Treatment response of murine sclerosing cholangitis to systemic versus intestinal FXR agonists segregates with their effects on hepatic pro-inflammatory cytokine production

Oral presentation at XXV International Bile Acid Meeting: Bile Acids in Health and Disease, July 2018

Tiffany Shi1, Celine S. Lages1, Ramesh Kudira1, Louis Matuschek1, Mary Mullen1, Alvaro Ortiz2, Kyoung-Jin Lee2, Douglas Zook2, Brandee Wagner2, Alexander Miethke1

1. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
2. Metacrine, Inc., San Diego, CA, USA

Introduction: FXR agonists are potent therapeutic regulators of liver metabolic function. Their role in the treatment of inflammatory cholestatic liver disease is less defined. Here, we use Mdr2-/- mice, a model of defective canalicular excretion of phospholipids which leads to biliary precipitation of bile acids, cholangiocyte injury, sterile inflammation and fibrosis.

Methods: 45-day-old mdr2-/- female mice underwent oral gavage for 7 days with 30 mg/kg/day of systemic FXR agonist M345 or 100 mg/kg/day of intestinal FXR agonist M379, both derivatives of fexaramine, or with vehicle (corn oil) in controls. Serum liver biochemistries and bile acid levels were determined by colorimetric assays and liver and intestinal gene expression (8hr after the last oral dose of FXR agonist) was quantitated by Taqman-based qPCR.

Results: Compared to vehicle control mice, M345-treated mice displayed improved weight gain (+4.8 vs -0.9 g compared to baseline; p=0.00), lower serum liver biochemistries (ALT 298 vs 981 IU/L; p=0.01, ALP 149 vs 197 IU/L; p= 0.03, TB 1.2 vs 6.8 mg/dL; p= 0.01) and decreased serum bile acid levels (282 vs 923 umol/L; p=0.03). In contrast, M379-treated mice showed continued weight loss and no significant change in serum liver biochemistries or serum bile acid levels when compared to controls. While both M345- and M379 significantly induced intestinal Shp and Fgf15 gene expression and reduced hepatic mRNA expression of Cyp8b1 (down 91% vs 79%; p=0.22) and liver bile acid levels (down 38% vs 29%; p=0.36), only M345-treatment reduced hepatic TNFα mRNA expression when compared to controls (down-89%; p=0.00).

Discussion / Conclusion: While both systemic and intestinal FXR agonists down-regulate transcription of key enzymes of de novo bile acid synthesis and subsequently liver bile acid concentration, only the systemic FXR agonist M345 represses hepatic TNFα expression, which is associated with attenuation of the sclerosing cholangitis phenotype.