Toxic bile and sclerosing cholangitis: Is there a role for pharmacological interruption of the bile acid enterohepatic circulation?
Authors: Paul A. Dawson
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Dawson has previously consulted for Lumena. This work was supported by NIH research grant DK047987 (P.A.D). See Article on Page 512 Chronic 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.1 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,2 where the investigators treated mice lacking the phosphatidylcholine flippase (MDR2; gene symbol: ABCB4), a well‐characterized animal model of chronic cholestasis, with a small molecule inhibitor of the ileal apical sodium‐dependent 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.3 As the major portal for intestinal reclamation of BA, the ASBT was initially targeted for development of nonabsorbable, high‐affinity ASBT inhibitors (ASBTis) as more palatable alternatives to BA sequestrants for treatment of hypercholesterolemia.4 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.5 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.6 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 F4/80+CD11b+ Kupffer cells and Gr1+CD11b+ neutrophils, as well as a shift in the monocyte population with reduction in the proinflammatory Ly6c+ subset and increase in anti‐inflammatory 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. Total BA levels were measured in serum, liver, and bile of Mdr2−/− mice, but levels of the individual hydrophobic and ‐philic BA species were measured only in serum. As such, it is unclear whether the reduction in liver and bile was evenly distributed between the BA species or whether the more hydrophobic, and presumably more injurious, BAs were especially affected. RNA sequencing was performed to follow global gene expression changes. However, many questions remain regarding the underlying molecular mechanisms responsible for the observed protection. A potential role for the microbiota cannot be excluded, as suggested by the recent study of Tabibian et al., where absence of the gut microbiota exacerbated the hepatobiliary disease in the Mdr2−/− model.7 Finally, it is reassuring that a similar protective response was also observed in Mdr2−/− mice when treated with another ASBTi, suggesting that the response is not molecule specific, or when treated with an adeno‐associated virus overexpressing forms of fibroblast growth factor 19 to suppress hepatic BA synthesis.8 As with Rome, there may be many paths to therapeutically alter the load or composition of the hepatic BA pool. Altogether, this first description of the use of an ASBTi in an animal model of sclerosing cholangitis is supportive of an important role of BA cytotoxicity in the pathogenesis. This important work by Miethke et al. also provides additional insight to the complex intersection between BAs and hepatobiliary injury. Author names in bold designate shared co‐first authorship.