Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid

BACKGROUND AND AIMS: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. METHODS: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages. RESULTS: Cyp2c70(-/-) mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70(-/-) mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70(-/-) mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70(-/-) mice up to 8 months of age. In female Cyp2c70(-/-) mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70(-/-) mice. CONCLUSION: Cyp2c70(-/-) mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.

Automated summary

The study found that Cyp2c70(-/-) mice, lacking MCAs, had different effects on microbiome composition and varied consequences between sexes. Male mice showed early high plasma BAs and transaminases, which decreased over time, while females experienced sustained elevated levels with age, impaired gut barrier function, and progression to bridging fibrosis. Treatments with UDCA normalized hepatic and intestinal functions in female Cyp2c70(-/-) mice, suggesting a role of BA hydrophobicity in disease development.