Bile is released into the duodenum after a meal in response to cholecystokinin (CCK) which induces contraction of the gallbladder (GB) and relaxation of the sphincter of Oddi. The amphipathic nature of BA enables them to emulsify the lipid component of a meal and form mixed micelles with fatty acids and monoglycerides within the small bowel. This greatly enhances the passive diffusion and absorption of fatty acids and monoglycerides at the brush border membrane.

The majority of BA are conjugated and ionized before secretion from the liver, which ensures they stay in the intestinal lumen until they meet the BA transporter proteins of the terminal ileum. The specific BA transporter protein is the apical sodium-linked bile acid transporter (ASBT) which mediates a Na-dependent reabsorption of BA from the intestinal lumen, against a concentration gradient of BA into the enterocytes of the terminal ileum [1,2] . Passive diffusion of unconjugated BA throughout the distal small bowel also occurs but this is less important [3] . The ileal reabsorption of conjugated BA is highly efficient, with less than 5% of BA passing the ileum into the colon at each pass. The reabsorption of this specific component of biliary secretions in the distal small bowel leads to a pool of BA that cycles several times between liver and ileum after each meal. The BA pool is approximately 2-3 g; the liver secretes around 12 g per day but only needs to synthesize an average of 400 mg per day to keep up with the small amounts lost from the body. The homeostasis of this enterohepatic circulation of BA is complex; BA production in the liver matches the amount of BA lost in the feces.

BA-farnesoid X receptor-FGF19 signaling

In animal studies, diverting BA away from this enterohepatic circulation (such as a biliary fistula) will lead to increased hepatic biosynthesis [4] . However, animal models involving bile duct ligation, which increase hepatic concentrations of BA, are also found to have an increase in hepatic synthesis of BA [5] . In this situation, duodenal administration of BA (chenodeoxycholic acid [CDCA]) reduces hepatic BA synthesis but intravenous administration does not [6] . Thus, an intestinal negative feedback signal from the gut to the liver was proposed. In 2005, such a signal was found to be an atypical fibroblast growth factor, FGF15 in the mouse [7] . The orthologous gut hormone in humans is FGF19, a 21 kDa protein that is able to send negative-feedback signals to more proximal parts of the gastrointestinal system, similar to other distal gut hormones (PYY, enteroglucagon) [8,9] . FGF15/19 inhibits de novo BA synthesis by inhibiting the transcription of cholesterol 7[alpha]-hydroxylase CYP7A1, the rate limiting enzyme in the production of primary...

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Gale Document Number: GALE|A312892150