Cyp2c70 knockout mice lack the
enzyme that produces muricholic
acids and show a "human-like" hydrophobic
bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-
cholestasis effect of
glycine-conjugated β
muricholic acid (G-β-MCA) in male Cyp2c70 KO mice based on its hydrophilic physiochemical property and signaling property as an farnesoid X receptor (FXR) antagonist. Our results showed that G-β-MCA treatment for 5 weeks alleviated ductular reaction and
liver fibrosis and improved gut barrier function. Analysis of
bile acid metabolism suggested that exogenously administered G-β-MCA was poorly absorbed in the small intestine and mostly deconjugated in the large intestine and converted to
taurine-conjugated MCA (T-MCA) in the liver, leading to T-MCA enrichment in the bile and small intestine. These changes decreased the biliary and intestine
bile acid hydrophobicity index. Furthermore, G-β-MCA treatment decreased intestine
bile acid absorption via unknown mechanisms, resulting in increased fecal
bile acid excretion and a reduction in total
bile acid pool size. In conclusion, G-β-MCA treatment reduces the
bile acid pool size and hydrophobicity and improves
liver fibrosis and gut barrier function in Cyp2c70 KO mice.