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Toxic bile and sclerosing cholangitis: Is there a role for pharmacological interruption of the bile acid enterohepatic circulation?

C hronic fibrosing cholangiopathies, such as primary sclerosing cholangitis (PSC), are characterized by biliary fibrosis, development of cholestasis, and end-stage liver disease as well as the associated complications of portal hypertension and high risk for malignancy. For PSC, the pathogenesis is poorly understood and there is no medical treatment with proven efficacy. Bile acids (BAs) are likely to play a role either directly or indirectly in the pathogenesis or progression of the chronic fibrosing cholangiopathies. Indeed, it has been proposed that bile duct injury may be a result, in part, from “toxic bile.” As such, interventions that correct the abnormal bile composition may provide new insights to the underlying pathophysiology and avenues for treatment. Such an example is the recent work in the current issue of HEPATOLOGY, where the investigators treated mice lacking the phosphatidylcholine flippase (MDR2; gene symbol: ABCB4), a wellcharacterized animal model of chronic cholestasis, with a small molecule inhibitor of the ileal apical sodiumdependent bile acid transporter (ASBT). Hepatic bile formation depends on the synthesis, canalicular secretion, and efficient intestinal reabsorption of BA. In fact, only around 5% of biliary BAs are newly synthesized, and most have already been secreted by the liver into small intestine and returned by the enterohepatic circulation. Active reabsorption of BA in the small intestine is mediated by the ASBT (also called IBAT; gene symbol: SLC10A2), an efficient uptake system specific for BAs whose intestinal expression is restricted to the terminal ileum. As the major portal for intestinal reclamation of BA, the ASBT was initially targeted for development of nonabsorbable, high-affinity inhibitors (ASBTis) as more palatable alternatives to BA sequestrants for treatment of hypercholesterolemia. More recently, ASBTis are being explored as potential therapies for chronic constipation, and constipation-predominant irritable bowel syndrome, whereby reducing active ileal absorption of BAs increases the flux of BAs into the colon to stimulate colonic secretion and motility. However, interrupting the enterohepatic circulation of BAs by blocking the ASBT may also reduce the circulating BA pool and hepatic levels of potentially cytotoxic BA in cholestatic liver disease. In brief, 30-day-old female Mdr2 mice were treated with a minimally absorbable ASBTi for 2 weeks. After confirming that fecal excretion of BAs was elevated in Mdr2 mice after treatment with the ASBTi, in agreement with the known effects on ileal absorption and derepression of hepatic BA synthesis, the investigators proceeded to characterize the hepatic response of the mice. Serum, liver, and bile levels of bile acids were reduced, as were plasma markers of liver injury and cholestasis (alanine aminotransferase, alkaline phosphatase, and total bilirubin) in ASBTi-treated Mdr2 mice. Liver histology was significantly improved, with reductions in periportal inflammation, bile duct proliferation, necrosis and fibrosis, and markers of cholangiocyte proliferation. Livers from ASBTi-treated Mdr2 mice also showed reduced levels of F4/80CD11b Kupffer cells and Gr1CD11b neutrophils, as well as a shift in the monocyte population with reduction in the proinflammatory Ly6c subset and increase in antiinflammatory Ly6c cells. Overall, the results generally support the concept that toxic bile plays an important role in the pathogenesis of sclerosing cholangitis. However, details of the molecular mechanisms underlying the protection conferred by blocking ileal absorption of BAs are still unclear. Abbreviations: ASBT, apical sodium-dependent bile acid transporter; ASBTi, apical sodium-dependent bile acid transporter inhibitor; BAs, bile acids; PSC, primary sclerosing cholangitis. Received November 13, 2015; accepted November 23, 2015. This work was supported by NIH research grant DK047987 (P.A.D). Address reprint requests to: Paul A. Dawson, Ph.D., Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Health Sciences Research Building, 1760 Haygood Drive Northeast, Suite E200, Atlanta, GA 30322. E-mail: paul.dawson@emory.edu; fax: 11 404-727-5737. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.28363 Potential conflict of interest: Dr. Dawson has previously consulted for Lumena.