Toxic Bile and Sclerosing Cholangitis: Is there a role for pharmacological interruption of the bile acid enterohepatic circulation?

Chronic fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) are progressive liver disease, characterized by biliary fibrosis, development of cholestasis and end stage liver disease, and the associated complications of portal hypertension and high risk for malignancy¹. For PSC, the pathogenesis is poorly understood and there are is no medical treatment with proven efficacy. Bile acids (BA) 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 the 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 HEPATOLOGY², 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 about 5% of the biliary BA are newly synthesized, and most have already been secreted by the liver into small intestine and returned via the enterohepatic circulation. The 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 bile acids whose intestinal expression is restricted to the terminal ileum³. As the major portal for intestinal reclamation of BA, non-absorbable, high affinity ASBT inhibitors (ASBTi) were initially sought as more palatable alternatives to bile acid sequestrants for treatment of hypercholesterolemia⁴. More recently, ASBTi’s are being explored as potential therapies for chronic constipation, and constipation-predominant irritable bowel syndrome, whereby reducing active ileal absorption of bile acids increases the flux of bile acids into the colon to stimulate colonic secretion and motility⁵. However, interrupting the enterohepatic circulation of bile acids by blocking the ASBT may also reduce the circulating BA pool and hepatic levels of potentially cytotoxic BA in cholestatic liver disease⁶.

In brief, 30-day old female Mdr2^−/− mice were treated with a minimally absorbable ASBT inhibitor (ASBTi) for 2 weeks. After confirming that fecal excretion of bile acids was elevated in the Mdr2^−/− mice after treatment with the ASBTi, in agreement with the known effects on ileal absorption and derepression of hepatic bile acid synthesis, the authors proceeded to characterize the hepatic response of the mice. The serum, liver and bile levels of bile acids were reduced, as were plasma markers of liver injury and cholestasis (ALT, ALP, and total bilirubin) in the 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 the ASBTi-treated Mdr2^−/− mice also showed reduced levels of F4/80⁺CD11b⁺ Kupffer cells and Gr1⁺CD11b⁺ neutrophils, and a shift in the monocyte population with reduction in the pro-inflammatory Ly6c⁺ subset and increase in the 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 the ileal absorption of bile acids are still unclear. Total bile acid levels were measured in serum, liver, and bile of the Mdr2^−/− mice, but the levels of the individual hydrophobic and hydrophilic bile acid species were measured only in serum. As such, it is unclear whether the reduction in liver and bile was evenly distributed between the bile acid species or if the more hydrophobic and presumably more injurious bile acids were especially affected. RNAseq 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 the response is not molecule-specific, or when treated with an adeno-associated virus overexpressing forms of Fibroblast Growth Factor 19 (FGF19) to suppress hepatic bile acid synthesis ^8,9. As with Rome, there may be many paths leading to therapeutically alter the load or composition of the hepatic bile acid pool.

Altogether, this first description of the use of an ASBTi in this animal model of sclerosing cholangitis is supportive of an important role of bile acid cytotoxicity in the pathogenesis. This important work by Miethke et al also provides additional insight to the complex intersection between bile acids and hepatobiliary injury.

Abbreviations

ABC

ATP-binding cassette

ALP

alkaline phosphatase

ALT

alanine amino transferase

ASBT

apical sodium-dependent bile acid transporter

ASBTi

apical sodium-dependent bile acid transporter inhibitor

BA

bile acids

FGF19

Fibroblast Growth Factor 19

MDR

multidrug resistance

PSC

primary sclerosing cholangitis